Oncology Intelligence


BCR-ABL is a constitutively active non-RTK.(1) Bcr-Abl activates a number of cell cycle-controlling proteins and enzymes, speeding up cell division, inhibiting DNA repair, causing genomic instability, and potentially causing blast crisis in CML.(2) BCR-ABL initiates numerous signal transduction pathways that influence the growth and survival of hematopoietic cells and collectively induce leukemic transformation, such as: STAT5, MEK1/2/ERK1/2, and NF-KB. It also activates Ras small GTPase, MAPK, STAT, JNK, PI3K, and c-Myc, through which BCR-ABL promotes survival and proliferation and reduces apoptosis of leukemia cells.(1, 3-5) Because the Abl gene expresses a membrane-associated protein, a TYK, the Bcr-Abl transcript is also translated into a TYK.(2) The fused Bcr-Abl protein interacts with the IL-3 receptor c subunit.(2) Three predominant products are formed depending on which breakpoint located within the BCR gene is fused with exon a2 of ABL. The corresponding fusion protein will encode a p190, p210, or p230 molecular weight protein; each form of the BCR-ABL oncogene is mainly associated with a distinct type of human leukemia: P230 is associated with a very mild form of CML.(6-8)
CML is induced by the BCR-ABL oncogene, a product of the Philadelphia chromosome (Ph).(4) Ph is the result of a reciprocal translocation between chromosome 9 and 22. The presence of this translocation is a highly sensitive test for CML, since 95% of people with CML have this abnormality.(2)
Therapies that target Bcr-Abl in CML, including imatinib, dasatinib, and nilotinib, have dramatically improved patient outcome.(9, 10) Imatinib and sunitinib are important drugs against a variety of other cancers including RCC and GISTs.(2,4)

Marketed Drugs
Generic Code Old Code Brand Company Indication trials
imatinib STI571 CGP57148, CTI571, QTI571, ST571 Gleevec, Glivec, Luckyvec Novartis Mkt: GIST, ALL, CML, dermatofibrosarcoma, MDS, mastocytosis; P3: PC, BC; P2: AML, mesothelioma, GBM, lung, SCLC, melanoma, ovarian, peritoneal, meningioma, uterine, MDS, chordoma, cholangiocellular, HNN, NSCLC, brain, CNS, MM, CRC, solid, NET; P1/2: sarcoma; P1: leukemia trials
nilotinib AMN107    Tasigna Novartis Mkt: CML; P3: GIST, melanoma; P2: ALL; P1: CRC, HNN, chordoma, solid trials
bosutinib PF-05208763 SKI-606
Pfizer Mkt: CML; P2: BC, GBM; P1/2: ALL, pancreatic; P1: solid trials
ponatinib AP24534    Iclusig Ariad Mkt: CML, ALL; P2/3: NSCLC, HNN; P2: GIST, thyroid, HCC, SCLC trials
dasatinib, desatinib BMS-354825 Sprycel BMS Mkt: CML, ALL; P3: PC; P2: pancreatic, BC, CLL, MDS, NSCLC, fallopian, HNN, endometrial, lymphoma, neuroblastoma, GIST, SCLC, melanoma, rhabdomysarcoma; P1/2: GBM, NHL, brain, CNS; P1: CRC, mesothelioma, MM, solid, ovarian, peritoneal trials
Trial Drugs/Indications
Generic Code Old Code Brand Company Indication trials
radotinib     Supect Il-Yang  Mkt (Korea): CML; P3: CML trials
flumatinib     Jiangsu  P3: CML trials
  AstraZeneca P2/3: ovarian, fallopian, peritoneal; P2: osteosarcoma, pancreatic, NSCLC, gastroesophageal, BC, PC, HNN, CRC (terminated), thyroid, bibrosarcoma, leiomyosarcoma; P1: solid trials
bafetinib NS-187 INNO-406   CytRx P2: PC, CLL trials
Astex P2: MM; P1/2: AML; P1: NHL, solid trials
ABL001 Novartis P1: CML, ALL trials
metatinib Jiangsu P1: solid trials
Failed Drugs
Generic Code Old Code Brand Company Indication trials
  XL228     Exelixis terminated; P1: CML, ALL, lymphoma trials
Bcr-abl peptide vaccination noncorporate Last trial started in 1008; P2: leukemia; P1: myeloid trials

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Subscription portal Bcr-Abl therapeutics

1. S. L. Src-family kinases in the development and therapy of Philadelphia chromosome-positive chronic myeloid leukemia and acute lymphoblastic leukemia. Leuk Lymphoma. 2008;49(1):19-26. PMCID: 18203007.

2. Bcr-Abl. [cited]; Available from:

3. Sattler M GJS. Molecular mechanisms of transformation by the BCR-ABL oncogene. Hematol. 2003;40( 2 Suppl 2):4-10. PMCID: 12783368.

4. Chen Y PC, Sullivan C, Li D, Li S. Novel therapeutic agents against cancer stem cells of chronic myeloid leukemia. Anticancer Agents Med Chem. 2010;10(2):111-5. PMCID: 20184539.

5. RA. VE. Mechanisms of transformation by the BCR-ABL oncogene: new perspectives in the post-imatinib era. Leuk Res. 2004;28((Suppl 1)):S21 - S8.

6. Deininger MW GJ, Melo JV. . The molecular biology of chronic myeloid leukemia. Blood. 2000;96(10):3343-56. PMCID: 11071626.

7. Lori A. Hazlehurst P, Nadine N. Bewry, PhD, Rajesh R. Nair, PhD, and Javier Pinilla-Ibarz, MD, PhD. Signaling Networks Associated With BCR-ABL-Dependent Transformation. Cancer Control. 2009:100-7.

8. Pane F FF, Sindona M, Luciano L, Ferrara F, Cimino R, Meloni G, Saglio G, Salvatore F, Rotoli B. Neutrophilic-chronic myeloid leukemia: a distinct disease with a specific molecular marker (BCR/ABL with C3/A2 junction). Blood. 1996;88(7):2410-4. PMCID: 8839830.

9. Andreas Hochhaus PLR, Martin C. Müller, Thomas Ernst, Nicholas C.P. Cross. Impact of BCR-ABL mutations on patients with chronic myeloid leukemia. Cell Cycle. 2011;10(2):250-60.

10. Kim DH ST. Chemical kinomics: a powerful strategy for target deconvolution. BMB Rep. 2010;43(11):711-9. PMCID: 21110913.

11. Goldman TIMaJM. Chronic myeloid leukemia: why does it evolve from chronic phase to blast transformation? Frontiers in Bioscience. 2006;11:198-208.

6:46 AM|INAYAT, F., SAIF, M. W.|Anticancer Research current issue|Labels: Bcr-Abl, GIST

Background: Molecularly targeted therapy has revolutionized the treatment of advanced gastrointestinal stromal tumors (GISTs). Specifically, the consistent dependence of GISTs on proto-oncogene c-KIT signaling led to the development and successful implementation of imatinib, a small-molecule c-KIT inhibitor. Imatinib induces, rapid and sustained clinical benefit by blocking the signaling via c-KIT. The most frequently reported adverse reactions (>30%) include edema, nausea, vomiting, muscle cramps, musculoskeletal pain, diarrhea, rash, fatigue and abdominal pain. Case Series: Herein, we report a case series of cutaneous squamous cell carcinoma (SCC) occurring secondary to imatinib in two patients treated for GISTs. Both patients were successfully managed with surgical resection of SCC and the discontinuation of the drug. Furthermore, we undertook a comprehensive literature review on this association. Few cases of cutaneous SCC secondary to imatinib therapy were reported in patients with chronic myeloid leukemia. However, there was no clinical evidence on causation of imatinib-associated SCC in patients with GIST. Conclusion: To our knowledge, the present report is the first to describe imatinib-related SCC in patients undergoing treatment for GISTs. This implicates that safety and long-term tolerability of imatinib in patients with GISTs warrant rigorous testing and close monitoring.

Thursday, October 27, 2016 12:00 PM|R. H.|JournalTOCs API - Blood (22 articles)|Labels: Bcr-Abl, leukemia

MicroRNA-139-5p regulates proliferation of hematopoietic progenitors and is repressed during BCR-ABL-mediated leukemogenesis
Choi, J Kim, Y.-K, Park, K, Nah, J, Yoon, S.-S, Kim, D.-W, Kim, V. N, Seong, R. H.
Blood, Vol. 128, No. 17 (2016) pp. 2117 - 2129
MicroRNAs (miRNAs) have emerged as important regulators of the immune system. However, despite this prominence, our understanding of the function of miRNAs in the early hematopoietic stages is incomplete. In this study, we found that miR-139-5p negatively regulated the proliferation of hematopoietic stem cells and progenitor cells and that downregulation of miR-139-5p expression was associated with hematopoietic malignancy, such as chronic myeloid leukemia (CML). Knockdown of miR-139-5p resulted in myeloid-biased differentiation with expansion of myeloid progenitor cells. In contrast, miR-139-5p expression inhibited the proliferation of hematopoietic progenitors and resulted in the remission of a CML-like disease that is induced by breakpoint cluster region–Abelson (BCR-ABL) transformation. We also found that Brg1 is a functional target of miR-139-5p and that Brg1 is involved in BCR-ABL–induced leukemogenesis. Thus, our results identify miR-139-5p as a key regulator of cellular proliferation during early hematopoiesis and suggest that it is a potent antileukemic molecule.

Saturday, October 15, 2016 10:21 PM|Current Cancer Drug Targets (Volume 16 - Issue 8)|Labels: Bcr-Abl, INT, leukemia
Chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease characterized by the accumulation/expansion of a clonal population of neoplastic cells with the morphological appearance of small mature B lymphocytes in blood, bone marrow, and lymphoid organs. CD49d, the α chain of the α4β1 integrin heterodimer, is one of the main interactors between CLL cells and accessory cells in the microenvironmental sites and one of the main predictors of overall survival. In particular, CD49d is known to play a pivotal role in mediating both cell-cell and cell-matrix interactions in CLL-involved tissues eventually delivering prosurvival signals and protecting CLL cells from drug-induced damages. Treatment strategies targeting the α4β1 integrin could represent an interesting option in CLL. In this context, the recombinant anti-CD49d antibody natalizumab demonstrated the potential to overcome stromal cell-induced resistance of B cell lymphoma cells against cytotoxic drugs and rituximab in vitro. Moreover, a specific interest for the CD49d molecule raises from the clinical activity of the recently proposed inhibitors of kinases downstream the BCR that has been recently related with the inside-out activation of the α4ÎČ1 integrin. In the review, we addressed in detail the role of CD49d in CLL cells, including clinical impact, relationship with specific cytogenetic features, and CD49d-dependent interactions in lymph node and bone marrow microenvironment responsible for growth- and survival- supporting signals, eventually influencing CLL prognosis and therapeutic options.
Saturday, October 15, 2016 10:21 PM|Current Cancer Drug Targets (Volume 16 - Issue 8)|Labels: Bcr-Abl, leukemia
Various signal transduction pathways have been implicated in the pathogenesis of chronic lymphocytic leukemia (CLL), which is characterized by the progressive accumulation of monoclonal CD5+ B cells in the blood. B cell receptor (BCR) signaling appears to have a crucial role in disease onset and is thought to be induced by self or non-self-antigen recognition leading to chronic stimulation. Several of the kinases functioning downstream of the BCR are aberrantly expressed or constitutively activated in CLL. Yet, these kinases have additional roles, particularly in chemokine receptor signaling, which is essential for homing and survival of CLL cells in lymphoid organs, or in toll-like receptor signaling. Recently, small molecule inhibitors of kinases in the BCR signaling pathway have shown impressive anti-tumor activity in clinical trials. Remarkably, the observed durable responses in CLL patients were accompanied by transient increases in blood lymphocyte numbers, indicating the importance of these kinases in chemokine receptor signaling. In this review, we therefore highlight the role of BCR signaling and the important other associated signal transduction cascades for CLL cells and give an overview of novel agents that target these specific pathways and were shown to be successful for CLL treatment in clinical trials.
Friday, October 14, 2016 4:45 PM|Onclive Articles|Labels: Bcr-Abl, 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 11:01 AM|X.|JournalTOCs API - Journal of Virology (48 articles)|Labels: Bcr-Abl, lymphoma

CD95 Signaling Inhibits B Cell Receptor-Mediated Gammaherpesvirus Replication in Apoptosis-Resistant B Lymphoma Cells [Virus-Cell Interactions]
Tan, L Zhang, C, Dematos, J, Kuang, L, Jung, J. U, Liang, X.
Journal of Virology, Vol. 90, No. 21 (2016) pp. 9782 - 9796
While CD95 is an apoptosis-inducing receptor and has emerged as a potential anticancer therapy target, mounting evidence shows that CD95 is also emerging as a tumor promoter by activating nonapoptotic signaling pathways. Gammaherpesviral infection is closely associated with lymphoproliferative diseases, including B cell lymphomas. The nonapoptotic function of CD95 in gammaherpesvirus-associated lymphomas is largely unknown. Here, we show that stimulation of CD95 agonist antibody drives the majority of sensitive gammaherpesvirus-transformed B cells to undergo caspase-dependent apoptosis and promotes the survival and proliferation of a subpopulation of apoptosis-resistant B cells. Surprisingly, CD95-mediated nonapoptotic signaling induced beta interferon (IFN-β) expression and correlatively inhibited B cell receptor (BCR)-mediated gammaherpesviral replication in the apoptosis-resistant lymphoma cells without influencing BCR signaling. Further analysis showed that IFN-β alone or synergizing with CD95 blocked the activation of lytic switch proteins and the gene expression of gammaherpesviruses. Our findings indicate that, independent of its apoptotic activity, CD95 signaling activity plays an important role in blocking viral replication in apoptosis-resistant, gammaherpesvirus-associated B lymphoma cells, suggesting a novel mechanism that indicates how host CD95 prototype death receptor controls the life cycle of gammaherpesviruses independent of its apoptotic activity. IMPORTANCE Gammaherpesviruses are closely associated with lymphoid malignancies and other cancers. Viral replication and persistence strategies leading to cancer involve the activation of antiapoptotic and proliferation programs, as well as evasion of the host immune response. Here, we provide evidence that the stimulation of CD95 agonist antibody, mimicking one of the major mechanisms of cytotoxic T cell killing, inhibits B cell receptor-mediated gammaherpesviral replication in CD95 apoptosis-resistant lymphoma cells. CD95-induced type I interferon (IFN-β) contributes to the inhibition of gammaherpesviral replication. This finding sheds new light on the CD95 nonapoptotic function and provides a novel mechanism for gammaherpesviruses that helps them to escape host immune surveillance.

Friday, October 14, 2016 3:00 AM|MIT Biotech Group - Essential Biotech RSS Feed|Labels: Bcr-Abl, cost
Ariad Pharmaceuticals Inc. (NASDAQ:ARIA) fell $1.93 (15%) to $11.14 on Friday after Sen. Bernie Sanders (I-Vt.) criticized the company's pricing strategy for leukemia drug Iclusig ponatinib. In a Twitter post, Sanders linked to a media report describing four price hikes in 2016, leading to a cumulative 27% increase in the drug's price this year."Drug corporations' greed is unbelievable," Sanders' tweet read. "Ariad has raised the price of a leukemia drug to almost $199,000 a year."Sales of the pan-BCR-ABL tyrosine kinase inhibitor (TKI) were $112.5 million in 2015. In July, the company reported 1H16 sales of $99 million, up 91% from $51.7 million in 1H15.Since last fall, Turing Pharmaceuticals AG (New York, N.Y.), Valeant Pharmaceuticals International Inc. (TSX:VRX; NYSE:VRX) and Mylan N.V. (NASDAQ:MYL) have also been chastised by politicians for price increases. All three companies have faced congressional hearings to address pricing decisions.
Wednesday, October 12, 2016 3:27 PM| Yanli Jin, Jingfeng Zhou, Fang Xu, Bei Jin, Lijing Cui, Yun Wang, Xin Du, Juan Li, Peng Li, Ruibao Ren, Jingxuan Pan |The Journal of Clinical Investigation -- Current Issue|Labels: Bcr-Abl, WNT, CML
Imatinib-insensitive leukemia stem cells (LSCs) are believed to be responsible for resistance to BCR-ABL tyrosine kinase inhibitors and relapse of chronic myelogenous leukemia (CML). Identifying therapeutic targets to eradicate CML LSCs may be a strategy to cure CML. In the present study, we discovered a positive feedback loop between BCR-ABL and protein arginine methyltransferase 5 (PRMT5) in CML cells. Overexpression of PRMT5 was observed in human CML LSCs. Silencing PRMT5 with shRNA or blocking PRMT5 methyltransferase activity with the small-molecule inhibitor PJ-68 reduced survival, serial replating capacity, and long-term culture-initiating cells (LTC-ICs) in LSCs from CML patients. Further, PRMT5 knockdown or PJ-68 treatment dramatically prolonged survival in a murine model of retroviral BCR-ABL–driven CML and impaired the in vivo self-renewal capacity of transplanted CML LSCs. PJ-68 also inhibited long-term engraftment of human CML CD34+ cells in immunodeficient mice. Moreover, inhibition of PRMT5 abrogated the Wnt/ÎČ-catenin pathway in CML CD34+ cells by depleting dishevelled homolog 3 (DVL3). This study suggests that epigenetic methylation modification on histone protein arginine residues is a regulatory mechanism to control self-renewal of LSCs and indicates that PRMT5 may represent a potential therapeutic target against LSCs.
Wednesday, October 12, 2016 3:26 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: ANG, Bcr-Abl, FGFR, childhood cancer, clinical trial
Although regorafenib was approved for use in patients who had progressive GIST despite imatinib and/or sunitinib on the basis of phase II and phase III data, it has not been examined in a systematic fashion in patients with other forms of sarcoma. Given the activity of sorafenib, sunitinib and pazopanib in soft tissue sarcomas, and evidence of activity of sorafenib in osteogenic sarcoma and possibly Ewing/Ewing-like sarcoma, there is precedent to examine SMOKIs (small molecule oral kinase inhibitors) such as regorafenib in sarcomas other than GIST. It is also recognized that SMOKIs (small molecule oral kinase inhibitors)such as regorafenib, sorafenib, pazopanib, and sunitinib have overlapping panels of kinases that are inhibited simultaneously. While not equivalent, most of these SMOKIs (small molecule oral kinase inhibitors) block vascular endothelial growth factor and platelet derived growth factors receptors (VEGFRs and PDGFRs), speaking to a common mechanism of action of several of these agents.
Wednesday, October 12, 2016 3:26 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: Bcr-Abl, leukemia, clinical trial
The purpose of this study is to fulfill the post-authorization commitment made by Pfizer to the European Medicines Agency in providing additional safety and efficacy data in approximately 150 Philadelphia Chromosome Positive Chronic Myeloid Leukemia patients with high unmet medical need, including 75 Chronic Phase, Accelerated Phase or Blast Phase patients in the fourth or later line treatment setting (i.e., after treatment with at least 3 other Tyrosine Kinase Inhibitors).
Wednesday, October 12, 2016 3:24 PM|Na Xu, Yu-ling Li, Xuan Zhou, Rui Cao, Huan Li, Qi-si Lu, Lin Li, Zi-yuan Lu, Ji-xian Huang, Jing Sun, Qi-fa Liu, Qing-feng Du, Xiao-li Liu|Journal of Cancer (RSS 2.0)|Labels: Bcr-Abl, ALL, leukemia

Deletion of cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) is well known in many hematologic malignancies, but only few reports have investigated this deletion effect on clinical prognosis. This study performed analysis of the CDKN2 deletion in 215 adult B- lineage acute lymphoblastic leukemia (B-ALL) patients, and related cytogenetic prognostic factors (BCR/ABL; E2A/PBXl; TEL/AML1; Mixed Lineage Leukemia (MLL) rearrangement; MYC, Immunoglobulin heavy locus (IGH) translocation). The prevalence of CDKN2 deletions in all study populations was 28.4%. There is no difference between patients with CDKN2 deletion and wild-type patients in sex, age, white blood cells (WBC) count, BM blast percentage, extra infiltration and induction complete remission (CR) rate. Analysis in relapse patients revealed that the distribution of CDKN2 deletion is higher in relapse patients (44.6%) than all patients (28.4%, P=0.006). Deletion of CDKN2 was significantly associated with poor outcomes including decreased overall survival (OS) (P<0.001), lower disease free-survival (DFS) (P<0.001), and increased cumulative incidence of relapse (P=0.002); Also, CDKN2 deletion was strongly associated with IGH translocation (P=0.021); and had an adverse effect on patients with BCR-ABL fusion gene or with MLL rearrangement. Patients with CDKN2 gene deletion benefited from allogenic hematopoietic stem cell transplantation (Allo-HSCT). Deletion of CDKN2 gene was commonly observed through leukemia progression and was poor prognostic marker in long-term outcomes.

Wednesday, October 12, 2016 3:24 PM|Yubing Peng, Qi Chen, Meng Gu, Yanbo Chen, Ming Zhang, Juan Zhou, Hao Wang, Yan Gao, Wenji Li, Zhong Wang, Zhikang Cai|Journal of Cancer (RSS 2.0)|Labels: Bcr-Abl, prostate cancer

Objective: Most prostate cancers originate from the prostatic peripheral zone (PZ). We tested the hypothesis that the stromal cells from PZ and transitional zone (TZ) have differential effects on the ability of tumorigenesis.

Methods: Stromal cells isolated from the PZ and TZ of normal human prostates mixed with DU145 cells subcutaneously injected into athymic nude mice. The volume and weight of tumors was measured and analyzing the ability of purified DU145 cells isolated from the tumors to migrate and proliferate. The expression patterns of stem cell-specific genes of these DU145 cells were examined. The C-Kit inhibitor, imatinib mesylate, was administrated to confirm the effect of stromal cells on the tumorigenesis.

Results: The volume and weight of tumors were significantly higher in mice transplanted with DU145 and stromal cells from PZ. In contrast, the data was significantly lower with DU145 and stromal cells from TZ than DU145 alone. The purified DU145 cells isolated from the tumors with DU145 and stromal cells in PZ had increased ability to migrate and proliferate, and had increased expression of C-Kit. These effects of the stromal cells in the PZ on DU145 cells could be blocked using imatinib mesylate.

Conclusions: Human stromal cells in the PZ promote the in vivo tumorigenesis of DU145 through up-regulating C-Kit; in contrast, the stromal cells in the TZ inhibit it through down-regulating the expression of C-Kit. The model will be useful for understanding the mechanisms by which the prostatic stem cell niche controls the tumorigeneis of prostatic cancer stem cells.

Wednesday, October 12, 2016 3:24 PM|Antonino Grassadonia, Marta Caporale, Nicola Tinari, Marinella Zilli, Michele DeTursi, Teresa Gamucci, Patrizia Vici, Clara Natoli|Journal of Cancer (RSS 2.0)|Labels: Bcr-Abl, EGFR, mTOR, breast cancer, clinical trial

Inhibition of aberrantly activated pathways cross-talking with hormone receptor (HR) improves response to endocrine therapy in patients with HR-positive advanced breast cancer. We performed a Pubmed database systematic review to ascertain the existence of a better clinical response when combining endocrine therapy with targeted agents in the neoadjuvant setting. Preclinical studies or trials evaluating toxicity were excluded.

We found nine phase II trials that fulfilled the research criteria. The endocrine agents used were third generation aromatase inhibitors (AIs), anastrozole, letrozole or exemestane. The investigated targeted agents were inhibitors of tyrosine kinase receptors such as gefitinib, imatinib or trastuzumab/lapatinib, inhibitors of mTOR, such as everolimus, inhibitors of COX-2, such as celecoxib, and inhibitors of angiogenesis, such as bevacizumab. The response rate (RR) observed combining endocrine and targeted agents ranged between 36% and 90%.

Overall the studies failed to show a remarkable advantage in RR in the combination group compared to historical control subjects receiving AIs alone.

Wednesday, October 12, 2016 3:24 PM|Qianxiang Zhou, Yali Chen, Xi Chen, Wennan Zhao, Yuxu Zhong, Ran Wang, Meihua Jin, Yuling Qiu, Dexin Kong|International Journal of Biological Sciences|Labels: Bcr-Abl, leukemia, clinical trial

Chronic myelogenous leukemia (CML) is a malignant hematological disorder mainly caused by the Bcr-Abl tyrosine kinase. While Bcr-Abl inhibitors including Imatinib showed antitumor efficacy on many CML patients, resistance was frequently reported in recent years. Therefore, novel drugs for CML are still expected. ZSTK474 is a specific phosphatidylinositol 3-kinase (PI3K) inhibitor that we identified. In the present study, the efficacy of ZSTK474, alone or in combination with Imatinib, on K562 CML cells as well as on its multidrug resistance counterpart K562/A02 cells, was investigated. ZSTK474 inhibited the cell proliferation with an IC50 of 4.69 μM for K562 and 7.57 μM for K562/A02 cells, respectively. Treatment by ZSTK474 resulted in cell cycle arrest in G1 phase, which might be associated with upregulation of p27, and downregulation of cyclin D1. ZSTK474 also inhibited phosphorylation of Akt and GSK-3β, which might be involved in the effect on the above cell cycle-related proteins. Moreover, combination of ZSTK474 and Imatinib indicated synergistic effect on both cell lines. In conclusion, ZSTK474 exhibited antileukemia activity alone, and showed synergistic effect when combined with Imatinib, on CML K562 cells as well as the multidrug resistant ones, providing a potential therapeutic approach for CML patients.

Wednesday, October 12, 2016 3:23 PM|Lin Li, Na Xu, Jin-fang Zhang, Lu-lu Xu, Xuan Zhou, Bin-tao Huang, Yu-ling Li, Xiao-li Liu|International Journal of Medical Sciences|Labels: Bcr-Abl, leukemia, clinical trial

Introduction: The mechanism of EphB4/ephrinB2 in the resistance of chronic myelogenous leukemia to imatinib keeps unknown.

Methods: The imatinib resistant chronic myelogenous leukemia cell line-K562-R, was established. EphB4 receptor expression was detected in patients and resistant cells. Cell migration and drug sensitivity were tested in the EphB4 knockdown cells and mouse models.

Results: The EphB4 receptor was over-expressed in blast crisis patients compared to chronic phase patients. The level of EphB4 receptor expression was associated with a complete cytogenetic response within 12 months. Enhanced expression of the EphB4 receptor was detected in the K562-R cells. EphB4 knockdown inhibited cell migration ability and restored sensitivity to imatinib in vitro and in vivo. Restored sensitivity to imatinib was observed in K562-R cells, along with increased levels of phospho-EphB4 and decreased phosphorylation levels of RhoA, Rac1, and Cdc42.

Conclusion: Our study illustrates that aberrant activation of EphB4/ephrinB2 may mediate chronic myeloid leukemia resistance involved in cytoskeletal proteins.

Sunday, October 9, 2016 8:00 PM|Phuong-Hien Nguyen, Oleg Fedorchenko, Natascha Rosen, Maximilian Koch, Romy Barthel, Tomasz Winarski, Alexandra Florin, F. Thomas Wunderlich, Nina Reinart, Michael Hallek|Cancer Cell|Labels: Bcr-Abl, CLL
Nguyen et al. show that LYN kinase in the tumor microenvironment is important for CLL progression. Leukemic cell-specific loss of Lyn reduces BCR signaling without affecting leukemic cell expansion. Lyn- or its substrate Btk-deficient mice transplanted with CLL cells have delayed progression and prolonged survival.
Tuesday, October 4, 2016 1:28 PM|Dave Levitan|Chronic Myeloid Leukemia on Cancer Network|Labels: Bcr-Abl, CML
The STIM1 study shows that patients with chronic myeloid leukemia who have undetectable minimal residual disease can safely discontinue imatinib therapy.
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: Bcr-Abl, STAT, CLL

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|Olsson, P. O., Gustafsson, R., in 't Zandt, R., Friman, T., Maccarana, M., Tykesson, E., Oldberg, A., Rubin, K., Kalamajski, S.|Molecular Cancer Therapeutics current issue|Labels: Bcr-Abl

A typical obstacle to cancer therapy is the limited distribution of low molecular weight anticancer drugs within the carcinoma tissue. In experimental carcinoma, imatinib (STI571) increases efficacy of synchronized chemotherapy, reduces tumor interstitial fluid pressure, and increases interstitial fluid volume. STI571 also increases the water-perfusable fraction in metastases from human colorectal adenocarcinomas. Because the mechanism(s) behind these effects have not been fully elucidated, we investigated the hypothesis that STI571 alters specific properties of the stromal extracellular matrix. We analyzed STI571-treated human colorectal KAT-4/HT-29 experimental carcinomas, known to have a well-developed stromal compartment, for solute exchange and glycosaminoglycan content, as well as collagen content, structure, and synthesis. MRI of STI571-treated KAT-4/HT-29 experimental carcinomas showed a significantly increased efficacy in dynamic exchanges of solutes between tumor interstitium and blood. This effect was paralleled by a distinct change of the stromal collagen network architecture, manifested by a decreased average collagen fibril diameter, and increased collagen turnover. The glycosaminoglycan content was unchanged. Furthermore, the apparent effects on the stromal cellular composition were limited to a reduction in an NG2-positive stromal cell population. The current data support the hypothesis that the collagen network architecture influences the dynamic exchanges of solutes between blood and carcinoma tissue. It is conceivable that STI571 reprograms distinct nonvascular stromal cells to produce a looser extracellular matrix, ultimately improving transport characteristics for traditional chemotherapeutic agents. Mol Cancer Ther; 15(10); 2455–64. ©2016 AACR.

Monday, October 3, 2016 12:05 AM|Murone, M., Vaslin Chessex, A., Attinger, A., Ramachandra, R., Shetty, S. J., Daginakatte, G., Sengupta, S., Marappan, S., Dhodheri, S., Rigotti, S., Bachhav, Y., Brienza, S., Traxler, P., Lang, M., Aguet, M., Zoete, V., Michielin, O., Nicholas, C., Johnson, F. M., Ramachandra, M., McAllister, A.|Molecular Cancer Therapeutics current issue|Labels: Bcr-Abl, EGFR, FGFR, Src, STAT

Tumor survival, metastases, chemoresistance, and escape from immune responses have been associated with inappropriate activation of STAT3 and/or STAT5 in various cancers, including solid tumors. Debio 0617B has been developed as a first-in-class kinase inhibitor with a unique profile targeting phospho-STAT3 (pSTAT3) and/or pSTAT5 in tumors through combined inhibition of JAK, SRC, ABL, and class III/V receptor tyrosine kinases (RTK). Debio 0617B showed dose-dependent inhibition of pSTAT3 in STAT3-activated carcinoma cell lines; Debio 0617B also showed potent antiproliferative activity in a panel of cancer cell lines and in patient-derived tumor xenografts tested in an in vitro clonogenic assay. Debio 0617B showed in vivo efficacy by inhibiting tumor growth in several mouse xenograft models. To increase in vivo efficacy and STAT3 inhibition, Debio 0617B was tested in combination with the EGFR inhibitor erlotinib in a non–small cell lung cancer xenograft model. To evaluate the impact of in vivo STAT3 blockade on metastases, Debio 0617B was tested in an orthotopic tumor model. Measurement of primary tumor weight and metastatic counts in lung tissue demonstrated therapeutic efficacy of Debio 0617B in this model. These data show potent activity of Debio 0617B on a broad spectrum of STAT3-driven solid tumors and synergistic activity in combination with EGFR inhibition. Mol Cancer Ther; 15(10); 2334–43. ©2016 AACR.

Monday, October 3, 2016 12:05 AM|Unknown Author|Cancer Discovery current issue|Labels: Bcr-Abl, leukemia

Dual targeting of the ABL and LYN kinases and BCL2 synergizes to promote Ph+ALL cell apoptosis.

Thursday, September 22, 2016 12:00 PM|Pavlasova, G., Borsky, M., Seda, V., Cerna, K., Osickova, J., Doubek, M., Mayer, J., Calogero, R., Trbusek, M., Pospisilova, S., Davids, M. S., Kipps, T. J., Brown, J. R., Mraz, M.|Blood LYMPHOID NEOPLASIA|Labels: Bcr-Abl, CLL

Agents targeting B-cell receptor (BCR) signaling-associated kinases such as Bruton tyrosine kinase (BTK) or phosphatidylinositol 3-kinase can induce mobilization of neoplastic B cells from the lymphoid tissues into the blood, which makes them potentially ideal to combine with anti-CD20 monoclonal antibodies (such as rituximab, obinutuzumab, or ofatumumab) for treatment of B-cell lymphomas and chronic lymphocytic leukemia (CLL). Here we show that interactions between leukemia cells and stromal cells (HS-5) upregulate CD20 on CLL cells and that administering ibrutinib downmodulates CD20 (MS4A1) expression in vivo. We observed that CLL cells that have recently exited the lymph node microenvironment and moved into the peripheral blood (CXCR4dimCD5bright subpopulation) have higher cell surface levels of CD20 than the cells circulating in the bloodstream for a longer time (CXCR4brightCD5dim cells). We found that CD20 is directly upregulated by CXCR4 ligand stromal cell-derived factor 1 (SDF-1α, CXCL12) produced by stromal cells, and BTK-inhibitor ibrutinib and CXCR4-inhibitor plerixafor block SDF-1α–mediated CD20 upregulation. Ibrutinib also downmodulated Mcl1 levels in CLL cells in vivo and in coculture with stromal cells. Overall, our study provides a first detailed mechanistic explanation of CD20 expression regulation in the context of chemokine signaling and microenvironmental interactions, which may have important implications for microenvironment-targeting therapies.

Wednesday, September 14, 2016 5:00 PM|Bioorganic and Medicinal Chemistry Letters|Bioorganic and Medicinal Chemistry Letters via|Comments|Labels: Bcr-Abl
In this study, BCR-ABL protein degradation inducers called SNIPER(ABL) (Specific and Non-genetic inhibitors of apoptosis protein [IAP]-dependent Protein Erasers) were developed. The designed molecules contained two biologically active scaffolds: one was an imatinib derivative that binds to BCL-ABL and the other was a methyl bestatin that binds to cellular IAP 1 (cIAP1). The hybrid molecules, SNIPER(ABL), were expected to recruit BCR-ABL to cIAP1 for removal by proteasomes. In fact, SNIPER(ABL) induced the degradation of BCR-ABL protein and a subsequent reduction in cell growth. Thus, the degradation of BCR-ABL by SNIPER(ABL) is one potential strategy for treating BCR-ABL driven chronic myelogenous leukemia. PMID: 27666635 [PubMed - as supplied by publisher] (Source: Bioorganic and Medi...
Wednesday, September 7, 2016 9:03 AM|Mato, A. R., Nabhan, C., Barr, P. M., Ujjani, C. S., Hill, B. T., Lamanna, N., Skarbnik, A. P., Howlett, C., Pu, J. J., Sehgal, A. R., Strelec, L. E., Vandegrift, A., Fitzpatrick, D. M., Zent, C. S., Feldman, T., Goy, A., Claxton, D. F., Bachow, S. H., Kaur, G., Svoboda, J., Nasta, S. D., Porter, D., Landsburg, D. J., Schuster, S. J., Cheson, B. D., Kiselev, P., Evens, A. M.|BLOOD First Edition Papers|Labels: Bcr-Abl, CLL, leukemia

B Cell receptor (BCR) kinase inhibitor (KI) therapy represents a paradigm shift in Chronic Lymphocytic Leukemia (CLL) management, but data on practice patterns after KI discontinuation and optimal sequencing are limited. We conducted a multicenter, retrospective, comprehensive analysis on 178 CLL patients (ibrutinib=143; idelalisib=35) who discontinued KI therapy. We examined responses, toxicity, post-KI therapies, and overall survival (OS). Patients had a median of 3 prior therapies (range 0-11); del17p (34%), p53 mutation (27%), del11q (33%), and complex karyotype (29%). Overall response rate (ORR) to first KI was 62% (complete response (CR) 14%). The most common reasons for KI discontinuation were toxicity (51%), CLL progression (29%), and Richter's transformation (RT) (8%). Median progression free survival (PFS) and OS from KI initiation were 10.5 and 29 months, respectively. Notably, initial KI choice did not impact PFS or OS, however, RT portended significantly inferior OS (P=0.0007). 114 patients received subsequent salvage therapy following KI discontinuation with an ORR to subsequent KI at 50% and a median PFS of 11.9 months. Median PFS in KI intolerant patients treated with an alternate KI was not reached (NR) versus 7 months for patients with CLL progression. In summary, these data demonstrate that toxicity was the most common reason for KI discontinuation, and that patients who discontinue KI due to toxicity can respond to an alternate KI, and these responses may be durable.

Sunday, September 4, 2016 8:00 PM|Chiara Castelli|JournalTOCs API - Journal of Investigative Dermatology (875 articles)|Labels: Bcr-Abl, sarcoma

Adaptive immunity in fibrosarcomatous dermatofibrosarcoma protuberans and response to imatinib treatment
Marcella Tazzari Valentina Indio, Barbara Vergani, Loris De Cecco, Francesca Rini, Tiziana Negri, Chiara Camisaschi, Marco Fiore, Silvia Stacchiotti, G.Paolo Dagrada, Paolo G. Casali, Alessandro Gronchi, Annalisa Astolfi, Maria A. Pantaleo, Antonello Villa, Claudia Lombardo, Flavio Arienti, Silvana Pilotti, Licia Rivoltini, Chiara Castelli
Journal of Investigative Dermatology, Vol. , No. (2016) pp. -
Dermatofibrosarcoma protuberans (DFSP), although rare, is the most frequent skin sarcoma. Here, we focus on DFSP carrying the fibrosarcomatous transformation (FS-DFSP). FS-DFSP responds to imatinib (IM); however, tumor relapse often occurs. In a series of 21 pre- and post-treatment FS-DFSP samples, the present study explored the events that occur at the tumor site during IM therapy. Gene expression profile (GEP) and immunohistochemistry (IHC) analyses documented the occurrence of IM-induced senescence phenotype in the tumor cells and showed the accumulation of activated CD3+ T cells and CD163+CD14+ myeloid cells expressing the CD209 marker in post-therapy lesions.

Thursday, September 1, 2016 12:05 AM|Hung, A. C., Lo, S., Hou, M.-F., Lee, Y.-C., Tsai, C.-H., Chen, Y.-Y., Liu, W., Su, Y.-H., Lo, Y.-H., Wang, C.-H., Wu, S.-C., Hsieh, Y.-C., Hu, S. C.-S., Tai, M.-H., Wang, Y.-M., Yuan, S.-S. F.|Clinical Cancer Research recent issues|Labels: Bcr-Abl, breast cancer

Purpose: Visfatin is an adipocytokine involved in cellular metabolism, inflammation, and cancer. This study investigated the roles of extracellular visfatin in breast cancer, and explored underlying mechanisms in clinical and experimental settings.

Experimental Design: Associations of serum visfatin with clinicopathologic characteristics and patient survival were assessed with Cox regression models and Kaplan–Meier analyses. Effects of extracellular visfatin on cultured breast cancer cells were examined, followed by in vivo investigation of tumor growth and metastasis in xenograft animal models. Imatinib and Stattic were used to inhibit c-Abl and STAT3 activation, respectively.

Results: Breast cancer patients with high serum visfatin levels were associated with advanced tumor stage, increased tumor size and lymph node metastasis, and poor survival. Elevated phosphorylation of c-Abl and STAT3 in breast tumor tissues were correlated with high serum visfatin levels in patients. Visfatin-promoted in vitro cell viability and metastatic capability were suppressed by imatinib (c-Abl inhibitor) and Stattic (STAT3 inhibitor). Increased in vivo cell invasiveness was observed in zebrafish xenografted with visfatin-pretreated breast cancer cells. Tumor growth and lung metastasis occurred in visfatin-administered mice xenografted with breast cancer cells. Tail vein–injected mice with visfatin-pretreated breast cancer cells showed increased lung metastasis, which was suppressed by imatinib.

Conclusions: Serum visfatin levels in breast cancer patients reveal potential prognostic values, and our findings that visfatin promoted breast cancer through activation of c-Abl and STAT3 may provide an important molecular basis for future design of targeted therapies that take into account different serum visfatin levels in breast cancer. Clin Cancer Res; 22(17); 4478–90. ©2016 AACR.

Thursday, September 1, 2016 12:05 AM|Wang, Y., Dehigaspitiya, D. C., Levine, P. M., Profit, A. A., Haugbro, M., Imberg-Kazdan, K., Logan, S. K., Kirshenbaum, K., Garabedian, M. J.|Cancer Research recent issues|Labels: Bcr-Abl, prostate cancer
Development of resistance to antiandrogens for treating advanced prostate cancer is a growing concern and extends to recently developed therapeutics, including enzalutamide. Therefore, new strategies to block androgen receptor (AR) function in prostate cancer are required. Here, we report the characterization of a multivalent conjugate presenting two bioactive ethisterone ligands arrayed as spatially defined pendant groups on a peptoid oligomer. The conjugate, named Multivalent Peptoid Conjugate 6 (MPC6), suppressed the proliferation of multiple AR-expressing prostate cancer cell lines including those that failed to respond to enzalutamide and ARN509. The structure–activity relationships of MPC6 variants were evaluated, revealing that increased spacing between ethisterone moieties and changes in peptoid topology eliminated its antiproliferative effect, suggesting that both ethisterone ligand presentation and scaffold characteristics contribute to MPC6 activity. Mechanistically, MPC6 blocked AR coactivator–peptide interaction and prevented AR intermolecular interactions. Protease sensitivity assays suggested that the MPC6-bound AR induced a receptor conformation distinct from that of dihydrotestosterone- or enzalutamide-bound AR. Pharmacologic studies revealed that MPC6 was metabolically stable and displayed a low plasma clearance rate. Notably, MPC6 treatment reduced tumor growth and decreased Ki67 and AR expression in mouse xenograft models of enzalutamide-resistant LNCaP-abl cells. Thus, MPC6 represents a new class of compounds with the potential to combat treatment-resistant prostate cancer. Cancer Res; 76(17); 5124–32. ©2016 AACR.
Wednesday, August 17, 2016 3:13 PM|Amin, N., Balasubramanian, S., Saiya-Cork, K., Shedden, K., Hu, N., Malek, S.|Clinical Cancer Research Online First Articles|Labels: Bcr-Abl, CLL

Purpose: Ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, is approved for the treatment of relapsed CLL and CLL with del17p. Mechanistically, ibrutinib interferes with BCR signaling as well as multiple CLL cell to microenvironment interactions. Given the importance of ibrutinib in the management of CLL, a deeper understanding of factors governing sensitivity and resistance is warranted. Experimental Design: We studied 48 longitudinally sampled paired CLL samples, 42 of which were procured before and after standard CLL chemotherapies, and characterized them for well-studied CLL molecular traits as well as by whole exome sequencing and SNP 6.0 array profiling. We exposed these samples to 0.25 µM - 5 µM of ibrutinib ex vivo and measured apoptosis fractions as well as BCR signaling by immunoblotting. We disrupted TP53 in HG3, PGA1 and PG-EBV cell lines and measured BCR signaling and ibrutinib responses. Results: CLL samples demonstrated a surprisingly wide range of ex vivo sensitivities to ibrutinib with IC50 values ranging from 0.4 µM - 9.7 µM. Unmutated IGVH status, elevated ZAP70 expression and trisomy 12 were associated with heightened sensitivity to ibrutinib treatment. Five CLL samples were substantially more resistant to ibrutinib following relapse from chemotherapy; of these, three had acquired a del17p/TP53 mutated status. A validation sample of 15 CLL carrying TP53 mutations, of which 13 carried both del17p and a TP53 mutation confirmed substantially less sensitivity to ibrutinib-induced apoptosis. Conclusions: This study identifies that CLL harboring del17p/TP53 mutated cells are substantially less sensitive to ibrutinib-induced apoptosis than del17p/TP53 wild type cells.

Monday, August 15, 2016 3:37 PM|Dave Levitan|Chronic Myeloid Leukemia on Cancer Network|Labels: Bcr-Abl, leukemia, clinical trial
A propensity score–matched comparison of two phase II trials found that dasatinib and nilotinib offer similar responses and outcomes as first-line therapy for patients with chronic-phase CML.
Tuesday, August 9, 2016 5:00 PM|Cancer|Cancer via|Comments|Labels: Bcr-Abl, leukemia, clinical trial
CONCLUSIONSIn a PS‐matched cohort of patients with newly diagnosed CML‐CP, dasatinib and nilotinib offer similar response and survival outcomes. Both drugs can be considered reasonable standard‐of‐care options as first‐line therapy for patients with CML‐CP. Cancer 2016. © 2016 American Cancer Society. (Source: Cancer)
Monday, August 1, 2016 12:05 AM|Browning, R. L., Byrd, W. H., Gupta, N., Jones, J., Mo, X., Hertlein, E., Yu, L., Muthusamy, N., Byrd, J. C.|Cancer Immunology Research recent issues|Labels: Bcr-Abl, CLL

The immunomodulatory drug lenalidomide has demonstrated efficacy in patients with chronic lymphocytic leukemia (CLL), despite a lack of direct cytotoxic effects in vitro. The mechanism of lenalidomide efficacy in vivo is thought to occur via a combination of enhanced immune activity and an alteration of tumor cell–microenvironment interactions. We demonstrate in whole blood from patients with CLL that lenalidomide significantly depletes malignant B cells. Lenalidomide also induced production of interleukin-21 (IL21) and its mRNA in T cells from patients with CLL. In addition, lenalidomide enhanced upregulation of functional IL21 receptor (IL21R) on the cell surface and increased receptor mRNA in vitro. The in vitro combination of IL21 and lenalidomide enhanced IL21-mediated cytotoxicity toward CLL cells through a variety of mechanisms. We show association of cell death with upregulation of Bid by IL21, enhanced upregulation of Bid by the combination therapy, and diminished Lck and downstream BCR signaling activation of Syk and PLCG2. Collectively, we demonstrated an immune cell–tumor cell interaction through lenalidomide-mediated induction of IL21 and IL21R, with enhanced IL21-mediated cytotoxicity, which provides justification for this combination in clinical trials for patients with CLL. Cancer Immunol Res; 4(8); 698–707. ©2016 AACR.

Thursday, July 28, 2016 10:48 AM|Seifert, A. M., Zeng, S., Zhang, J. Q., Kim, T. S., Cohen, N. A., Beckman, M. J., Medina, B. D., Maltbaek, J. H., Loo, J. K., Crawley, M. H., Rossi, F., Besmer, P., Antonescu, C. R., DeMatteo, R. P.|Clinical Cancer Research Online First Articles|Labels: Bcr-Abl, PD-1/PD-L1, GIST

Purpose: Tyrosine kinase inhibitors are effective in gastrointestinal stromal tumor (GIST), but often are of transient benefit as resistance commonly develops. Immunotherapy, particularly blockade of the inhibitory receptor programmed death 1 (PD-1) or the ligand programmed death ligand 1 (PD-L1), has shown effectiveness in a variety of cancers. The functional effects of PD-1/PD-L1 blockade are unknown in GIST. Experimental Design: We analyzed tumor and matched blood samples from 85 patients with GIST and determined the expression of immune checkpoint molecules using flow cytometry. We investigated the combination of imatinib with PD-1/PD-L1 blockade in KitV558/+ mice that develop GIST. Results: The inhibitory receptors PD-1, lymphocyte activation gene 3 (LAG-3), and T cell immunoglobulin mucin-3 (TIM-3) were upregulated on tumor-infiltrating T cells compared to T cells from matched blood. PD-1 expression on T cells was highest in imatinib-treated human GISTs. Meanwhile, intratumoral PD-L1 expression was variable. In human GIST cell lines, treatment with imatinib abrogated the IFN--induced upregulation of PD-L1 via STAT1 inhibition. In KitV558/+ mice imatinib downregulated IFN--related genes and reduced PD-L1 expression on tumor cells. PD-1 and PD-L1 blockade in vivo each had no efficacy alone, but enhanced the antitumor effects of imatinib by increasing T cell effector function in the presence of KIT and IDO inhibition. Conclusions: PD-1/PD-L1 blockade is a promising strategy to improve the effects of targeted therapy in GIST. Collectively, our results provide the rationale to combine these agents in human GIST.

Friday, July 1, 2016 9:56 AM|Zook, P., Pathak, H. B., Belinsky, M., Gersz, L., Devarajan, K., Zhou, Y., Godwin, A. K., von Mehren, M., Rink, L. A.|Clinical Cancer Research Online First Articles|Labels: Bcr-Abl, GIST

Purpose: Gastrointestinal stromal tumors (GIST) generally harbor activating mutations in the receptor tyrosine kinase KIT or in the related platelet derived growth factor receptor alpha (PDGFRA). GIST treated with imatinib mesylate (IM) or second-line therapies that target mutant forms of these receptors generally escape disease control and progress over time. Inhibiting additional molecular targets may provide more substantial disease control. Recent studies have implicated the PI3-kinase/AKT pathway in the survival of IM-resistant GIST cell lines and tumors. Experimental Design: Here, we performed in vitro and in vivo studies evaluating the novel combination of IM with the AKT inhibitor MK-2206 in GIST. Whole-transcriptome sequencing (WTS) of xenografts was performed to explore the molecular aspects of tumor response to this novel combination and to potentially identify additional therapeutic targets in GIST. Results: This drug combination demonstrated significant synergistic effects in a panel of IM-sensitive and -resistant GIST cell lines. Furthermore, combination therapy provided significantly greater efficacy, as measured by tumor response and animal survival, in IM-sensitive GIST xenografts as compared to treatment with IM or MK-2206 alone. WTS implicated two neural genes, brain expressed X-linked 1 (BEX1) and neuronal pentraxin I (NPTX1), whose expression was significantly up-regulated in combination-treated tumors compared to tumors treated with the two monotherapies. Conclusion: These studies provide strong preclinical justification for combining IM with an AKT inhibitor as a front-line therapy in GIST. In addition, the WTS implicated the BCL-2/BAX/BAD apoptotic pathway as a potential mechanism for this enhanced combination effect.

Thursday, June 16, 2016 1:19 PM|Dave Levitan|Chronic Myeloid Leukemia on Cancer Network|Labels: Bcr-Abl, CML
Two studies show that early deep responses with TKIs yield lasting positive outcomes in CML patients, and that dasatinib outperforms imatinib.
Tuesday, May 31, 2016 3:00 AM|Koji Fukuda, Kazuhiro Shimazu, Taichi Yoshida, Masahiro Inoue, Masatomo Miura, Hiroyuki Shibata|International Journal of Cancer Therapy and Oncology|Labels: Bcr-Abl, GIST

Many molecular target agents are continuously administered at fixed dosages. Imatinib, which can control the growth of a gastrointestinal stromal tumor, is administrated at 400 mg/day. However, many patients cannot continue treatment because of adverse events, such as neutropenia. To obtain the best therapeutic response while maintaining quality of life, individualization should be considered. Study participants were gastrointestinal stromal tumor patients who required treatment with imatinib. Therapeutic drug monitoring was conducted using high-performance liquid chromatography. In our study, the trough (lowest) concentration that a drug reaches before the next dose is administered differed among patients. The grades of adverse events also differed individually. Moreover, the dosage that was necessary to shrink gastrointestinal stromal tumor differed in cases by cases. Dosage was modified according to the balance between blood concentration and therapeutic responses in order to minimize adverse events for individual patients, and to maximize the effect as the responses differed among patients. It was shown that based on therapeutic drug monitoring, individualization enabled the patients who may not normally continue the typical treatment to tolerate imatinib. According to the therapeutic drug monitoring, individualization of dosage of imatinib could improve the patients’ outcomes in both ends, therapeutic and adeverse responses.  

Monday, May 23, 2016 4:00 PM|Dave Levitan|Chronic Myeloid Leukemia on Cancer Network|Labels: Bcr-Abl, CML
A 5-year analysis of the DASISION trial showed that dasatinib continued to offer better responses than imatinib in patients with chronic myeloid leukemia.
Wednesday, May 18, 2016 5:15 PM|News-Medical.Net Chronic myeloid leukaemia News Feed|Comments|Labels: Bcr-Abl, leukemia, clinical trial
The primary endpoint of major molecular response at 12 months for ponatinib versus imatinib in patients with newly diagnosed chronic phase-chronic myeloid leukaemia remains undetermined, report the EPIC trial investigators.
Friday, April 22, 2016 11:00 AM|Dave Levitan|Chronic Myeloid Leukemia on Cancer Network|Labels: Bcr-Abl, leukemia, clinical trial
The efficacy of ponatinib in patients with newly diagnosed CML compared with imatinib remains to be established, as a randomized phase III trial was terminated early due to concerns regarding arterial occlusive events with ponatinib.
Thursday, April 21, 2016 5:15 PM|News-Medical.Net Chronic myeloid leukaemia News Feed|Comments|Labels: Bcr-Abl, CML
Calculating halving time of the BCR-ABL transcript after 3 months may help determine prognosis in chronic myeloid leukaemia patients undergoing first-line tyrosine kinase inhibitor therapy, say researchers.
Friday, April 15, 2016 6:00 AM|Dave Levitan|Chronic Myeloid Leukemia on Cancer Network|Labels: Bcr-Abl, leukemia
A rapid reduction in BCR-ABL transcript levels and the halving time of those levels are predictive of better outcomes in patients with chronic myeloid leukemia.
Tuesday, March 29, 2016 12:57 PM|Dave Levitan|Chronic Myeloid Leukemia on Cancer Network|Labels: Bcr-Abl, leukemia
Patients with CML who are treated with dasatinib commonly experience lymphocytosis, and the condition is associated with higher response rates and increased survival in patients who are refractory or intolerant of imatinib.
Friday, September 12, 2014 8:00 PM|Department of Clinical Science|Labels: Bcr-Abl, CML, clinical trial
Dasatinib induces fast and deep responses in newly diagnosed chronic myeloid leukaemia patients in chronic phase: Clinical results from a randomised phase-2 study (NordCML006) Hjorth-Hansen, Henrik; Stenke, Leif; Söderlund, Stina; Dreimane, Arta; Ehrencrona, Hans; Gedde-Dahl, Thobias; Gjertsen, BjÞrn Tore; Höglund, Martin; Koskenvesa, Perttu; Lotfi, Kourosh; Majeed, Mohammed Waleed; MarkevÀrn, Berit; Ohm, Lotta; Olsson-Strömberg, Ulla; Remes, Kari; Suominen, Merja; Simonsson, Bengt; Porkka, Kimmo; Mustjoki, Satu; Richter, Johan Journal article We randomised 46 newly diagnosed patients with chronic myeloid leukaemia (median age 56) to receive dasatinib 100 mg QD or imatinib 400 mg QD and report outcome as an intention-to-treat analysis with 36 months follow-up. Early cytogenetic and molecular responses were superior in the dasatinib group, with a tendency that imatinib patients caught up with time. For instance, MR3.0 was reached at 3 months in 36% vs. 8% (P = 0.02), at 12 months in 81% vs. 46% (P = 0.02) and at 18 months in 73% vs. 65% (n.s.) of the patients in the two groups. In contrast, MR4.5 was consistently superior in the dasatinib group at all time points from 6 months onwards, reaching 61% vs. 21% (P < 0.05) at 36 months. Sixty-four vs. 71% of the patients in the dasatinib and imatinib arms, respectively, remained on assigned drug. Dasatinib dose was frequently reduced, but with maintained excellent effect. One imatinib patient progressed to blastic phase, but no CML-related deaths occurred. In conclusion, our data compare favourably with those of the dasatinib registration study, DASISION. The fast and deep molecular responses induced by dasatinib compared with imatinib may be exploited to increase the proportion of patients who can achieve a treatment-free remission after treatment discontinuation.