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Bcl-2
Bcl-2 Bcl-2(12)
Proteins of the Bcl-2 family have either pro- or anti-apoptotic activities and regulate the mitochondrial pathway of apoptosis by controlling the permeabilization of the outer mitochondrial membrane.(2, 3) Members of the Bcl-2 protein include three sub-groups of proteins that promote cell survival (e.g. Bcl-2 and Bcl-xL), initiate cell killing (e.g. Bim, Puma, and Bid), or activate the effector pathways of apoptosis (Bax, Bak).(4) The two isoforms of Bcl-2, 1G5M and 1G5O/1GJH, exhibit similar fold, but the disparate binding to BAD and BAK proteins, suggesting different anti-apoptotic activity.(1) The intrinsic apoptotic pathway involves Bcl-2 family of proteins-mediated alterations in mitochondrial membrane integrity and potential in response to cellular insults or other stress signals.(5) Several Bcl-2 family members, including Bcl-2 and Bak, reside not only on mitochondria but also on the ER/nuclear envelope, where they may regulate cytosolic Ca2+ levels.(6) The pro-apoptotic BCL-2 members are divided into the effector proteins and the BH3-only proteins. It is controversial whether some BH3-domain proteins (Bim or tBid) directly activate multidomain pro-apoptotic proteins (e.g., Bax and Bak) or act via inhibition of those anti-apoptotic Bcl-2 proteins (Bcl-2, Bcl-XL, Bcl-w, Mcl-1, Bfl1/A-1, and Bcl-B) that stabilize pro-apoptotic proteins.(7) The BH3-only proteins sense and relay stress signals, but commitment to apoptosis requires Bax or Bak. The BH3-only proteins appear to activate Bax and Bak indirectly, by engaging and neutralizing their pro-survival relatives, which otherwise constrain Bax and Bak from permeabilizing mitochondria.(6) The effector proteins BAK and BAX were originally described to contain only BH1-3; however, structure-based alignment of globular BCL-2 family proteins revealed a conserved BH4 motif. The proapoptotic BCL-2 members are divided into the effector proteins and the BH3-only proteins. The effector proteins BAK and BAX were originally described to contain only BH1-3; however, structure-based alignment of globular BCL-2 family proteins revealed a conserved BH4 motif.(8) Upon activation, BAK and BAX homo-oligomerize into proteolipid pores within the OMM to promote MOMP There is a potential third effector molecule, BCL-2-related ovarian killer (BOK), but no biochemical evidence supports a function akin to BAK or BAX.(9)
In most cell types, caspase-8 catalyzes the cleavage of the pro-apoptotic BH3-only protein Bid into its truncated form, tBid. BH-3 only members of the Bcl-2 family exclusively engage anti-apoptotic members of the family (Bcl-2, Bcl-xL), allowing Bak and Bax to translocate to the outer mitochondrial membrane, thus permeabilizing it and facilitating release of pro-apoptotic proteins such as Cytc and Smac/DIABLO, an antagonist of IAPs.(10)
PUMA is a BH3-only protein that binds and inhibits all of the anti-apoptotic BCL-2 proteins. It is a direct transcriptional target of p53 and is also induced by FOXO3a under conditions of growth factor deprivation. PUMA may also activate BAX and BAK, although it has been shown to promote MOMP predominantly through displacement of other proteins with this function from anti-apoptotic BCL-2 proteins.(11) The BH3-only proteins sense and relay stress signals, but commitment to apoptosis requires Bax or Bak. The BH3-only proteins appear to activate Bax and Bak indirectly, by engaging and neutralizing their pro-survival relatives, which otherwise constrain Bax and Bak from permeabilizing mitochondria.(6) It is controversial whether some BH3-domain proteins (Bim or tBid) directly activate multidomain pro-apoptotic proteins (e.g., Bax and Bak) or act via inhibition of those anti-apoptotic Bcl-2 proteins (Bcl-2, Bcl-XL, Bcl-w, Mcl-1, Bfl1/A-1, and Bcl-B) that stabilize pro-apoptotic proteins.(7)
Cancer cells may escape from apoptosis in response to various stimuli, such as chemotherapy and radiotherapy, by increasing anti-apoptotic proteins of Bcl-2 protein family, including Bcl-2, Bcl-xL, Bcl-w, Mcl-1 and Bfl-1.(3) Loss of PUMA accelerates Myc-induced lymphomagenesis. Importantly, in a survey of a large number of human tumors of different types, deletion of PUMA was found to be one of the most common copy-number abnormalities.(11)
Clinical studies on ABT-263 and AT-101 are currently ongoing and whether these compounds can find their way into routine clinical use will depend not only on efficacy but also on manageable, acceptable toxicities. Thrombocytopenia, for example, may limit the value of ABT-263 in patients with heavy bone marrow infiltration; the long-term toxicities of prolonged Bcl-2 suppression remain to be determined.(5)

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References

1. TumorSuppressLEC. [cited]; Available from: http://biochemistry.ucsf.edu/programs/ptf/m3%20links/TumorSuppressLEC.pdf.

2. Brunelle JK LA. Control of mitochondrial apoptosis by the Bcl-2 family. J Cell Sci. 2009;122(Pt 4):437-41. PMCID: 19193868.

3. Gul O BH, Kutuk O. Apoptotic blocks and chemotherapy resistance: strategies to identify Bcl-2 protein signatures. Brief Funct Genomic Proteomic. 2008;7(1):27-34. PMCID: 18283052.

4. Kelly PN SA. The role of Bcl-2 and its pro-survival relatives in tumourigenesis and cancer therapy. Cell Death Differ. 2011;18(9):1414-24. PMCID: 21415859.

5. Azmi AS WZ, Philip PA, Mohammad RM, Sarkar FH. Emerging Bcl-2 inhibitors for the treatment of cancer. Expert Opin Emerg Drugs. 2011;16(1):59-70. PMCID: 20812891.

6. Adams JM CS. Bcl-2-regulated apoptosis: mechanism and therapeutic potential. Curr Opin Immunol. 2007;19(5):488-96. PMCID: 17629468.

7. Kang MH RC. Bcl-2 inhibitors: targeting mitochondrial apoptotic pathways in cancer therapy. Clin Cancer Res. 2009;15(4):1126-32. PMCID: 19228717.

8. Kvansakul M YH, Fairlie WD, Czabotar PE, Fischer SF, Perugini MA, Huang DC, Colman PM. Vaccinia virus anti-apoptotic F1L is a novel Bcl-2-like domain-swapped dimer that binds a highly selective subset of BH3-containing death ligands. . Cell Death Differ. 2008;15:1564-71. PMCID: 18551131.

9. Chipuk JE MT, Llambi F, Parsons MJ, Green DR. The BCL-2 family reunion. Mol Cell. 2010;37(3):299-310. PMCID: 20159550.

10. Schaller MD. Cellular functions of FAK kinases: insight into molecular mechanisms and novel functions. Journal of Cell Science. 2010;123(7):1007-13.

11. Llambi F GD. Apoptosis and oncogenesis: give and take in the BCL-2 family. Curr Opin Genet Dev. 2011;21(1):12-20. PMCID: 21236661.

12. Tilly JL. Commuting the death sentence: how oocytes strive to survive. Nature Reviews Molecular Cell Biology. 2001;2:838-48.



News


1:00 AM|Tang, Jian-ming; Min, Jie; Li, Bing-shu; Hong, Sha-sha; Liu, Cheng; Hu, Ming; Li, Yang; Yang, Jiang; Hong, Li|International Journal of Gynecological Cancer - Current Issue|Labels: Bcl-2
imageAim: The aim of this study was to investigate the effects of punicalagin, a polyphenol isolated from Punica granatum, on human A2780 ovarian cancer cells in vitro. Methods: The viability of human A2780 ovarian cells was evaluated using Cell Counting Kit-8 assay. Cell cycle was detected with flow cytometry analysis. The protein expression levels of Bcl-2, Bax, β-catenin, cyclin D1, survivin, tissue inhibitor of metalloproteinase (TIMP)-2, and TIMP-3 were measured using Western blot analysis. Matrix metalloproteinase (MMP)-2 and MMP-9 activity was determined with gelatin zymography. Wound healing assay was used to determine cell migration. Results: Punicalagin inhibited the cell viability of A2780 cells in a dose- and time-dependent manner, and the cell cycle of A2780 cells was arrested in G1/S phase transition. The treatment also induced apoptosis as shown by the up-regulation of Bax and down-regulation of Bcl-2. On the other hand, punicalagin treatment increased the expressions of TIMP-2 and TIMP-3, decreased the activities of MMP-2 and MMP-9, and inhibited cell migration. In addition, the β-catenin pathway was suppressed as shown by the down-regulations of β-catenin and its downstream factors including cyclin D1 and survivin. Conclusions: Punicalagin may have cancer-chemopreventive as well as cancer-chemotherapeutic effects against human ovarian cancer in humans through the inhibition of β-catenin signaling pathway.
Wednesday, October 26, 2016 1:00 AM|Farhadi, Elham; Safa, Majid; Sharifi, Ali M.; Bashash, Davood|Anti-Cancer Drugs - Published Ahead-of-Print|Labels: Bcl-2, NFKb, P53, PARP, leukemia
Restoration of p53 function triggers cell death and eliminates tumors in vivo. Identification of p53-reactivating small molecules such as PRIMA-1 holds promise for effective new anticancer therapies. Here, we investigated the effects of small molecule PRIMA-1 on cell viability and expression of p53-regulated genes and proteins in the acute promyelocytic leukemia-derived NB4 cell line. Our results showed that PRIMA-1 had antileukemic properties in acute promyelocytic leukemia-derived NB4 cells. PRIMA-1-triggered apoptosis in a dose-dependent and time-dependent manner as indicated by the MTT assay and annexin-V staining. Apoptosis induction by PRIMA-1 was associated with caspase-9, caspase-7 activation and PARP cleavage. p21 protein expression was increased after PRIMA-1 treatment and real-time PCR analysis of proapoptotic p53 target genes indicated upregulation of Bax and Noxa. Western blot analysis showed that I[kappa]B[alpha] phosphorylation and its degradation were inhibited by PRIMA-1. Moreover, protein expression of nuclear factor-[kappa]B-regulated antiapoptotic (Bcl-2 and XIAP) and proliferative (c-Myc) gene products was decreased. Importantly, PRIMA-1 did not show any significant apoptotic effect in normal human peripheral blood mononuclear cells. These in-vitro studies imply that p53 reactivation by small compounds may become a novel anticancer therapy in acute promyelocytic leukemia. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.
Monday, October 24, 2016 2:55 PM|Xu-Monette, Z. Y., Li, L., Byrd, J. C., Jabbar, K. J., Manyam, G. C., de Winde, C. M., van den Brand, M., Tzankov, A., Visco, C., Wang, J., Dybkaer, K., Chiu, A., Orazi, A., Zu, Y., Bhagat, G., Richards, K. L., Hsi, E. D., Choi, W. W. L., Huh, J., Ponzoni, M., Ferreri, A. J. M., Moller, M. B., Parsons, B. M., Winter, J. N., Wang, M., Hagemeister, F. B., Piris, M. A., van Krieken, J. H., Medeiros, L. J., Li, Y., van Spriel, A. B., Young, K. H.|BLOOD First Edition Papers|Labels: Bcl-2, lymphoma

CD37 (tetraspanin TSPAN26) is a B-cell surface antigen widely expressed on mature B-cells. CD37 is involved in immune regulation and tumor suppression but its function has not been fully elucidated. In this study, we assessed CD37 expression in de novo diffuse large B-cell lymphoma (DLBCL), and investigated its clinical and biologic significance in 773 patients treated with rituximab-CHOP and 231 patients treated with CHOP chemotherapy. We found CD37 loss (CD37-) in ~60% of DLBCL predicted significantly decreased survival rates in R-CHOP-treated patients, independent of the International Prognostic Index (IPI), germinal-center-B-cell–like (GCB)/activated-B-cell–like (ABC) cell-of-origin, nodal/extranodal primary origin, and the prognostic factors associated with CD37-, including TP53 mutation, NF-Bhigh, Mychigh, p-STAT3high, survivinhigh, p63-, and BCL6 translocation. Conversely, CD37 positivity predicted superior survival, abolishing the prognostic impact of high IPI and above biomarkers in GCB-DLBCL but not in ABC-DLBCL. Combining CD37- status and ABC cell-of-origin risk scores with the IPI, defined as M-IPI-R (molecularly-adjusted-IPI-for-R-CHOP), or IPI-plus-immunohistochemistry for CD37, Myc, and Bcl-2 (defined as IPI+IHC), significantly improved risk prediction over IPI alone. Gene expression profiling suggested that decreased CD20 and increased PD-1 levels in CD37- DLBCL, ICOSLG upregulation in CD37+ GCB-DLBCL, and CD37 functions during rituximab-CHOP treatment, underlie the pivotal role of CD37 signaling to clinical outcomes. In conclusion, CD37 is a critical determinant of rituximab-CHOP outcome in DLBCL especially in GCB-DLBCL, representing its importance for optimal rituximab action and sustained immune responses. The combined molecular and clinical prognostic indices, M-IPI-R and IPI+IHC, have remarkable predictive values in rituximab-CHOP-treated DLBCL.

Monday, October 24, 2016 12:29 PM|Francis S. Wolenski|RSC - Toxicol. Res. latest articles|Labels: Bcl-2, MM

Toxicol. Res., 2016, 5,1619-1628
DOI: 10.1039/C6TX00220J, Paper
Open Access Open Access
Creative Commons Licence  This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence.
Vilmos Csizmadia, Paul Hales, Christopher Tsu, Jingya Ma, Jiejin Chen, Pooja Shah, Paul Fleming, Joseph J. Senn, Vivek J. Kadambi, Larry Dick, Francis S. Wolenski
The proteasome inhibitor bortezomib is associated with the development of peripheral neuropathy in patients, but the mechanism is not fully understood.
The content of this RSS Feed (c) The Royal Society of Chemistry
Tuesday, October 18, 2016 11:45 AM|Beider, K., Rosenberg, E., Bitner, H., Shimoni, A., Leiba, M., Koren-Michowitz, M., Ribakovsky, L., Klein, S., Olam, D., Wald, H., Weiss, L., Abraham, M., Galun, E., Peled, A., Nagler, A.|Clinical Cancer Research Online First Articles|Labels: Bcl-2, proteasome, S1P, MM

Purpose: To explore the functional consequences of possible cross-talk between the CXCR4/CXCL12 and the S1P pathways in multiple myeloma (MM) cells and to evaluate the effect of S1P targeting with FTY720 modulator as a potential anti-MM therapeutic strategy. Experimental design and results: S1P targeting with FTY720 induces MM cell apoptosis. The combination of FTY720 with SPHK1 inhibitor SKI-II results in synergistic inhibition of MM growth. CXCR4/CXCL12-enhanced expression correlates with reduced MM cell sensitivity to both FTY720 and SKI-II inhibitors, and with SPHK1 co-expression in both cell lines and primary MM bone marrow samples, suggesting regulative cross-talk between CXCR4/CXCL12 and SPHK1 pathways in MM cells. FTY720 was found to directly target CXCR4. FTY720 profoundly reduces CXCR4 cell-surface levels and abrogates the CXCR4-mediated functions of migration toward CXCL12 and signaling pathways activation. Moreover, FTY720 cooperates with bortezomib, inducing its cytotoxic activity and abrogating the bortezomib-mediated increase in CXCR4 expression. FTY720 effectively targets bortezomib-resistant cells and increases their sensitivity to bortezomib, promoting DNA damage. Finally, in a recently developed novel xenograft model of CXCR4-dependent systemic MM with BM involvement, FTY720 treatment effectively reduces tumor burden in the BM of MM-bearing mice. FTY720 in combination with bortezomib demonstrates superior tumor growth inhibition and abrogates bortezomib-induced CXCR4 increase on MM cells. Conclusions: Altogether, our work identifies a cross-talk between S1P and CXCR4 pathways in MM cells, and provides a preclinical rationale for the therapeutic application of FTY720 in combination with bortezomib in patients with MM.

Friday, October 14, 2016 4:45 PM|Onclive Articles|Labels: Bcl-2, CLL, regulatory
The Committee for Medicinal Products for Human Use has recommended approval of venetoclax for the treatment of patients with chronic lymphocytic leukemia who have a 17p deletion (del[17p]) or TP53 mutation and are not good candidates for or have failed on a B-cell receptor pathway inhibitor. The potential indication would also be for patients who do not harbor the deletion or mutation but have progressed on both a BCR inhibitor and chemoimmunotherapy.
Friday, October 14, 2016 3:42 PM|Medscape Medical News Headlines|Labels: Bcl-2, CML
Recommendations included granting a conditional marketing authorization for venetoclax for the treatment of adults with chronic lymphocytic leukemia.
International Approvals
Friday, October 14, 2016 9:12 AM|Medications/Drugs News Headlines - Yahoo! News|Attachments|Labels: Bcl-2, CLL

A screen displays the share price for pharmaceutical maker AbbVie on the floor of the New York Stock Exchange(Reuters) - AbbVie Inc won the conditional backing of an advisory committee of the European Medicines Agency (EMA) on Friday for a drug to treat a form of blood cancer. The tablet, venclyxto, or venetoclax, is aimed at chronic lymphocytic leukemia (CLL) patients with either 17p gene deletion or TP53 mutation, which are markers for a particularly aggressive form of the disease. The EMA grants conditional approval for drugs that fill an unmet medical need for serious conditions and show early evidence of clinical benefits outweighing the risks.


Friday, October 14, 2016 7:28 AM|FinanzNachrichten.de: Nachrichten zu Pharma|Labels: Bcl-2, CLL, regulatory
- CHMP recommends VENCLYXTO monotherapy for the treatment of chronic lymphocytic leukaemia (CLL) in the presence of 17p deletion or TP53 mutation in adult patients who are unsuitable for or have f...
Friday, October 14, 2016 7:09 AM|Reuters: Healthcare|Labels: Bcl-2, leukemia, regulatory
* EU Medicines Agency recommends approval of Abbvie Inc'S Venetoclax/Venclexta to treat leukaemia
Friday, October 14, 2016 3:00 AM|MIT Biotech Group - Essential Biotech RSS Feed|Labels: Bcl-2, PD-1/PD-L1, CML, skin cancer, regulatory, HL
EMA's CHMP recommended conditional approval of both Ocaliva obeticholic acid to treat primary biliary cholangitis and Venclyxto venetoclax as monotherapy to treat chronic lymphocytic leukemia (CLL). Intercept Pharmaceuticals Inc. (NASDAQ:ICPT) markets Ocaliva. The committee recommended its approval in combination with ursodeoxycholic acid (UDCA) in patients with inadequate response to UDCA, or as monotherapy in patients unable to tolerate UDCA. In May, FDA granted accelerated approval to the oral farnesoid X receptor (FXR; NR1H4) agonist for the same indication (see BioCentury Extra, May 31). CHMP recommended Venclyxto's approval for adult CLL patients with the 17p deletion or TP53 mutation who are unsuitable for or have failed a B cell receptor pathway inhibitor, or for patients without the mutations who have failed both chemo-immunotherapy and a B cell receptor pathway inhibitor. Venclyxto, a small molecule B cell lymphoma 2 (BCL-2; BCL2) inhibitor, is known as Venclexta in the U.S. In April, FDA granted accelerated approval to the drug to treat CLL in patients with the 17p deletion who have received at least one prior therapy. Roche (SIX:ROG; OTCQX:RHHBY) and its Genentech Inc. unit share rights to the drug with AbbVie Inc. (NYSE:ABBV). CHMP also recommended expanding the label of PD-1 inhibitor Opdivo nivolumab from Bristol-Myers Squibb Co. (NYSE:BMY) to include treatment of relapsed or refractory classical Hodgkin's lymphoma after autologous stem cell transplant and treatment with Adcetris brentuximab vedotin. Opdivo is approved in the U.S. for that indication, and in both the U.S. and EU to treat non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC) and melanoma. Takeda Pharmaceutical Co. Ltd. (Tokyo:4502) and Seattle Genetics Inc. (NASDAQ:SGEN) share rights to Adcetris, an antibody-drug conjugate (ADC) composed of an anti-CD30 mAb and monomethyl auristatin E (MMAE).
Friday, October 14, 2016 12:05 AM|Croce, C. M., Reed, J. C.|Cancer Research current issue|Labels: Bcl-2
Resistance to cell death represents one of the hallmarks of cancer. Various genetic and epigenetic changes in malignant cells afford cytoprotection in the face of genomic instability, oncogene activation, microenvironment stress, chemotherapy, targeted anticancer drugs, and even immunotherapy. Central among the regulators of cell life and death are Bcl-2 family proteins, with the founding member of the family (B-cell lymphoma/leukemia-2) discovered via its involvement in chromosomal translocations in lymphomas. The quest for therapeutics that target cell survival protein Bcl-2 represents a long road traveled, with many dead-ends, disappointments, and delays. Finally, a Bcl-2–targeting medicine has gained approval as a new class of anticancer agent. Cancer Res; 76(20); 5914–20. ©2016 AACR.
Wednesday, October 12, 2016 3:27 PM| Patrick D. Bhola, Brenton G. Mar, R. Coleman Lindsley, Jeremy A. Ryan, Leah J. Hogdal, Thanh Trang Vo, Daniel J. DeAngelo, Ilene Galinsky, Benjamin L. Ebert, Anthony Letai |The Journal of Clinical Investigation -- Current Issue|Labels: Bcl-2, leukemia
Upfront resistance to chemotherapy and relapse following remission are critical problems in leukemia that are generally attributed to subpopulations of chemoresistant tumor cells. There are, however, limited means for prospectively identifying these subpopulations, which hinders an understanding of therapeutic resistance. BH3 profiling is a functional single-cell analysis using synthetic BCL-2 BH3 domain–like peptides that measures mitochondrial apoptotic sensitivity or “priming.” Here, we observed that the extent of apoptotic priming is heterogeneous within multiple cancer cell lines and is not the result of experimental noise. Apoptotic priming was also heterogeneous in treatment-naive primary human acute myeloid leukemia (AML) myeloblasts, and this heterogeneity decreased in chemotherapy-treated AML patients. The priming of the most apoptosis-resistant tumor cells, rather than the median priming of the population, best predicted patient response to induction chemotherapy. For several patients, these poorly primed subpopulations of AML tumor cells were enriched for antiapoptotic proteins. Developing techniques to identify and understand these apoptosis-insensitive subpopulations of tumor cells may yield insights into clinical chemoresistance and potentially improve therapeutic outcomes in AML.
Wednesday, October 12, 2016 3:26 PM|Deanna J. Fall, Holly Stessman, Sagar S. Patel, Zohar Sachs, Brian G. Van Ness, Linda B. Baughn, Michael A. Linden|Journal of Cancer|Labels: Bcl-2, FGFR, proteasome, MM

Multiple myeloma (MM) is an incurable malignant neoplasm hallmarked by a clonal expansion of plasma cells, the presence of a monoclonal protein in the serum and/or urine (M-spike), lytic bone lesions, and end organ damage. Clinical outcomes for patients with MM have improved greatly over the last decade as a result of the re-purposing of compounds such as thalidomide derivatives, as well as the development of novel chemotherapeutic agents including first and second generation proteasome inhibitors, bortezomib (Bz) and carfilzomib. Unfortunately, despite these improvements, the majority of patients relapse following treatment. While Bz, one of the most commonly used proteasome inhibitors, has been successfully incorporated into clinical practice, some MM patients have de novo resistance to Bz, and the majority of the remainder subsequently develop drug resistance following treatment. A significant gap in clinical care is the lack of a reliable clinical test that would predict which MM patients have or will subsequently develop Bz resistance. Thus, as Bz resistance remains a significant challenge, research efforts are needed to identify novel biomarkers of early Bz resistance, particularly when an early therapeutic intervention can be initiated. Recent advances in MM research indicate that genomic data can be extracted to identify novel biomarkers that can be utilized to select more effective, personalized treatment protocols for individual patients. Computationally integrating large patient databases with data from whole transcriptome profiling and laboratory-based models can potentially revolutionize our understanding of MM disease mechanisms. This systems-wide approach can provide rational therapeutic targets and novel biomarkers of risk and treatment response. In this review, we discuss the use of high-content datasets (predominantly gene expression profiling) to identify novel biomarkers of treatment response and resistance to Bz in MM.

Wednesday, October 12, 2016 3:26 PM|Guillemette Fouquet, Benjamin Hebraud, Sylvain Garciaz, Anne Marie Stoppa, Murielle Roussel, Denis Caillot, Marie Lorraine Chrétien, Bertrand Arnulf, Raphael Szalat, Laurent Garderet, Lina Benajiba, Brigitte Pegourie, Caroline Regny, Bruno Royer, Alexis Caulier, Cyrille Touzeau, Benoit Tessoulin, Jean Paul Fermand, Thierry Facon, Michel Attal, Hervé Avet Loiseau, Philippe Moreau, Xavier Leleu|Journal of Cancer|Labels: Bcl-2, FGFR, proteasome, MM

The impact of consolidation on response rates and PFS has recently been demonstrated after induction and autotransplantation upfront in Multiple Myeloma (MM). We further showed that patients in ≥VGPR following the intensification procedure benefited most from consolidation. Question remains as to the benefit of consolidation for patients in PR at completion of induction - feature of partial resistance to the induction regimen.

We collected data from 54 newly diagnosed MM treated with VTd-auto-VTd regimen that reached only PR at completion of the induction procedure.

Overall, 37 patients (68%) improved depth of response (≥VGPR) at completion of consolidation, including 35% that reached CR and 38% solely related to consolidation. Of patients that remained on PR or improved depth of response after ASCT, 26% and 38% further responded to consolidation, respectively. With a median follow-up of 36 months, improved depth of response translated into lower relapse rate compared with patients remaining in PR, 19% vs. 36%. This difference was more striking in patients that reached CR vs. others, 8% and 38%, respectively (p=0.039). The median TTP was prolonged in patients that improved depth of response after consolidation (p=0.012), with a 3-year TTP of 87% vs. 18% otherwise. In multivariate analysis, lack of improved depth of response to consolidation independently predicted shorten median TTP [OR=4.4, 95%CI=1-21; p=0.039], with elevated LDH and beta2m, and adverse FISH.

This study shows that VTd consolidation should be recommended to patients solely on PR at completion of induction with VTd, feature of lower sensitivity to VTd.

Wednesday, October 12, 2016 3:26 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: Bcl-2, lymphoma, clinical trial
This phase II trial studies how well ixazomib citrate and rituximab work in treating patients with B-cell non-Hodgkin lymphoma that grows slowly (indolent). Ixazomib citrate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as rituximab, may block cancer growth in different ways by targeting certain cells. Giving ixazomib citrate together with rituximab may work better in treating indolent B-cell non-Hodgkin lymphoma.
Wednesday, October 12, 2016 3:26 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: Bcl-2, proteasome, ALL, leukemia, clinical trial
This randomized phase III trial compares how well combination chemotherapy works when given with or without bortezomib in treating patients with newly diagnosed T-cell acute lymphoblastic leukemia or stage II-IV T-cell lymphoblastic lymphoma. Bortezomib may help reduce the number of leukemia or lymphoma cells by blocking some of the enzymes needed for cell growth. It may also help chemotherapy work better by making cancer cells more sensitive to the drugs. It is not yet known if giving standard chemotherapy with or without bortezomib is more effective in treating T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma.
Wednesday, October 12, 2016 3:26 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: Bcl-2, FGFR, proteasome, leukemia, clinical trial
This randomized phase III trial studies how well bortezomib and sorafenib tosylate work in treating patients with newly diagnosed acute myeloid leukemia. Bortezomib and sorafenib tosylate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving bortezomib and sorafenib tosylate together with combination chemotherapy may be an effective treatment for acute myeloid leukemia.
Wednesday, October 12, 2016 3:26 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: Bcl-2, FGFR, proteasome, MM, clinical trial
This is a dose finding pilot study to evaluate the safety and determine the maximum tolerated dose of the combination of carfilzomib and pomalidomide with dexamethasone (CPD) in patients with relapsed or refractory multiple myeloma followed by a phase II expansion at the MTD to evaluate efficacy. The study will explore the efficacy of CPD including overall response, time to progression, progression free survival, and time to next therapy.
Wednesday, October 12, 2016 3:26 PM|Miaoxia He, Keting Chen, Suhong Li, Shimin Zhang, Jianming Zheng, Xiaoxia Hu, Lei Gao, Jie Chen, Xianmin Song, Weiping Zhang, Jianmin Wang, Jianmin Yang|Journal of Cancer|Labels: Bcl-2, lymphoma

BACKGROUND AND AIMS: Primary gastric B-cell lymphoma is the second most common malignancy of the stomach. There are many controversial issues about its diagnosis, treatment and clinical management. “Double-hit” and “double-protein” involving gene rearrangement and protein expression of c-Myc and bcl2/bcl6 are the most used terms to describe DLBCL poor prognostic factors in recent years. However, very little is known about the role of these prognostic factors in primary gastric B-cell lymphomas. This study aims to obtain a molecular pathology prognostic model of gastric B-cell lymphoma for clinical stratified management by evaluating how the “double-hit” and “double-protein” in tumor cells as well as microenvironmental reaction of tumor stromal tissue affect clinical outcome in primary gastric B-cell lymphomas.

METHODS: Data and tissues of 188 cases diagnosed with gastric B-cell lymphomas were used in this study. Tumor tissue microarray (TMA) of formalin fixed and paraffin embedded (FFPE) tissues was constructed for fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) analysis with a serial of biomarkers containing MYC, BCL2, BCL6, CD31, SPARC, CD10, MUM1 and Ki-67. Modeled period analysis was used to estimate 3-year and 5-year overall survival (OS) and disease-free survival (DFS) distributions.

RESULTS: There was no definite “double-hit” case though the gene rearrangement of c-Myc (5.9%), bcl2 (0.1%) and bcl6 (7.4%) was found in gastric B-cell lymphomas. The gene amplification or copy gains of c-Myc (10.1%), bcl-2 (17.0%) and bcl-6 (0.9%) were present in these lymphomas. There were 12 cases of the lymphomas with the “double-protein” expression of MYC and BCL2/BCL6. All patients with “double-protein” gastric B-cell lymphomas had poor outcome compared with those without. More importantly, “MYC-BCL2-BCL6” negative group of gastric B-cell lymphoma patients had favorable clinical outcome regardless clinical stage, pathological types and therapeutic modalities. And the similar better prognosis was found in the cases with low microvessel density (MVD) in tumor tissue and high expression of SPARC (SPARC≥5%) in stromal cells.

CONCLUSIONS: “Double-hit” lymphoma was rare among primary gastric lymphoma, while patients with multiple gene amplification and/or copy gains of c-Myc, bcl2 and bcl6, and “double-protein” gastric B-cell lymphomas had a poor clinical outcome. In addition, patients with MYC, BCL2 and BCL6 expression negative or low MVD in tumor tissue with high expression of SPARC in stromal cells could have better prognosis than other gastric B-cell lymphomas regardless of their clinical stage and pathological types. These results would be of very importance for clinical stratified management and precision medicine of gastric B-cell lymphomas.

Wednesday, October 12, 2016 3:26 PM|Hui Yang, Lin Wu, Shaobo Ke, Wenbo Wang, Lei Yang, Xiaojia Gao, Hongyan Fang, Haijun Yu, Yahua Zhong, Conghua Xie, Fuxiang Zhou, Yunfeng Zhou|Journal of Cancer|Labels: Bcl-2, esophageal cancer, clinical trial

Ubiquitin-conjugating enzyme UBE2D3 is an important member of the ubiquitin-proteasome pathways. Our previous study showed that the expression of UBE2D3 was negatively related to human telomerase reverse transcriptase (hTERT) and radioresistance in human breast cancer cells. However, in esophageal carcinoma, the exact effects and mechanisms of UBE2D3 in radioresistance remain unclear. This study shows that UBE2D3 knockdown was associated with significant increases in radioresistance to X-rays, telomerase activity, telomere length, and telomere shelterins. UBE2D3 knockdown-mediated radioresistance was related to a decrease in the spontaneous and ionizing radiation-induced apoptosis, resulting from a decrease in the Bax/Bcl-2 ratio. Furthermore, UBE2D3 downregulation was associated with increased G1-S phase transition and prolonged IR-induced G2/M arrest through over expression of cyclin D1, decrease of CDC25A expression and promotion of the ATM/ATR-Chk1-CDC25C pathway. Moreover, UBE2D3 downregulation reduced spontaneous DNA double-strand breaks and accelerated the repair of DNA damage induced by IR. The current data thus demonstrate that UBE2D3 downregulation enhances radioresistance by increased telomere homeostasis and prolonged IR-induced G2/M arrest, but decreases the IR-induced apoptosis and the number of DNA damage foci. These results suggest that UBE2D3 might be a potential molecular target to improve radiotherapy effects in esophageal carcinoma.

Wednesday, October 12, 2016 3:26 PM|Wei Huang, Quan Zhou, Xia Yuan, Ze-mei Ge, Fu-xiang Ran, Hua-yu Yang, Guang-liang Qiang, Run-tao Li, Jing-rong Cui|Journal of Cancer|Labels: Bcl-2, NFKb, proteasome, ovarian cancer

Cisplatin is one of the most common drugs used for treatment of solid tumors such as ovarian cancer. Unfortunately, the development of resistance against this cytotoxic agent limits its clinical use. Here we report that YSY01A, a novel proteasome inhibitor, is capable of suppressing survival of cisplatin-resistant ovarian cancer cells by inducing apoptosis. And YSY01A treatment enhances the cytotoxicity of cisplatin in drug-resistant ovarian cancer cells. Specifically, YSY01A abrogates regulatory proteins important for cell proliferation and anti-apoptosis including NF-κB p65 and STAT3, resulting in down-regulation of Bcl-2. A dramatic increase in cisplatin uptake was also observed by inductively coupled plasma-mass spectrometry following exposure to YSY01A. Taken together, YSY01A serves as a potential candidate for further development as anticancer therapeutics targeting the proteasome.

Wednesday, October 12, 2016 3:26 PM|Shu-mei Yang, Kuen-daw Tsai, Ho-Yiu Wong, Yi-Heng Liu, Ta-Wei Chen, Jonathan Cherng, Kwang-Ching Hsu, Yao-Uh Ang, Jaw-Ming Cherng|Journal of Cancer|Labels: Bcl-2, lung cancer

Cinnamomum verum is used to make the spice cinnamon and has been used as a traditional Chinese herbal medicine. We evaluated the effects and the molecular mechanisms of cuminaldehyde (CuA), a constituent of the bark of Cinnamomum verum, on human lung squamous cell carcinoma NCI-H520 cells. Specifically, cell viability was evaluated by colorimetric assay; cytotoxicity by LDH release; apoptosis was determined by Western blotting, and morphological analysis with, acridine orange and neutral red stainings and comet assay; topoisomerase I activity was assessed using assay based upon DNA relaxation and topoisomerase II by DNA relaxation plus decatentation of kinetoplast DNA; lysosomal vacuolation and volume of acidic compartments (VAC) were evaluated with neutral red staining. The results show that CuA suppressed proliferation and induced apoptosis as indicated by an up-regulation of pro-apoptotic bax and bak genes and a down-regulation of anti-apoptotic bcl-2 and bcl-XL genes, mitochondrial membrane potential loss, cytochrome c release, activation of caspase 3 and 9, and morphological characteristics of apoptosis, including blebbing of the plasma membrane, nuclear condensation, fragmentation, apoptotic body formation, and comet with elevated tail intensity and moment. In addition, CuA also induced lysosomal vacuolation with increased VAC, cytotoxicity, as well as suppressions of both topoisomerase I and II activities in a dose-dependent manner. Further study revealed the growth-inhibitory effect of CuA was also evident in a nude mice model. Taken together, the data suggest that the growth-inhibitory effect of CuA against NCI-H520 cells is accompanied by downregulations of proliferative control involving apoptosis and both topoisomerase I and II activities, and upregulation of lysosomal with increased VAC and cytotoxicity. Similar effects were found in other cell lines, including human lung adenocarcinoma A549 cells and colorectal adenocarcinoma COLO 205 (results not shown). Our data suggest that CuA could be a potential agent for anticancer therapy.

Wednesday, October 12, 2016 3:25 PM|Mayo Clinic Cancer Center - Research news|Labels: Bcl-2, proteasome, MM
PHOENIX — In the treatment of multiple myeloma, the addition of carfilzomib to a currently accepted two-drug combination produced significantly better results than using the two drugs alone, according to a worldwide research team led by investigators from Mayo Clinic. Their findings will be reported online Dec. 6 in the New England Journal of Medicine, [...]
Wednesday, October 12, 2016 3:25 PM|Mayo Clinic Cancer Center - Research news|Labels: Bcl-2, proteasome, MM, clinical trial
ROCHESTER, Minn. — The investigational drug ixazomib taken orally in combination with lenalidomide and dexamethasone shows promise in patients with newly diagnosed multiple myeloma, according to the results of a phase 1/2 study published in the journal Lancet Oncology. "Ixazomib is an investigational, oral proteasome inhibitor with promising anti-myeloma effects and low rates of peripheral [...]
Wednesday, October 12, 2016 3:25 PM|Daniel Benharroch, Shai Pilosof, Jacob Gopas, Itai Levi|Journal of Cancer|Labels: Bcl-2, lymphoma, HL

We recognized a few possible complications of classical Hodgkin lymphoma therapy in a cohort of 209 patients: 8 developed a primary refractory disease (primary progression), 36 showed an early relapse and 21 showed a late relapse. Sialyl-CD15 expression in Hodgkin-Reed-Sternberg cells was significantly more positive in primary refractory Hodgkin lymphoma, which confirms our previously published findings. Bcl-2 showed a significantly lower level of expression in primary refractory disease than in the other follow-up groups. This is in contrast with a previous finding of Bcl-2, associated with a poor prognosis in primary refractory illness. Another category of variables, old age and advanced stages, was significantly different in the various complications but this finding is probably to be expected. We could not demonstrate a difference between the sequels and the control group with regard to several clinical and immunohistochemical markers. Sialyl-CD15 and Bcl-2 expression, in contrast, were confirmed as prognostic factors, mainly of tumor progression into primary refractory disease.

Wednesday, October 12, 2016 3:24 PM|Allal Ouhtit, Rajiv Lochan Gaur, Mohamed Abdraboh, Shubha K. Ireland, Prakash N Rao, Shailaja G Raj, Hamad Al-Riyami, Somya Shanmuganathan, Ishita Gupta, Subramanyam N Murthy, Andrew Hollenbach, Madhwa HG Raj|Journal of Cancer|Labels: Bcl-2, P53, breast cancer

Traditional chemotherapy and radiotherapy for cancer treatment face serious challenges such as drug resistance and toxic side effects. Complementary / Alternative medicine is increasingly being practiced worldwide due to its safety beneficial therapeutic effects. We hypothesized that a super combination (SC) of known phytochemicals used at bioavailable levels could induce 100% killing of breast cancer (BC) cells without toxic effects on normal cells and that microarray analysis would identify potential genes for targeted therapy of BC. Mesenchymal Stems cells (MSC, control) and two BC cell lines were treated with six well established pro-apoptotic phytochemicals individually and in combination (super cocktail), at bioavailable levels. The compounds were ineffective individually. In combination, they significantly suppressed BC cell proliferation (>80%), inhibited migration and invasion, caused cell cycle arrest and induced apoptosis resulting in 100% cell death. However, there were no deleterious effects on MSC cells used as control. Furthermore, the SC down-regulated the expression of PCNA, Rb, CDK4, BcL-2, SVV, and CD44 (metastasis inducing stem cell factor) in the BC cell lines. Microarray analysis revealed several differentially expressed key genes (PCNA, Rb, CDK4, Bcl-2, SVV, P53 and CD44) underpinning SC-promoted BC cell death and motility. Four unique genes were highly up-regulated (ARC, GADD45B, MYLIP and CDKN1C). This investigation indicates the potential for development of a highly effective phytochemical combination for breast cancer chemoprevention / chemotherapy. The novel over-expressed genes hold the potential for development as markers to follow efficacy of therapy.

Wednesday, October 12, 2016 3:24 PM|Chengmeng Jin, Wei Yu, Xiaoyan Lou, Fan Zhou, Xu Han, Na Zhao, Biaoyang Lin|Journal of Cancer|Labels: Bcl-2, P53, ovarian cancer

Ubiquitin carboxyl terminal hydrolase 1 (UCHL1) catalyzes the hydrolysis of COOH-terminal ubiquityl esters and amides. It has been reported as either an oncogene or a tumor suppressor in cancers. However, UCHL1's role in ovarian cancer is still unclear. Therefore, we conducted an analysis to understand the role of UCHL1 in ovarian cancer. Firstly, we detected UCHL1 promoter methylation status in 7 ovarian cancer cell lines. 4 of them with UCHL1 silencing showed heavy promoter methylation while the other 3 with relative high UCHL1 expression showed little promoter methylation. Then we reduced UCHL1 expression in ovarian cancer cell line A2780 and IGROV1 and found that inhibition of UCHL1 promoted cell proliferation by increasing cells in S phases of cell cycle. Knockdown of UCHL1 also reduced cell apoptosis and contributed to cisplatin resistance. Furthermore, the expression level of UCHL1 in several ovarian cancer cell lines correlated negatively with their cisplatin resistance levels. Microarray data revealed that UCHL1 related genes are enriched in apoptosis and cell death gene ontology (GO) terms. Several apoptosis related genes were increased after UCHL1 knockdown, including apoptosis regulator BCL2, BCL11A, AEN and XIAP. Furthermore, we identified up-regulation of Bcl-2 and pAKT as well as down-regulation of Bax in UCHL1 knockdown cells, while no significant alteration of p53 and AKT1 was found. This study provides a new and promising strategy to overcome cisplatin resistance in ovarian cancer via UCHL1 mediated pathways.

Wednesday, October 12, 2016 3:22 PM|Muhammad Khan, Chuan Ding, Azhar Rasul, Fei Yi, Ting Li, Hongwen Gao, Rong Gao, Lili Zhong, Kun Zhang, Xuedong Fang, Tonghui Ma|International Journal of Biological Sciences|Labels: Bcl-2, MapK, ROS, pancreatic cancer, clinical trial

Isoalantolactone, a sesquiterpene lactone compound possesses antifungal, antibacteria, antihelminthic and antiproliferative activities. In the present study, we found that isoalantolactone inhibits growth and induces apoptosis in pancreatic cancer cells. Further mechanistic studies revealed that induction of apoptosis is associated with increased generation of reactive oxygen species, cardiolipin oxidation, reduced mitochondrial membrane potential, release of cytochrome c and cell cycle arrest at S phase. N-Acetyl Cysteine (NAC), a specific ROS inhibitor restored cell viability and completely blocked isoalantolactone-mediated apoptosis in PANC-1 cells indicating that ROS are involved in isoalantolactone-mediated apoptosis. Western blot study showed that isoalantolactone increased the expression of phosphorylated p38 MAPK, Bax, and cleaved caspase-3 and decreased the expression of Bcl-2 in a dose-dependent manner. No change in expression of phosphorylated p38 MAPK and Bax was found when cells were treated with isoalantolactone in the presence of NAC, indicating that activation of these proteins is directly dependent on ROS generation. The present study provides evidence for the first time that isoalantolactone induces ROS-dependent apoptosis through intrinsic pathway. Furthermore, our in vivo toxicity study demonstrated that isoalantolactone did not induce any acute or chronic toxicity in liver and kidneys of CD1 mice at dose of 100 mg/kg body weight. Therefore, isoalantolactone may be a safe chemotherapeutic candidate for the treatment of human pancreatic carcinoma.

Wednesday, October 12, 2016 3:22 PM|Zhaocai Li, Xingang Xu, Yong Huang, Li Ding, Zhisheng Wang, Gaoshui Yu, Dan Xu, Wei Li, Dewen Tong|International Journal of Biological Sciences|Labels: Bcl-2, PARP, lung cancer

Swainsonine (1, 2, 8-trihyroxyindolizidine, SW), a natural alkaloid, has been reported to exhibit anti-cancer activity on several mouse models of human cancer and human cancers in vivo. However, the mechanisms of SW-mediated tumor regression are not clear. In this study, we investigated the effects of SW on several human lung cancer cell lines in vitro. The results showed that SW significantly inhibited these cells growth through induction of apoptosis in different extent in vitro. Further studies showed that SW treatment up-regulated Bax, down-regulated Bcl-2 expression, promoted Bax translocation to mitochondria, activated mitochondria-mediated apoptotic pathway, which in turn caused the release of cytochrome c, the activation of caspase-9 and caspase-3, and the cleavage of poly (ADP-ribose) polymerase (PARP), resulting in A549 cell apoptosis. However, the expression of Fas, Fas ligand (FasL) or caspase-8 activity did not appear significant changes in the process of SW-induced apoptosis. Moreover, SW treatment inhibited Bcl-2 expression, promoted Bax translocation, cytochrome c release and caspase-3 activity in xenograft tumor cells, resulting in a significant decrease of tumor volume and tumor weight in the SW-treated xenograft mice groups in comparison to the control group. Taken together, this study demonstrated for the first time that SW inhibited A549 cancer cells growth through a mitochondria-mediated, caspase-dependent apoptotic pathway in vitro and in vivo.

Sunday, October 9, 2016 7:00 PM|PBR - News|Labels: Bcl-2, proteasome, MM, regulatory
The US Food and Drug Administration (FDA) has granted Priority Review to Genmab's supplemental Biologics License Application (sBLA) for the use of daratumumab (DARZALEX) in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, to treat patients with multiple myeloma who have received at least one prior therapy.
Friday, October 7, 2016 3:00 AM|MIT Biotech Group - Essential Biotech RSS Feed|Labels: Bcl-2, FGFR, proteasome, MM, regulatory
Genmab A/S (CSE:GEN) said FDA granted Priority Review to an sBLA for Darzalex daratumumab in combination with Revlimid lenalidomide or Velcade bortezomib and dexamethasone to treat multiple myeloma in patients who have received at least one prior therapy. The PDUFA date is Feb. 17, 2017.Genmab said FDA also granted standard review to the human IgG1k mAb against CD38 in combination with Pomalyst pomalidomide and dexamethasone in third-line MM patients previously treated with a PI therapy and an immunomodulatory agent. The PDUFA date in that indication is June 17, 2017.Darzalex has accelerated approval to treat MM in patients who have failed at least three prior therapies, including a proteasome inhibitor (PI) and an immunomodulatory agent, or who are double-refractory to a PI and an immunomodulatory agent.The Janssen Biotech unit of Johnson & Johnson (NYSE:JNJ) has rights to the drug from Genmab. Celgene Corp. (NASDAQ:CELG) markets Revlimid and Pomalyst. Takeda Pharmaceutical Co. Ltd. (Tokyo:4502) and J&J market Velcade.
Wednesday, October 5, 2016 8:00 PM|James Driscoll|Genes|Labels: Bcl-2, proteasome, MM
While the clinical benefit of proteasome inhibitors (PIs) for multiple myeloma (MM) treatment remains unchallenged, dose‐limiting toxicities and the inevitable emergence of drug resistance limit their long‐term utility. Disease eradication is compromised by drug resistance that is either present de novo or therapy‐induced, which accounts for the majority of tumor relapses and MM‐related deaths. Non‐coding RNAs (ncRNAs) are a broad class of RNA molecules, including long non‐coding RNAs (lncRNAs), that do not encode proteins but play a major role in regulating the fundamental cellular processes that control cancer initiation, metastasis, and therapeutic resistance. While lncRNAs have recently attracted significant attention as therapeutic targets to potentially improve cancer treatment, identification of lncRNAs that are deregulated in cells resistant to PIs has not been previously addressed. We have modeled drug resistance by generating three MM cell lines with acquired resistance to either bortezomib, carfilzomib, or ixazomib. Genome‐wide profiling identified lncRNAs that were significantly deregulated in all three PIresistant cell lines relative to the drug‐sensitive parental cell line. Strikingly, certain lncRNAs deregulated in the three PI‐resistant cell lines were also deregulated in MM plasma cells isolated from newly diagnosed patients compared to healthy plasma cells. Taken together, these preliminary studies strongly suggest that lncRNAs represent potential therapeutic targets to prevent or overcome drug resistance. More investigations are ongoing to expand these initial studies in a greater number of MM patients to better define lncRNAs signatures that contribute to PI resistance in MM.
Tuesday, October 4, 2016 3:42 PM|Kumar, S. K., LaPlant, B. R., Reeder, C. B., Roy, V., Halvorson, A. E., Buadi, F., Gertz, M. A., Bergsagel, P. L., Dispenzieri, A., Thompson, M. A., Crawley, J., Kapoor, P., Mikhael, J., Stewart, K., Hayman, S. R., Hwa, Y. L., Gonsalves, W., Witzig, T. E., Ailawadhi, S., Dingli, D., Go, R. S., Lin, Y., Rivera, C. E., Rajkumar, S. V., Lacy, M. Q.|BLOOD First Edition Papers|Labels: Bcl-2, proteasome, MM, clinical trial

Proteasome inhibitors have become an integral part of myeloma therapy. Considerable efforts have gone into optimizing this therapeutic approach in order to obtain maximal proteasome inhibition with least toxicity. Ixazomib is the first oral proteasome inhibitor to enter the clinic and has been studied as a single agent as well as in various combinations. The current trial was designed to examine the efficacy and toxicity of combining two different doses of ixazomib (4 mg and 5.5mg given weekly for 3 of 4 weeks) with 40 mg weekly of dexamethasone, in relapsed myeloma. Seventy patients were enrolled, 35 patients randomly assigned to each Ixazomib dose. Overall, 30 (43%, 95% CI: 31-55) of the patients achieved a confirmed partial response or better, with 31% achieving a response with 4 mg and 54% with 5.5 mg of ixazomib. The median event free survival (EFS) for the entire study population was 8.4 months and 1-year overall survival was 96%. The EFS was 5.7 months for patients with prior bortezomib exposure and 11.0 months for bortezomib naïve patients. A grade 3 or 4 adverse event considered at least possibly related to treatment was seen in 11 (32%) patients at 4 mg and in 21 (60%) at 5.5 mg. Dose reductions were more frequent with 5.5 mg dose. Overall, the ixazomib with dexamethasone has good efficacy in relapsed myeloma, is well tolerated and with higher response rate at 5.5 mg, albeit with more toxicity.

Monday, October 3, 2016 3:05 PM|Chiron, D., Bellanger, C., Papin, A., Tessoulin, B., Dousset, C., Maiga, S., Moreau, A., Esbelin, J., Trichet, V., Chen-Kiang, S., Moreau, P., Touzeau, C., Le Gouill, S., Amiot, M., Pellat-Deceunynck, C.|BLOOD First Edition Papers|Labels: Bcl-2, NFKb, lymphoma

Mantle cell lymphoma (MCL) accumulates in lymphoid organs but disseminates early on in extranodal tissues. Although proliferation remains located in lymphoid organs only, suggesting a major role of the tumor ecosystem, few studies have assessed MCL microenvironment. We therefore cocultured primary circulating MCL cells from 21 patients several weeks ex vivo with stromal or lymphoid-like (CD40L) cells to determine which interactions could support their proliferation. We showed that coculture with lymphoid-like cells, but not stromal cells, induced cell-cycle progression, which was amplified by MCL-specific cytokines (IGF-1, BAFF, IL-6, IL-10). Of interest, we showed that our model recapitulated the MCL in situ molecular signatures i.e., proliferation, NFkB and survival signatures. We further demonstrated that proliferating MCL harbored an imbalance in Bcl-2 family expression leading to a consequent loss of mitochondrial priming. Interestingly, this loss of priming was overcome by the Type II anti-CD20 antibody obinutuzumab, which counteracted Bcl-xL induction through NFkB inhibition. Finally, we showed that the mitochondrial priming directly correlated with the sensitivity toward venetoclax and alkylating drugs. By identifying the microenvironment as the major support for proliferation and drug resistance in MCL, our results highlight a selective approach to target the lymphoma niche.

Monday, October 3, 2016 2:48 PM|Blunt, M. D., Koehrer, S., Dobson, R., Larrayoz, M., Wilmore, S., Hayman, A., Parnell, J., Smith, L. D., Davies, A., Johnson, P. W., Conley, P. B., Pandey, A., Strefford, J. C., Stevenson, F. K., Packham, G., Forconi, F., Coffey, G. P., Burger, J., Steele, A. J.|Clinical Cancer Research Online First Articles|Labels: Bcl-2, Bcr-Abl, STAT, leukemia

Purpose: B-cell receptor (BCR)-associated kinase inhibitors such as ibrutinib have revolutionised the treatment of chronic lymphocytic leukemia (CLL). However, these agents are not curative and resistance is already emerging in a proportion of patients. Interleukin-4 (IL-4), expressed in CLL lymph nodes, can augment BCR-signalling and reduce the effectiveness of BCR-kinase inhibitors. Therefore simultaneous targeting of the IL-4- and BCR-signalling pathways by cerdulatinib, a novel dual Syk/JAK inhibitor currently in clinical trials (NCT01994382), may improve treatment responses in patients. Experimental Design: PBMCs from CLL patients were treated with cerdulatinib alone or in combination with venetoclax. Cell death, chemokine and cell signalling assay were performed and analysed by flow cytometry, immunoblotting, Q-PCR and ELISA as indicated. Results: At concentrations achievable in patients, cerdulatinib inhibited BCR- and IL-4-induced downstream signalling in CLL cells using multiple read outs and prevented anti-IgM- and nurse-like cell (NLC)-mediated CCL3/CCL4 production. Cerdulatinib induced apoptosis of CLL cells, in a time- and concentration dependent manner, and particularly in IGHV unmutated samples with greater BCR-signalling capacity and response to IL-4, or samples expressing higher levels of sIgM, CD49d+ or ZAP70+. Cerdulatinib overcame anti-IgM, IL-4/CD40L or NLC-mediated protection by preventing upregulation of MCL-1- and BCL-XL, however BCL-2 expression was unaffected. Furthermore in samples treated with IL-4/CD40L, cerdulatinib synergised with venetoclax in vitro to induce greater apoptosis than either drug alone. Conclusion: Cerdulatinib is a promising therapeutic for the treatment of CLL either alone or in combination with venetoclax, with the potential to target critical survival pathways in this currently incurable disease.

Monday, October 3, 2016 12:05 AM|Hoda, M. A., Pirker, C., Dong, Y., Schelch, K., Heffeter, P., Kryeziu, K., van Schoonhoven, S., Klikovits, T., Laszlo, V., Rozsas, A., Ozsvar, J., Klepetko, W., Döme, B., Grusch, M., Hegedüs, B., Berger, W.|Molecular Cancer Therapeutics current issue|Labels: Bcl-2, mesothelioma

Malignant pleural mesothelioma (MPM) is characterized by widespread resistance to systemic therapy. Trabectedin is an antineoplastic agent targeting both the malignant cells and the tumor microenvironment that has been approved for the treatment of advanced soft tissue sarcoma and ovarian cancer. In this preclinical study, we evaluated the antineoplastic potential of trabectedin as a single agent and in drug combination approaches in human MPM. Therefore, we utilized an extended panel of MPM cell lines (n = 6) and primary cell cultures from surgical MPM specimens (n = 13), as well as nonmalignant pleural tissue samples (n = 2). Trabectedin exerted a dose-dependent cytotoxic effect in all MPM cell cultures in vitro when growing as adherent monolayers or nonadherent spheroids with IC50 values ≤ 2.6 nmol/L. Nonmalignant mesothelial cells were significantly less responsive. The strong antimesothelioma activity was based on cell-cycle perturbation and apoptosis induction. The activity of trabectedin against MPM cells was synergistically enhanced by coadministration of cisplatin, a drug routinely used for systemic MPM treatment. Comparison of gene expression signatures indicated an inverse correlation between trabectedin response and bcl-2 expression. Accordingly, bcl-2 inhibitors (Obatoclax, ABT-199) markedly synergized with trabectedin paralleled by deregulated expression of the bcl-2 family members bcl-2, bim, bax, Mcl-1, and bcl-xL as a consequence of trabectedin exposure. In addition, trabectedin exerted significant antitumor activity against an intraperitoneal MPM xenograft model. Together, these data suggest that trabectedin exerts strong activity in MPM and synergizes with chemotherapy and experimental bcl-2 inhibitors in vitro. Thus, it represents a promising new therapeutic option for MPM. Mol Cancer Ther; 15(10); 2357–69. ©2016 AACR.

Monday, October 3, 2016 12:05 AM|Konopleva, M., Pollyea, D. A., Potluri, J., Chyla, B., Hogdal, L., Busman, T., McKeegan, E., Salem, A. H., Zhu, M., Ricker, J. L., Blum, W., DiNardo, C. D., Kadia, T., Dunbar, M., Kirby, R., Falotico, N., Leverson, J., Humerickhouse, R., Mabry, M., Stone, R., Kantarjian, H., Letai, A.|Cancer Discovery current issue|Labels: Bcl-2, leukemia, clinical trial

We present a phase II, single-arm study evaluating 800 mg daily venetoclax, a highly selective, oral small-molecule B-cell leukemia/lymphoma-2 (BCL2) inhibitor in patients with high-risk relapsed/refractory acute myelogenous leukemia (AML) or unfit for intensive chemotherapy. Responses were evaluated following revised International Working Group (IWG) criteria. The overall response rate was 19%; an additional 19% of patients demonstrated antileukemic activity not meeting IWG criteria (partial bone marrow response and incomplete hematologic recovery). Twelve (38%) patients had isocitrate dehydrogenase 1/2 mutations, of whom 4 (33%) achieved complete response or complete response with incomplete blood count recovery. Six (19%) patients had BCL2-sensitive protein index at screening, which correlated with time on study. BH3 profiling was consistent with on-target BCL2 inhibition and identified potential resistance mechanisms. Common adverse events included nausea, diarrhea and vomiting (all grades), and febrile neutropenia and hypokalemia (grade 3/4). Venetoclax demonstrated activity and acceptable tolerability in patients with AML and adverse features.

Significance: Venetoclax monotherapy demonstrated clinical activity in patients with AML (relapsed/refractory or unfit for intensive chemotherapy) with a tolerable safety profile in this phase II study. Predictive markers of response consistent with BCL2 dependence were identified. Clinical and preclinical findings provide a compelling rationale to evaluate venetoclax combined with other agents in AML. Cancer Discov; 6(10); 1106–17. ©2016 AACR.

See related commentary by Pullarkat and Newman, p. 1082.

This article is highlighted in the In This Issue feature, p. 1069

Monday, October 3, 2016 12:05 AM|Pullarkat, V. A., Newman, E. M.|Cancer Discovery recent issues|Labels: Bcl-2, leukemia

Summary: Venetoclax is an oral drug with an excellent side-effect profile that has the potential to revolutionize acute myeloid leukemia (AML) therapy in two areas. Venetoclax-based combination therapies could be a bridge to hematopoietic cell transplant with curative intent for patients with refractory/relapsed AML, and venetoclax-based therapy could provide meaningful survival prolongation for older patients with AML who are not candidates for more aggressive therapies. Cancer Discov; 6(10); 1082–3. ©2016 AACR.

See related article by Konopleva and colleagues, p. 1106.

Monday, October 3, 2016 12:05 AM|Pullarkat, V. A., Newman, E. M.|Cancer Discovery current issue|Labels: Bcl-2, leukemia

Summary: Venetoclax is an oral drug with an excellent side-effect profile that has the potential to revolutionize acute myeloid leukemia (AML) therapy in two areas. Venetoclax-based combination therapies could be a bridge to hematopoietic cell transplant with curative intent for patients with refractory/relapsed AML, and venetoclax-based therapy could provide meaningful survival prolongation for older patients with AML who are not candidates for more aggressive therapies. Cancer Discov; 6(10); 1082–3. ©2016 AACR.

See related article by Konopleva and colleagues, p. 1106.

Friday, September 30, 2016 6:06 AM|Mahesh Hegde; Divyaanka Iyer; Snehal Gaikwad; Vidya Gopalakrishnan; Mrinal Srivastava; Subhas S. Karki; Bibha Choudhary; Pritha Ray; T.R. Santhoshkumar; Sathees C. Raghavan|JournalTOCs API - Biochemical Pharmacology (50 articles)|Labels: Bcl-2

A Novel Inhibitor of BCL2, Disarib Abrogates Tumor Growth while Sparing Platelets, by Activating Intrinsic Pathway of Apoptosis
Supriya V. Vartak Mahesh Hegde; Divyaanka Iyer; Snehal Gaikwad; Vidya Gopalakrishnan; Mrinal Srivastava; Subhas S. Karki; Bibha Choudhary; Pritha Ray; T.R. Santhoshkumar; Sathees C. Raghavan
Biochemical Pharmacology, Vol. , No. (2016) pp. -
Publication date: Available online 29 September 2016 Source:Biochemical Pharmacology Author(s): Supriya V. Vartak, Mahesh Hegde, Divyaanka Iyer, Snehal Gaikwad, Vidya Gopalakrishnan, Mrinal Srivastava, Subhas S. Karki, Bibha Choudhary, Pritha Ray, T.R. Santhoshkumar, Sathees C. Raghavan Antiapoptotic protein BCL2, serves as an excellent target for anticancer therapy owing to its increased level in cancers. Previously, we have described characterization of a novel BCL2 inhibitor, Disarib, which showed selective cytotoxicity in BCL2 ‘high’ cancer cells and CLL patient cells. Here, we have investigated the mechanism of Disarib-induced cytotoxicity, and compared its efficacy with a well-established BCL2 inhibitor, ABT199. We show that Disarib administration caused tumor regression in mouse allograft and xenograft models, exhibited platelet sparing property and did not exhibit significant side effects. Importantly, comparison between Disarib and ABT199, revealed higher efficacy for Disarib in mouse tumor model and cancer cell lines. Disarib induced cell death by activating intrinsic apoptotic pathway. Interestingly, Disarib showed synergism with paclitaxel, suggesting its potential for combination therapy. Thus, we provide mechanistic insights into the cell death pathways induced by Disarib, report that Disarib exhibited better effect than currently used ABT199 and demonstrate its combinatorial potential with paclitaxel. Graphical abstract

Monday, September 19, 2016 1:57 PM|Nijhof, I. S., Franssen, L. E., Levin, M.-D., Bos, G. M. J., Broijl, A., Klein, S. K., Koene, H. R., Bloem, A. C., Beeker, A., Faber, L. M., van der Spek, E., Ypma, P. F., Raymakers, R., van Spronsen, D.-J., Westerweel, P. E., Oostvogels, R., van Velzen, J., van Kessel, B., Mutis, T., Sonneveld, P., Zweegman, S., Lokhorst, H. M., van de Donk, N. W. C. J.|BLOOD First Edition Papers|Labels: Bcl-2, proteasome, MM, clinical trial

The prognosis of multiple myeloma (MM) patients who become refractory to lenalidomide and bortezomib is very poor, indicating the need for new therapeutic strategies for these patients. Next to the development of new drugs, the strategy of combining agents with synergistic activity may also result in clinical benefit for patients with advanced myeloma. We have previously shown in a retrospective analysis that lenalidomide combined with continuous low-dose cyclophosphamide and prednisone (REP) had remarkable activity in heavily pretreated, lenalidomide-refractory MM patients. To evaluate this combination prospectively, we initiated a phase 1/2 study to determine the optimal dose and to assess its efficacy and safety in lenalidomide-refractory MM patients. The maximum tolerated dose (MTD) was defined as 25 mg lenalidomide (days 1-21/28 days), combined with continuous cyclophosphamide (50 mg/day) and prednisone (20 mg/day). At the MTD (n=67 patients), the overall response rate was 67%, and at least minimal response was achieved in 83% of the patients. Median PFS and OS were 12.1 and 29.0 months, respectively. Similar results were achieved in the subset of patients with lenalidomide- and bortezomib-refractory disease as well as in patients with high-risk cytogenetic abnormalities, defined as t(4;14), t(14;16), del(17p), and/or ampl(1q) as assessed by FISH. Neutropenia (22%) and thrombocytopenia (22%) were the most common grade 3-4 hematologic adverse events. Infections (21%) were the most common grade 3-5 non-hematologic adverse events. In conclusion, the addition of continuous low-dose oral cyclophosphamide to lenalidomide and prednisone offers a new therapeutic perspective for multidrug refractory MM patients. This trial was registered at www.clinicaltrials.gov as #NCT01352338.

Thursday, September 15, 2016 9:42 AM|Harrison, S. J., Mainwaring, P., Price, T., Millward, M. J., Padrik, P., Underhill, C. R., Cannell, P. K., Reich, S. D., Trikha, M., Spencer, A.|Clinical Cancer Research recent issues|Labels: Bcl-2, proteasome, MM, clinical trial

Purpose: Marizomib (NPI-0052) is an irreversible proteasome inhibitor, derived from a marine actinomycete, with activity and specificity that is distinct from other proteasome inhibitors.

Experimental Design: Phase I study (NPI-0052-102) evaluated the MTD, pharmacokinetics, and pharmacodynamics of marizomib intravenously on two dosing schedules.

Results: Forty-two patients with advanced malignancies received Schedule A (0.1–0.9 mg/m2 over 1–10 minutes on days 1, 8, 15 in 4-week cycles); 44 patients with relapsed and/or refractory multiple myeloma (RRMM) and other hematologic malignancies received Schedule B (0.075–0.6 mg/m2 over 1 minute to 2 hours on days 1, 4, 8, 11, in 3-week cycles). The Schedule A recommended phase II dose was 0.7 mg/m2 over 10 minutes; Schedule B was 0.5 mg/m2 over 2 hours. The most common (>25% of patients) related adverse events were fatigue, nausea, diarrhea, and infusion site pain (Schedule A); and fatigue (Schedule B). Overall response rate of 11% was seen in 27 efficacy-evaluable RRMM Schedule B patients (1 very good partial response, 3 partial responses, 4 minimal responses, and 12 stable disease). One Schedule A patient with transformed marginal zone lymphoma had complete response. Marizomib has a short half-life (<30 minutes), with high volume of distribution (~15–416 L) and clearance (~0.9–22 L/minutes).

Conclusions: Marizomib does not exhibit the severe peripheral neuropathy or hematologic toxicity observed with other proteasome inhibitors. Marizomib was generally well tolerated with low-dose dexamethasone, demonstrated activity in heavily pretreated RRMM patients, and warrants further evaluation. Clin Cancer Res; 22(18); 4559–66. ©2016 AACR.

Thursday, September 15, 2016 9:42 AM|Lamothe, B., Wierda, W. G., Keating, M. J., Gandhi, V.|Clinical Cancer Research recent issues|Labels: Bcl-2, proteasome, leukemia, biomarker diagnostic

Purpose: Carfilzomib, while active in B-cell neoplasms, displayed heterogeneous response in chronic lymphocytic leukemia (CLL) samples from patients and showed interpatient variability to carfilzomib-induced cell death. To understand this variability and predict patients who would respond to carfilzomib, we investigated the mechanism by which carfilzomib induces CLL cell death.

Experimental Design: Using CLL patient samples and cell lines, complementary knockdown and knockout cells, and carfilzomib-resistant cell lines, we evaluated changes in intracellular networks to identify molecules responsible for carfilzomib's cytotoxic activity. Lysates from carfilzomib-treated cells were immunoblotted for molecules involved in ubiquitin, apoptotic, and endoplasmic reticulum (ER) stress response pathways and results correlated with carfilzomib cytotoxic activity. Coimmunoprecipitation and pull-down assays were performed to identify complex interactions among MCL-1, Noxa, and Bak.

Results: Carfilzomib triggered ER stress and activation of both the intrinsic and extrinsic apoptotic pathways through alteration of the ubiquitin proteasome pathway. Consequently, the transcription factor CCAAT/enhancer-binding protein homology protein (CHOP) accumulated in response to carfilzomib, and CHOP depletion conferred protection against cytotoxicity. Carfilzomib also induced accumulation of MCL-1 and Noxa, whereby MCL-1 preferentially formed a complex with Noxa and consequently relieved MCL-1's protective effect on sequestering Bak. Accordingly, depletion of Noxa or both Bak and Bax conferred protection against carfilzomib-induced cell death.

Conclusions: Collectively, carfilzomib induced ER stress culminating in activation of intrinsic and extrinsic caspase pathways, and we identified the CHOP protein level as a biomarker that could predict sensitivity to carfilzomib in CLL. Clin Cancer Res; 22(18); 4712–26. ©2016 AACR.

Friday, September 2, 2016 12:05 AM|Ishibashi, M., Tamura, H., Sunakawa, M., Kondo-Onodera, A., Okuyama, N., Hamada, Y., Moriya, K., Choi, I., Tamada, K., Inokuchi, K.|Cancer Immunology Research recent issues|Labels: Bcl-2, PD-1/PD-L1, proteasome

B7 homolog 1 (B7-H1)–expressing myeloma cells not only inhibit myeloma-specific cytotoxic T lymphocytes (CTL), but also confer a proliferative advantage: resistance to antimyeloma chemotherapy. However, it remains unknown whether B7-H1 expressed on myeloma cells induces cellular responses associated with aggressive myeloma behaviors. To address this question, we analyzed the proliferation and drug sensitivity of B7-H1–expressing myeloma cells transfected with B7-H1–specific short-hairpin RNA or treated with programmed cell death (PD)-1-Fc–coupled beads. Knockdown of B7-H1 expression in myeloma cells significantly inhibited cell proliferation and increased apoptosis induced by the chemotherapeutic alkylating agent melphalan, with downregulation of the expression of cell cycle–related genes (CCND3 and CDK6) and antiapoptotic genes (BCL2 and MCL1). B7-H1 molecules thus contributed to myeloma cell-cycle progression and suppression of drug-induced apoptosis. B7-H1–expressing myeloma cells had a higher affinity for PD-1 than for CD80. PD-1-Fc bead–treated myeloma cells also became resistant to apoptosis that was induced by melphalan and the proteasome inhibitor bortezomib. Apoptosis resistance was associated with the PI3K/AKT pathway. Both myeloma cell drug resistance and antiapoptotic responses occurred through the PI3K/AKT signaling pathway, initiated from "reverse" stimulation of B7-H1 by PD-1. Therefore, B7-H1 itself may function as an oncogenic protein in myeloma cells. The interaction between B7-H1 on myeloma cells and PD-1 molecules not only inhibits tumor-specific CTLs but also induces drug resistance in myeloma cells through the PI3K/AKT signaling pathway. These observations provide mechanistic insights into potential immunotherapeutic benefits of blocking the B7-H1–PD-1 pathway. Cancer Immunol Res; 4(9); 779–88. ©2016 AACR.

Thursday, September 1, 2016 12:05 AM|Niu, X., Zhao, J., Ma, J., Xie, C., Edwards, H., Wang, G., Caldwell, J. T., Xiang, S., Zhang, X., Chu, R., Wang, Z. J., Lin, H., Taub, J. W., Ge, Y.|Clinical Cancer Research recent issues|Labels: Bcl-2, leukemia

Purpose: To investigate the molecular mechanism underlying intrinsic resistance to ABT-199.

Experimental Design: Western blots and real-time RT-PCR were used to determine levels of Mcl-1 after ABT-199 treatment alone or in combination with cytarabine or daunorubicin. Immunoprecipitation of Bim and Mcl-1 were used to determine the effect of ABT-199 treatment on their interactions with Bcl-2 family members. Lentiviral short hairpin RNA knockdown of Bim and CRISPR knockdown of Mcl-1 were used to confirm their role in resistance to ABT-199. JC-1 assays and flow cytometry were used to determine drug-induced apoptosis.

Results: Immunoprecipitation of Bim from ABT-199–treated cell lines and a primary patient sample demonstrated decreased association with Bcl-2, but increased association with Mcl-1 without corresponding change in mitochondrial outer membrane potential. ABT-199 treatment resulted in increased levels of Mcl-1 protein, unchanged or decreased Mcl-1 transcript levels, and increased Mcl-1 protein half-life, suggesting that the association with Bim plays a role in stabilizing Mcl-1 protein. Combining conventional chemotherapeutic agent cytarabine or daunorubicin with ABT-199 resulted in increased DNA damage along with decreased Mcl-1 protein levels, compared with ABT-199 alone, and synergistic induction of cell death in both AML cell lines and primary patient samples obtained from AML patients at diagnosis.

Conclusions: Our results demonstrate that sequestration of Bim by Mcl-1 is a mechanism of intrinsic ABT-199 resistance and supports the clinical development of ABT-199 in combination with cytarabine or daunorubicin for the treatment of AML. Clin Cancer Res; 22(17); 4440–51. ©2016 AACR.

Thursday, September 1, 2016 12:05 AM|Rasche, L., Menoret, E., Dubljevic, V., Menu, E., Vanderkerken, K., Lapa, C., Steinbrunn, T., Chatterjee, M., Knop, S., Düll, J., Greenwood, D. L., Hensel, F., Rosenwald, A., Einsele, H., Brändlein, S.|Clinical Cancer Research recent issues|Labels: Bcl-2, proteasome, MM

Purpose: Glucose-regulated protein (GRP) 78 is overexpressed in multiple myeloma, and both its surface expression and its biologic significance as key sensor of the unfolded protein response make GRP78 an ideal candidate for immunotherapeutic intervention. The monoclonal antibody PAT-SM6 targets surface GRP78 and leads to disease stabilization when used as single agent in a clinical trial. In this article, we evaluated expression of GRP78 in relapsed-refractory disease and explored PAT-SM6 therapy in combination regimens.

Experimental Design: GRP78 expression was immunohistochemically analyzed during disease progression and development of drug resistance throughout different stages of multiple myeloma. Activity of PAT-SM6 was evaluated in combination with anti–multiple myeloma agents lenalidomide, bortezomib, and dexamethasone in vitro. Finally, we report on a multiple myeloma patient with relapsed-refractory disease treated with PAT-SM6 in combination with bortezomib and lenalidomide.

Results: Although sGRP78 expression was present at all stages, it increased with disease progression and was even strongly elevated in patients with drug-resistant and extramedullary disease. Pretreatment with dexamethasone as well as dual combination of PAT-SM6/lenalidomide further increased sGRP78 expression and consecutively showed synergistic anti–multiple myeloma effects with PAT-SM6 in proliferation assays. As proof of concept, a 62-year-old male with triple resistant multiple myeloma treated with PAT-SM6, bortezomib, and lenalidomide experienced partial remission of both intra- and extramedullary lesions.

Conclusions: PAT-SM6 therapy in combination regimens showed efficacy in relapsed-refractory multiple myeloma. Clin Cancer Res; 22(17); 4341–9. ©2016 AACR.

Thursday, September 1, 2016 12:05 AM|Magrangeas, F., Kuiper, R., Avet-Loiseau, H., Gouraud, W., Guerin-Charbonnel, C., Ferrer, L., Aussem, A., Elghazel, H., Suhard, J., Der Sakissian, H., Attal, M., Munshi, N. C., Sonneveld, P., Dumontet, C., Moreau, P., van Duin, M., Campion, L., Minvielle, S.|Clinical Cancer Research recent issues|Labels: Bcl-2, proteasome, MM

Purpose: Painful peripheral neuropathy is a frequent toxicity associated with bortezomib therapy. This study aimed to identify loci that affect susceptibility to this toxicity.

Experimental Design: A genome-wide association study (GWAS) of 370,605 SNPs was performed to identify risk variants for developing severe bortezomib-induced peripheral neuropathy (BiPN) in 469 patients with multiple myeloma who received bortezomib–dexamethasone therapy prior to autologous stem cell in randomized clinical trials of the Intergroupe Francophone du Myelome (IFM) and findings were replicated in 114 patients with multiple myeloma of the HOVON-65/GMMG-HD4 clinical trial.

Results: An SNP in the PKNOX1 gene was associated with BiPN in the exploratory cohort [rs2839629; OR, 1.89, 95% confidence interval (CI), 1.45–2.44; P = 7.6 x 10–6] and in the replication cohort (OR, 2.04; 95% CI, = 1.11–3.33; P = 8.3 x 10–3). In addition, rs2839629 is in strong linkage disequilibrium (r2 = 0.87) with rs915854, located in the intergenic region between PKNOX1 and cystathionine-ß-synthetase (CBS). Expression quantitative trait loci mapping showed that both rs2839629 and rs915854 genotypes have an impact on PKNOX1 expression in nerve tissue, whereas rs2839629 affects CBS expression in skin and blood.

Conclusions: The use of GWAS in multiple myeloma pharmacogenomics has identified a novel candidate genetic locus mapping to PKNOX1 and in the immediate vicinity of CBS at 21q22.3 associated with the severe bortezomib-induced toxicity. The proximity of these two genes involved in neurologic pain whose tissue-specific expression is modified by the two variants provides new targets for neuroprotective strategies. Clin Cancer Res; 22(17); 4350–5. ©2016 AACR.

Thursday, September 1, 2016 12:05 AM|Tew, K. D.|Cancer Research recent issues|Labels: Bcl-2, proteasome, clinical trial, regulatory
The relatively recent clinical success of bortezomib, particularly in multiple myeloma, has established the validity of the proteasome as a viable target for anticancer drug development. This highly cited 1999 Cancer Research article from Adams and colleagues was published during the period when this drug was transitioning from preclinical studies to phase I clinical trial status. Their results detail structure–activity analyses using a series of boronic acid proteasome inhibitors and correlate cytotoxicity with inhibition of proteasome activity. In and of itself, the recognition that interference with proteasome functions represented a novel therapeutic approach likely underlies the popularity of this article. In addition, the provision of in vitro (at that time using the NCI 60 cell line panel) and in vivo antitumor activity, toxicology, and mouse pharmacokinetic and pharmacodynamic data provided a solid basis for establishing the future credentials for bortezomib to gain initial FDA approval in 2003. Cancer Res; 76(17); 4916–7. ©2016 AACR.See related article by Adams et al., Cancer Res 1999;59:2615–22.Visit the Cancer Research 75th Anniversary timeline.
Wednesday, August 31, 2016 9:55 PM|Shinsuke Iida, Daisuke Ogiya, Yasunobu Abe, Masafumi Taniwaki, Hiroya Asou, Kaijiro Maeda, Kazunori Uenaka, Soshi Nagaoka, Tsuyoshi Ishiki, Ilaria Conti, Kensei Tobinai|Cancer Science|Labels: Bcl-2, proteasome, MM, clinical trial
B-cell activating factor (BAFF) promotes the survival and adhesion of multiple myeloma (MM) cells. Tabalumab (LY2127399) is an anti-BAFF monoclonal antibody. This phase 1, multicenter, open-label, nonrandomized, dose-escalation study evaluated the safety, tolerability, pharmacokinetics, pharmacodynamics and efficacy of tabalumab in combination with bortezomib and dexamethasone in Japanese patients with relapsed or refractory MM (RRMM). Sixteen patients received intravenous i.v. tabalumab 100 mg (Cohort 1, n = 4) or i.v. tabalumab 300 mg (Cohort 2, n = 12) in combination with oral dexamethasone 20 mg/day and i.v. or s.c. bortezomib 1.3 mg/m2. All patients had treatment-emergent adverse events (TEAE) possibly related to study treatment; the most common TEAE were thrombocytopenia (81.3%), lymphopenia (43.8%) and increased alanine aminotransferase (43.8%). Two (20.0%) dose-limiting toxicities were observed, both in Cohort 2 (tabalumab 300 mg), which was below the predefined cutoff for tolerability (<33%). The pharmacokinetics of tabalumab were similar when bortezomib was coadministered i.v. versus s.c. The overall response rate was 56.3%, suggesting that the combined treatment was effective. In conclusion, combined treatment with these three agents was well tolerated in this population of Japanese patients with RRMM. The study was registered at www.clinicaltrials.gov (NCT01556438). Tabalumab (LY2127399) is a potent, selective, fully human, immunoglobulin G subclass 4 (IgG4) monoclonal antibody that neutralizes soluble and membrane-bound BAFF. Tabalumab prevents free BAFF from binding its receptor but does not interfere with bound BAFF and thus does not directly interact with B-cells. This phase 1, multicenter, open-label, nonrandomized, dose-escalation study evaluated the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of tabalumab in combination with bortezomib and dexamethasone in Japanese patients with relapsed or refractory multiple myeloma.
Monday, August 29, 2016 1:38 AM|News-Medical.Net Apoptosis News Feed|Comments|Labels: Bcl-2, proteasome, MM
Janssen-Cilag International NV has announced the submission of a Type II variation application to the European Medicines Agency (EMA), seeking to broaden the existing marketing authorisation for the immunotherapy DARZALEX® (daratumumab) to include treatment of adult patients with relapsed multiple myeloma who have received at least one prior therapy. The expanded indication is based on daratumumab in combination with lenalidomide (an immmunomodulatory agent) and dexamethasone, or bortezomib (a PI) and dexamethasone.
Thursday, August 25, 2016 12:20 AM|Shekman L. Wong|JournalTOCs API - Journal of Clinical Pharmacology (94 articles)|Labels: Bcl-2, leukemia, lymphoma, clinical trial, HL

Pharmacokinetics of Venetoclax, a Novel BCL‐2 Inhibitor, in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia or Non‐Hodgkin's Lymphoma
Ahmed Hamed Salem Suresh K. Agarwal, Martin Dunbar, Sari L. Heitner Enschede, Rod A. Humerickhouse, Shekman L. Wong
Journal of Clinical Pharmacology, Vol. , No. (2016) pp. -
Venetoclax is a selective BCL‐2 inhibitor that is now approved in the United States for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion who have received at least one prior therapy. The aim of this analysis was to characterize venetoclax pharmacokinetics in the plasma and urine of patients with hematological malignancies and evaluate the effect of dose proportionality, accumulation, weak and moderate CYP3A inhibitors as well as low and high fat meals on venetoclax pharmacokinetics. Patients received a once daily venetoclax dose of 20 mg to 1200 mg. Pharmacokinetic parameters were estimated using non‐compartmental methods. Venetoclax peak exposures were achieved at 5 to 8 hours under low fat conditions and the mean terminal phase elimination half‐life ranged between 14.1 and 18.2 hours at different doses. Venetoclax steady‐state exposures showed minimal accumulation and increased proportionally over the dose range of 300 to 900 mg. Low‐fat and high‐fat meals increased venetoclax exposures by approximately 4‐fold, relative to the fasting state. Moderate CYP3A inhibitors increased venetoclax exposures by 40% to 60% while weak CYP3A inhibitors had no effect. A negligible amount of venetoclax was excreted in the urine. In summary, venetoclax exhibits a pharmacokinetic profile that is compatible with once daily dosing with food regardless of fat content. Concomitant use of venetoclax with moderate CYP3A inhibitors should be avoided or venetoclax dose should be reduced during the venetoclax initiation and ramp‐up phase in CLL patients. Renal excretion plays a minimal role in the elimination of venetoclax. This article is protected by copyright. All rights reserved

Tuesday, August 23, 2016 11:25 PM|Yoichi Imai, Yoshiro Maru, Junji Tanaka|Cancer Science|Labels: Bcl-2, HDAC, HSP, proteasome, STAT, biomarker diagnostic
Histone deacetylases (HDACs) critically regulate gene expression by determining the acetylation status of histones. In addition, studies have increasingly focused on the activities of HDACs, especially involving non-histone proteins, and their various biological effects. Aberrant HDAC expression observed in several kinds of human tumors makes HDACs potential targets for cancer treatment. Several preclinical studies have suggested that HDAC inhibitors exhibit some efficacy in the treatment of acute myelogenous leukemia (AML) with AML1-ETO, which mediates transcriptional repression through its interaction with a complex including HDAC1. Recurrent mutations in epigenetic regulators are found in T-cell lymphomas (TCLs), and HDAC inhibitors and hypomethylating agents were shown to act cooperatively in the treatment of TCLs. Preclinical modeling has suggested that persistent activation of the signal transducer and activator of transcription (STAT) signaling pathway could serve as a useful biomarker of resistance to HDAC inhibitor in patients with cutaneous TCL. Panobinostat, a pan-HDAC inhibitor, in combination with bortezomib and dexamethasone, has achieved longer progression-free survival in patients with relapsed/refractory multiple myeloma (MM) than the placebo in combination with bortezomib and dexamethasone. Panobinostat inhibited MM cell growth by degrading protein phosphatase 3 catalytic subunit α (PPP3CA), a catalytic subunit of calcineurin. This degradation was suggested to be mediated by the blockade of the chaperone function of heat shock protein 90 (HSP90) due to HDAC6 inhibition. Aberrant PPP3CA expression in advanced MM indicated a possible correlation between high PPP3CA expression and the pathogenesis of MM. Furthermore, PPP3CA was suggested as a common target of panobinostat and bortezomib. This article is protected by copyright. All rights reserved.
Monday, August 22, 2016 10:35 AM|Nor, F., Warner, K., Zhang, Z., Acasigua, G., Pearson, A. T., Kerk, S., Helman, J. I., Sant'Ana Filho, M., Wang, S., Nor, J. E.|Clinical Cancer Research Online First Articles|Labels: Bcl-2, P53, biomarker diagnostic

Purpose: Conventional chemotherapy has modest efficacy in advanced adenoid cystic carcinomas (ACC). Tumor recurrence is a major challenge in the management of ACC patients. Here, we evaluated the anti-tumor effect of a novel small molecule inhibitor of the MDM2-p53 interaction (MI-773) combined with Cisplatin in patient-derived xenograft (PDX) ACC tumors. Experimental design: Therapeutic strategies with MI-773 and/or Cisplatin were evaluated in SCID mice harboring PDX ACC tumors (UM-PDX-HACC-5) and in low passage primary human ACC cells (UM-HACC-2A, -2B, -5, -6) in vitro. The effect of therapy on the fraction of cancer stem cells was determined by flow cytometry for ALDH activity and CD44 expression. Results: Combined therapy with MI-773 with Cisplatin caused p53 activation, induction of apoptosis, and regression of ACC PDX tumors. Western blots revealed induction of MDM2, p53 and downstream p21 expression, and regulation of apoptosis-related proteins PUMA, BAX, Bcl-2, Bcl-xL and active Caspase-9 upon MI-773 treatment. Both, single-agent MI-773, and MI-773 combined with Cisplatin, decreased the fraction of cancer stem cells in PDX ACC tumors. Notably, neoadjuvant MI-773 and surgery eliminated tumor recurrences during a post-surgical follow-up of more than 300 days. In contrast, 62.5% of mice that received vehicle control presented with palpable tumor recurrences within this time period (p=0.0097). Conclusions: Collectively, these data demonstrate that therapeutic inhibition of MDM2-p53 interaction by MI-773 decreased the cancer stem cell fraction, sensitized ACC xenograft tumors to Cisplatin, and eliminated tumor recurrence. These results suggest that patients with ACC might benefit from the therapeutic inhibition of the MDM2-p53 interaction.

Friday, August 12, 2016 7:36 AM|Leukemia News -- ScienceDaily|Labels: Bcl-2, leukemia, clinical trial
Patients whose acute myelogenous leukemia (AML) had relapsed or was resistant to chemotherapy and those who were deemed unable to tolerate chemotherapy experienced responses to the selective BCL-2 inhibitor venetoclax (Venclexta), with complete remissions in some, according to phase II clinical trial data.
Thursday, August 11, 2016 8:00 PM|Clinical Trials Corner|Labels: Bcl-2, leukemia
Dr. Abdel-Wahab and Dr. Taylor cover a study that measures the safety of combination ABT-199 and hypomethylating agents in older adults with acute myelogenous leukemia (AML), who are treatment-naive and not eligible for standard induction therapy.
Wednesday, August 3, 2016 8:00 PM|Mark P.A. Luna-Vargas, Jerry Edward Chipuk|Trends in Cell Biology|Labels: Bcl-2
Cellular commitment to the mitochondrial pathway of apoptosis is accomplished when proapoptotic B cell chronic lymphocytic leukemia/lymphoma (BCL)-2 proteins compromise mitochondrial integrity through the process of mitochondrial outer membrane permeabilization (MOMP). For nearly three decades, intensive efforts focused on the identification and interactions of two key proapoptotic BCL-2 proteins: BCL-2 antagonist killer (BAK) and BCL-2-associated X (BAX). Indeed, we now have critical insights into which BCL-2 proteins interact with BAK/BAX to either preserve survival or initiate MOMP.
Thursday, July 28, 2016 6:07 PM|Press Releases | AbbVie Newsroom|Labels: Bcl-2, proteasome, MM, clinical trial

NORTH CHICAGO, Ill., July 28, 2016 /PRNewswire/ -- AbbVie (NYSE: ABBV), a global biopharmaceutical company, today announced the initiation of a Phase 3 clinical trial to study the safety and efficacy of venetoclax in combination with bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma who are considered sensitive or naïve to proteasome inhibitors and have received one to three prior lines of therapy. The combination of venetoclax, bortezomib and dexamethasone will be compared to treatment with bortezomib, dexamethasone and placebo.1 Bortezomib, a proteasome inhibitor, and dexamethasone, a corticosteroid, are both common therapies used to treat symptomatic multiple myeloma.3  

Monday, July 18, 2016 5:00 PM|Cancer|Cancer via MedWorm.com|Comments|Labels: Bcl-2, proteasome, MM, clinical trial
CONCLUSIONSThe current phase 1 study established a dosing schedule for the combination of these agents that demonstrated a favorable safety profile with a low incidence of nonhematologic toxicity and manageable hematologic toxicity. The combination of filanesib, bortezomib, and dexamethasone appears to have durable activity in patients with recurrent/refractory multiple myeloma. Cancer 2016. © 2016 American Cancer Society. (Source: Cancer)
Saturday, July 16, 2016 5:00 PM|Bioorganic and Medicinal Chemistry Letters|Bioorganic and Medicinal Chemistry Letters via MedWorm.com|Comments|Labels: Bcl-2
Authors: Pyta K, Blecha M, Janas A, Klich K, Pecyna P, Gajecka M, Przybylski P Abstract Synthetic limitations in the copper-catalyzed azide alkyne cycloaddition (CuAAC) on gossypol's skeleton functionalized with alkyne (2) or azide (3) groups have been indicated. Modified approach to the synthesis of new gossypol-triazole conjugates yielded new compounds (24-31) being potential fungicides. Spectroscopic studies of triazole conjugates 24-31 have revealed their structures in solution, i.e., the presence of enamine-enamine tautomeric forms and π-π stacking intramolecular interactions between triazole arms. Biological evaluation of the new gossypol-triazole conjugates revealed the potency of 30 and 31 derivatives, having triazole-benzyloxy moieties, comparable with that of miconazole...
Saturday, June 18, 2016 2:05 PM|Davide Rossi|JournalTOCs API - The Lancet Oncology (50 articles)|Labels: Bcl-2, leukemia

Venetoclax: a new weapon to treat high-risk CLL
Davide Rossi
The Lancet Oncology, Vol. 17, No. 6 (2016) pp. 690 - 691
Publication date: June 2016 Source:The Lancet Oncology, Volume 17, Issue 6 Author(s): Davide Rossi

Friday, June 10, 2016 12:57 PM|Raje, N., Faber, E., Richardson, P. G., Schiller, G., Hohl, R. J., Cohen, A. D., Forero, A., Carpenter, S., Nguyen, T. S., Conti, I., Kaiser, C., Cronier, D. M., Wooldridge, J. E., Anderson, K. C.|Clinical Cancer Research Online First Articles|Labels: Bcl-2, proteasome, MM, clinical trial

Purpose: Tabalumab, a human monoclonal antibody that neutralizes B-cell activating factor (BAFF), demonstrated anti-tumor activity in xenograft models of multiple myeloma. Here we report on a phase 1 study of relapsed/refractory multiple myeloma patients in which the primary objective was to identify a tolerable and potentially efficacious dose of tabalumab when combined with bortezomib. Experimental Design: Forty-eight patients were enrolled; 20 to the dose-escalation cohort, and 28 to cohort expansion in which a dose of 100 mg of tabalumab was evaluated. All patients had received either prior bortezomib or an immunomodulatory drug; the median number of prior therapies was 3. Bortezomib was administered intravenously on days 1, 4, 8, and 11 of a 21-day schedule. Tabalumab was given every 21 days for 3 cycles, then every 42 days thereafter. Results: The most common grade 3/4 toxicities included thrombocytopenia, neutropenia, pneumonia and peripheral sensory neuropathy. There were no dose-limiting toxicities, the maximum tolerated dose was not reached. Pharmacokinetic data suggested serum exposure increased in a greater than dose-proportional manner up to a dose of 100 mg. Out of 46 evaluable patients, 20 had confirmed responses. The median time to progression (9 patients censored) was 4.8 months; the median response duration (4 patients censored) was 7.2 months. Conclusions: A dose of 100 mg tabalumab in combination with bortezomib was well tolerated and active and is currently under further investigation.

Thursday, June 9, 2016 3:06 AM|Press Releases | AbbVie Newsroom|Labels: AKT, Bcl-2

COPENHAGEN, Denmark, June 9, 2016 /PRNewswire/ -- AbbVie (NYSE: ABBV), a global biopharmaceutical company, will present data on its investigational medicine venetoclax, a B-cell lymphoma -2 (BCL-2) inhibitor, and duvelisib, an investigational phosphoinositide-3-kinase (PI3K)-delta and PI3K-gamma inhibitor, at the 21st European Hematology Association (EHA) Annual Congress, June 9-12, in Copenhagen, Denmark. Data will be presented in some of the most common hematological malignancies, including chronic lymphocytic leukemia (CLL), multiple myeloma (MM), acute myeloid leukemia (AML) and follicular lymphoma.

Sunday, May 29, 2016 3:00 AM|Seema Patel, Neeta Singh, Lalit Kumar|International Journal of Cancer Therapy and Oncology|Labels: Bcl-2, P53, ovarian cancer, clinical trial

Purpose: Epithelial ovarian cancer is the most common ovarian cancer and has life threatening implications. Despite the progress in surgical and therapeutic strategies, resistance to chemotherapy is still a major concern. Chemotherapeutic agents cause cytotoxicity, primarily by the induction of apoptosis. The status of p53 is a key factor in determining the efficacy of apoptotic signaling. p53 is the most commonly mutated tumor suppressor gene in ovarian cancer. Metformin (an antidiabetic drug) has shown putative effects in many solid tumors. Hence we aimed to study the role of metformin in p53 mutated cancer cells.

Methods: SKOV3 and OAW42 ovarian cancer cell line were used. The cancer cells were treated with metformin. MTT, Flow cytometry and Western blotting were used to characterize the effects of the different treatments.

Results: Metformin treatment leads to cell cycle arrest in the G0/G1, S and G2/M phase of the cell cycle in SKOV3 and OAW42 respectively. Moreover, there was upregulation of Bax and downregulation of Bcl-2 protein and increased apoptosis in SKOV3 and OAW42 ovarian cancer cells.

Conclusion: These findings support the potential of metformin to be used as chemoadjuvant and reflects its ability to sensitize cancer cells to apoptosis independent of p53 status.

Wednesday, May 18, 2016 6:05 AM|Press Releases | AbbVie Newsroom|Labels: Bcl-2

NORTH CHICAGO, Ill., May 18, 2016 /PRNewswire/ -- AbbVie (NYSE: ABBV), a global biopharmaceutical company, will present data from multiple clinical trials evaluating the company's portfolio of approved and investigational oncology medicines during the 52nd Annual Meeting of the American Society of Clinical Oncology (ASCO), June 3-7, in Chicago. Notably, researchers will present data from studies evaluating Venclexta™ (venetoclax), a BCL-2 inhibitor being developed by AbbVie and Genentech, a member of the Roche Group, and IMBRUVICA® (ibrutinib), an inhibitor of Bruton's tyrosine kinase (BTK), across multiple hematologic malignancies.

Saturday, May 14, 2016 5:00 PM|Cancer|Cancer via MedWorm.com|Comments|Labels: Bcl-2, proteasome, MM, clinical trial
CONCLUSIONSDespite inducing a superior time to progression, long‐term follow‐up revealed that PLD‐bortezomib did not improve OS compared with bortezomib alone in patients with relapsed/refractory multiple myeloma. The inability to sustain the early observed survival advantage may have been caused by the effects of subsequent lines of therapy, and underscores the need for long‐term follow‐up of phase 3 trials while recognizing the challenge of having adequate power to detect long‐term differences in OS. Cancer 2016;000:000–000. © 2016 American Cancer Society. (Source: Cancer)
Friday, April 29, 2016 3:48 PM|News-Medical.Net Erlotinib News Feed|Comments|Labels: Bcl-2, proteasome, MM
A gene known as TJP1 (tight junction protein 1) could help determine which multiple myeloma patients would best benefit from proteasome inhibitors such as bortezomib, as well as combination approaches to enhance proteasome inhibitor sensitivity, according to a study led by The University of Texas MD Anderson Cancer Center.
Tuesday, March 22, 2016 10:13 AM|Natural Product Communications|MedWorm: Cancer Therapy|Comments|Labels: Bcl-2, breast cancer
In this study, the anti-breast cancer property of cordycepin and its underlying mechanisms was investigated. The direct effects of cordycepin on breast cancer cells both in in vitro and in vivo experiments were evaluated. Cordycepin exerted cytotoxicity in MCF-7 and MDA-MB-231 cells confirmed by reduced cell viability, inhibition of cell proliferation, enhanced lactate dehydrogenase release and reactive oxygen species accumulation, induced mitochondrial dysfunction and nuclear apoptosis in human breast cancer cells. Cordycepin increased the activation of pro-apoptotic proteins, including caspase-8, caspase-9, caspase-3 and Bax, and suppressed the expression of the anti-apoptotic protein, B-cell lymphoma 2 (Bcl-2). The inhibition on MCF-7-xenografted tumor growth in nude mice further confir...

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Friday, March 18, 2016 6:00 PM|Cancer Chemotherapy and Pharmacology|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: Bcl-2, proteasome, lung cancer, clinical trial
Conclusion The incorporation of bortezomib into the gemcitabine/cisplatin regimen, in the dose and schedule used in this study, could not improve the efficacy of the chemotherapy regimen and has not to be further investigated. (Source: Cancer Chemotherapy and Pharmacology)
Wednesday, March 16, 2016 6:00 PM|Biochemical and Biophysical Research communications|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: Bcl-2, P53, lung cancer
Authors: Matsumoto M, Nakajima W, Seike M, Gemma A, Tanaka N Abstract Cisplatin is a highly effective anticancer drug for treatment of various tumors including non-small-cell lung cancer (NSCLC), and is especially useful in cases nonresponsive to molecular-targeted drugs. Accumulating evidence has shown that cisplatin activates the p53-dependent apoptotic pathway, but it also induces apoptosis in p53-mutated cancer cells. Here we demonstrated that DNA-damage inducible proapoptotic BH3 (Bcl-2 homology region 3)-only Bcl-2 family members, Noxa, Puma, Bim and Bid, are not involved in cisplatin-induced apoptosis in human NSCLC cell lines. In contrast, the expression of proapoptotic multidomain Bcl-2-family members, Bak and Bax, was induced by cisplatin in p53-dependent and -independent...
Sunday, March 13, 2016 7:00 PM|PLoS One|MedWorm: Cancer Therapy|Comments|Labels: Bcl-2, PARP, prostate cancer
Geranylated 4-phenylcoumarins, DMDP-1 & -2 isolated from Mesua elegans were investigated for anticancer potential against human prostate cancer cells. Treatment with DMDP-1 & -2 resulted in cell death in a time and dose dependent manner in an MTT assay on all cancer cell lines tested with the exception of lung adenocarcinoma cells. DMDP-1 showed highest cytotoxic efficacy in PC-3 cells while DMDP-2 was most potent in DU 145 cells. Flow cytometry indicated that both coumarins were successful to induce programmed cell death after 24 h treatment. Elucidation on the mode-of-action via protein arrays and western blotting demonstrated death induced without any significant expressions of caspases, Bcl-2 family proteins and cleaved PARP, thus suggesting the involvement of caspase-independent pathw...
Sunday, February 14, 2016 6:00 PM|Tumor Biology|MedWorm: Cancer Therapy|Comments|Labels: Bcl-2, leukemia
Abstract Obatoclax and ABT-737 belong to a new class of anticancer agents known as BH3-mimetics. These agents antagonize the anti-apoptotic members of Bcl-2 family. The Bcl-2 proteins modulate sensitivity of many types of cancer cells to chemotherapy. Therefore, the objective of the present study was to examine and compare the antileukemic activity of obatoclax and ABT-737 applied alone, and in combination with anticancer agent, mafosfamide and daunorubicin. The in vitro cytotoxic effects of the tested agents on human leukemia cells were determined using the spectrophotometric MTT test, Coulter electrical impedance method, flow cytometry annexin V–fluorescein/propidium iodide assay, and light microscopy technique. The combination index analysis was used to quantify the extent of...
Friday, February 12, 2016 7:08 PM|Journal of Cancer Research and Clinical Oncology|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: Bcl-2, HDAC, proteasome, lung cancer
Conclusion Combining proteasome inhibition with HDAC inhibition enhances ER stress, which may contribute to the synergistic anticancer activity observed in NSCLC cell lines. Further preclinical and clinical studies of CFZ + SAHA in NSCLC are warranted. (Source: Journal of Cancer Research and Clinical Oncology)
Wednesday, February 3, 2016 2:19 PM|Chemical and Pharmaceutical Bulletin|MedWorm: Cancer Therapy|Comments|Labels: Bcl-2, proteasome, regulatory
Authors: Tsukamoto S Abstract Since the approval of the proteasome inhibitor, Velcade(®), by the Food and Drug Administration (FDA) for the treatment of relapsed multiple myeloma, inhibitors of the ubiquitin-proteasome system have been attracting increasing attention as promising drug leads for cancer therapy. While the development of drugs for diseases related to this proteolytic system has mainly been achieved by searching libraries of synthetic small molecules or chemical modifications to drug leads, limited searches have been conducted on natural sources. We have been searching natural sources for inhibitors that target this proteolytic system through in-house screening. Our recent studies on the search for natural inhibitors of the ubiquitin-proteasome system, particularly, i...
Sunday, January 31, 2016 6:00 PM|Tumor Biology|MedWorm: Cancer Therapy|Comments|Labels: Bcl-2, HDAC, TNF, gastric
Abstract Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an ideal apoptosis inducer and believed to have promise in cancer therapy, yet part of cancer cells exhibit resistance to TRAIL-mediated apoptosis. This necessitates the exploration of agents that resensitizes cancer cells to TRAIL. In our study, we found that Trichostatin A (TSA), an histone deacetylase (HDAC) inhibitor, augmented TRAIL-induced apoptosis in gastric cancer cells in a caspase-dependent manner. Besides, upregulation of DR5 and downregulation of anti-apoptotic proteins including XIAP, Mcl-1, Bcl-2 and Survivin also contributed to this synergism. Noticeably, TSA treatment inhibited Forkhead boxM1 (FOXM1), which expression level showed negative correlation with TRAIL sensitivity. Similarly, sil...
Saturday, January 30, 2016 6:00 PM|Cancer Research|MedWorm: Cancer Therapy|Comments|Labels: Bcl-2, Src, prostate cancer
STAT3 offers an attractive target for cancer therapy, but small-molecule inhibitors with appealing pharmacologic properties have been elusive. Here, we report hydroxamic acid–based and benzoic acid–based inhibitors (SH5-07 and SH4-54, respectively) with robust bioactivity. Both inhibitors blocked STAT3 DNA-binding activity in vitro and in human glioma, breast, and prostate cancer cells and in v-Src–transformed murine fibroblasts. STAT3-dependent gene transcription was blocked along with Bcl-2, Bcl-xL, Mcl-1, cyclin D1, c-Myc, and survivin expression. Nuclear magnetic resonance analysis of STAT3-inhibitor complexes defined interactions with the SH2 and DNA-binding domains of STAT3. Ectopic expression of the SH2 domain in cells was sufficient to counter the STAT3-inhibitory effects of ...
Thursday, January 28, 2016 6:00 PM|Nature Reviews Cancer|MedWorm: Cancer Therapy|Comments|Labels: Bcl-2
Nature Reviews Cancer 16, 99 (2016). doi:10.1038/nrc.2015.17 Authors: Alex R. D. Delbridge, Stephanie Grabow, Andreas Strasser & David L. Vaux The 'hallmarks of cancer' are generally accepted as a set of genetic and epigenetic alterations that a normal cell must accrue to transform into a fully malignant cancer. It follows that therapies designed to counter these alterations might be effective as anti-cancer strategies. Over the (Source: Nature Reviews Cancer)

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Saturday, January 16, 2016 11:58 PM|P and T|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: Bcl-2, EGFR, MM, regulatory
Authors: Fellner C Abstract Elotuzumab (Empliciti) and ixazomib (Ninlaro) for some multiple myeloma patients; Fluad (influenza vaccine, adjuvanted) for immunization of persons 65 years of age and older; and osimertinib (Tagrisso) for certain non-small-cell lung cancers. PMID: 26766887 [PubMed] (Source: P and T)
Wednesday, January 13, 2016 10:49 PM|Postepy higieny i medycyny doswiadczalnej|MedWorm: Cancer Therapy|Comments|Labels: Bcl-2, proteasome, clinical trial, regulatory
Proteasomes are multisubunit enzyme complexes. They contain three enzymatic active sites which are termed chymotrypsin-like, trypsin-like, and caspase-like. The elementary function of the proteasomes is degradation of damaged proteins. Proteasome inhibition leads to accumulation of damaged protein, which leads to caspase activation and cell death. This relationship is used in cancer therapy. Bortezomib is the first proteasome inhibitor approved by the US Food and Drug Administration for the treatment of relapsed/refractory multiple myeloma. Carfilzomib belongs to the second generation of drugs, which was approved by the US FDA in 2012. Currently in the study phase there are four new inhibitors: ixazomib (MLN9780/MLN2238), delanzomib (CEP-18770), oprozomib (ONX0912/PR-047) and marizomib (NP...