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10:00 AM|Sumitomo, Y., Koya, J., Nakazaki, K., Kataoka, K., Tsuruta-Kishino, T., Morita, K., Sato, T., Kurokawa, M.|Blood current issue|Labels: AML

Despite advances in the treatment of acute myeloid leukemia (AML), relapse and drug resistance frequently occur. Therefore, detailed mechanisms of refractoriness, including leukemia-initiating cell (LIC) biology, should be elucidated to treat AML. The self-degradative property of cytosolic macromolecules is central to autophagy and can contribute to homeostasis and stress response. Recent reports suggest the importance of autophagy in hematopoietic stem cells and various tumors. Thus, this study investigated the functional role of autophagy in AML maintenance and drug resistance using tamoxifen-inducible conditional knockout mice of Atg5 or Atg7, which are essential genes for autophagy, combined with an mixed lineage leukemia–eleven nineteen leukemia–induced murine AML model. Inactivation of autophagy by deletion of Atg5 or Atg7 prolonged survival in leukemic mice and reduced functional LICs. Atg7-deficient LICs displayed enhanced mitochondrial activity and reactive oxygen species production together with increased cell death. In addition, Atg7 deletion markedly decreased peripheral blood leukemia cells, concurrent with increased apoptosis, suggesting a higher dependency on autophagy compared with bone marrow leukemia cells. Finally, cytarabine (AraC) treatment activated autophagy in LICs, and Atg7 deletion potentiated the therapeutic effects of AraC, which included decreased LICs and prolonged survival, suggesting that autophagy contributes to AraC resistance. Our results highlight the intratumoral heterogeneity related to autophagy in AML and the unique role of autophagy in leukemia development and drug resistance.

CAMBRIDGE, Mass.--(BUSINESS WIRE)--Syros Pharmaceuticals (NASDAQ: SYRS) announced today that the first patient has been dosed in the Phase 2 clinical trial of its lead drug candidate, SY-1425, a first-in-class selective retinoic acid receptor alpha (RARα) agonist, in genomically defined subsets of patients with relapsed or refractory acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS) identified using a novel biomarker discovered by its gene control platform. “This is an im

Wednesday, September 21, 2016 6:00 PM|Anne-Louise Latif, Tessa L. Holyoake|Cell|Labels: AML
Effective differentiation therapy for acute myeloid leukemia (AML) has been restricted to a small subset of patients with one defined genetic abnormality. Using an unbiased small molecule screen, Sykes et al. now identify a mechanism of de-repression of differentiation in several models of AML driven by distinct genetic drivers.
Wednesday, September 21, 2016 3:16 PM|News-Medical.Net Acute myeloid leukemia News Feed|Comments|Labels: AML
A new type of immunotherapy shows promise against cases of acute myeloid leukemia (AML) that recur after treatment or that never respond to therapy in the first place.
Wednesday, September 21, 2016 1:58 PM|Leukemia News -- ScienceDaily|Labels: AML
A promising new approach to the treatment of acute myeloid leukemia (AML) has been discovered by a team of researchers. In their report, the investigators have identified a crucial dysfunction in blood cell development that underlies AML and show that inhibiting the action of a specific enzyme prompts the differentiation of leukemic cells, reducing their number and decreasing their ability to propagate the cancer.
Wednesday, September 21, 2016 12:53 PM|Top Health News -- ScienceDaily|Labels: AML
'Training' immune cells boosts effectiveness in patients with acute myeloid leukemia (AML), report scientists. A small clinical trial provides evidence that the immune system's "natural killer" cells can be dialed up in the laboratory, trained to recall that activation and then effectively unleashed to destroy cancer cells in some patients.
Wednesday, September 21, 2016 11:48 AM|Romee, R., Rosario, M., Berrien-Elliott, M. M., Wagner, J. A., Jewell, B. A., Schappe, T., Leong, J. W., Abdel-Latif, S., Schneider, S. E., Willey, S., Neal, C. C., Yu, L., Oh, S. T., Lee, Y.-S., Mulder, A., Claas, F., Cooper, M. A., Fehniger, T. A.|Science Translational Medicine current issue|Labels: AML, clinical trial, IL

Natural killer (NK) cells are an emerging cellular immunotherapy for patients with acute myeloid leukemia (AML); however, the best approach to maximize NK cell antileukemia potential is unclear. Cytokine-induced memory-like NK cells differentiate after a brief preactivation with interleukin-12 (IL-12), IL-15, and IL-18 and exhibit enhanced responses to cytokine or activating receptor restimulation for weeks to months after preactivation. We hypothesized that memory-like NK cells exhibit enhanced antileukemia functionality. We demonstrated that human memory-like NK cells have enhanced interferon- production and cytotoxicity against leukemia cell lines or primary human AML blasts in vitro. Using mass cytometry, we found that memory-like NK cell functional responses were triggered against primary AML blasts, regardless of killer cell immunoglobulin-like receptor (KIR) to KIR-ligand interactions. In addition, multidimensional analyses identified distinct phenotypes of control and memory-like NK cells from the same individuals. Human memory-like NK cells xenografted into mice substantially reduced AML burden in vivo and improved overall survival. In the context of a first-in-human phase 1 clinical trial, adoptively transferred memory-like NK cells proliferated and expanded in AML patients and demonstrated robust responses against leukemia targets. Clinical responses were observed in five of nine evaluable patients, including four complete remissions. Thus, harnessing cytokine-induced memory-like NK cell responses represents a promising translational immunotherapy approach for patients with AML.

Tuesday, September 20, 2016 12:13 PM|DeRyckere, D., Lee Sherick, A. B., Huey, M. G., Hill, A. A., Tyner, J. W., Jacobsen, K. M., Page, L. S., Kirkpatrick, G. D., Eryildiz, F., Montgomery, S. A., Zhang, W., Wang, X., Frye, S. V., Earp, H. S., Graham, D. K.|Clinical Cancer Research Online First Articles|Labels: AML

Purpose: MerTK tyrosine kinase is ectopically expressed in 30-50% of acute lymphoblastic leukemias (ALL) and over 80% of acute myeloid leukemias (AML) and is a potential therapeutic target. Here, we evaluated the utility of UNC2025, a MerTK tyrosine kinase inhibitor, for treatment of acute leukemia. Experimental Design: Pre-clinical in vitro and in vivo assays using cell lines and primary leukemia patient samples were utilized to evaluate anti-leukemic effect of UNC2025. Results: UNC2025 potently inhibited pro-survival signaling, induced apoptosis and reduced proliferation and colony formation in MerTK-expressing ALL and AML cell lines and patient samples. Approximately 30% of primary leukemia patient samples (78 of 261 total) were sensitive to UNC2025. Sensitive samples were most prevalent in the AML, T-ALL, and minimally differentiated (M0) AML subsets. UNC2025 inhibited MerTK in bone marrow leukemia cells and had significant therapeutic effects in xenograft models, with dose-dependent decreases in tumor burden and consistent two-fold increases in median survival, irrespective of starting disease burden. In a patient-derived AML xenograft model, treatment with UNC2025 induced disease regression. Additionally, UNC2025 increased sensitivity to methotrexate in vivo, suggesting that addition of MerTK-targeted therapy to current cytotoxic regimens may be particularly effective and/or allow for chemotherapy dose reduction. Conclusions: The broad spectrum activity mediated by UNC2025 in leukemia patient samples and xenograft models, alone or in combination with cytotoxic chemotherapy, support continued development of MerTK inhibitors for treatment of leukemia.

Monday, September 19, 2016 6:00 AM|Business Wire Health: Pharmaceutical News|Attachments|Labels: AML, clinical trial
BOTHELL, Wash.--(BUSINESS WIRE)--Seattle Genetics, Inc. (NASDAQ: SGEN) today announced enrollment of the first patient in a multicenter phase 1 clinical trial of SGN-CD123A for patients with relapsed or refractory acute myeloid leukemia (AML). SGN-CD123A is an investigational antibody-drug conjugate (ADC) targeted to CD123 utilizing Seattle Genetics’ proprietary technology, an engineered cysteine antibody (EC-mAb) stably linked to a highly potent DNA binding agent called a pyrrolobenzodiazepine

Friday, September 16, 2016 10:23 AM|Jingrong Xian, Huiyuan Shao, Xianchun Chen, Shuaishuai Zhang, Jing Quan, Qin Zou, Hongjun Jin, Ling Zhang|International Journal of Biological Sciences|Labels: ERK, RAS, AML

Acute myeloid leukemia (AML) with mutated nucleophosmin (NPM1) has been defined as a unique subgroup in the new classification of myeloid neoplasm, and the AML patients with mutated NPM1 frequently present extramedullary infiltration, but how NPM1 mutants regulate this process remains elusive. In this study, we found that overexpression of type A NPM1 gene mutation (NPM1-mA) enhanced the adhesive, migratory and invasive potential in THP-1 AML cells lacking mutated NPM1. NPM1-mA had up-regulated expression and gelatinolytic matrix metalloprotease-2 (MMP-2)/MMP-9 activity, as assessed by real-time PCR, western blotting and gelatin zymography. Following immunoprecipitation analysis to identify the interaction of NPM1-mA with K-Ras, we focused on the effect of NPM1-mA overexpression on the Ras/Mitogen-activated protein kinase (MAPK) signaling axis and showed that NPM1-mA increased the MEK and ERK phosphorylation levels, as evaluated by western blotting. Notably, a specific inhibitor of the ERK/MAPK pathway (PD98059), but not p38/MAPK, JNK/MAPK or PI3-K/AKT inhibitors, markedly decreased the cell invasion numbers in a transwell assay. Further experiments demonstrated that blocking the ERK/MAPK pathway by PD98059 resulted in reduced MMP-2/9 protein levels and MMP-9 activity. Additionally, NPM1-mA overexpression had down-regulated gene expression and protein production of tissue inhibitor of MMP-2 (TIMP-2) in THP-1 cells. Furthermore, evaluation of gene expression data from The Cancer Genome Atlas (TCGA) dataset revealed that MMP-2 was overexpressed in AML patient samples with NPM1 mutated and high MMP-2 expression associated with leukemic skin infiltration. Taken together, our results reveal that NPM1 mutations contribute to the invasive potential of AML cells through MMPs up-regulation via Ras/ERK MAPK signaling pathway activation and offer novel insights into the potential role of NPM1 mutations in leukemogenesis.

Thursday, September 15, 2016 7:51 PM|Rui Zhang, Young-Mi Kim, Xianfu Wang, Yan Li, Xianglan Lu, Andrea R. Sternenberger, Shibo Li, Ji-Yun Lee|International Journal of Medical Sciences|Labels: AML, MDS

The most common chromosomal abnormalities in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are -5/del(5q) and -7/del(7q). When -5/del(5q) and -7/del(7q) coexist in patients, a poor prognosis is typically associated. Given that -5/del(5q) and/or -7/del(7q) often are accompanied with additional recurrent chromosomal alterations, genetic change(s) on the accompanying chromosome(s) other than chromosomes 5 and 7 may be important factor(s) affecting leukemogenesis and disease prognosis. Using an integrated analysis of karyotype, FISH and array CGH results in this study, we evaluated the smallest region of overlap (SRO) of chromosomes 5 and 7 as well as copy number alterations (CNAs) on the other chromosomes. Moreover, the relationship between the CNAs and del(5q) and -7/del(7q) was investigated by categorizing the cases into three groups based on the abnormalities of chromosomes 5 and 7 [group I: cases only with del(5q), group II: cases only with -7/del(7q) and group III: concurrent del(5q) and del(7q) cases]. The overlapping SRO of chromosome 5 from groups I and III was 5q31.1-33.1 and of chromosome 7 from groups II and III was 7q31.31-q36.1. A total of 318 CNAs were observed; ~ 78.3% of them were identified on chromosomes other than chromosomes 5 and 7, which were defined as 'other CNAs'. Group III was a distinctive group carrying the most high number (HN) CNAs, cryptic CNAs and 'other CNAs'. The loss of TP53 was highly associated with del(5q). The loss of ETV6 was specifically associated with group III. These CNAs or genes may play a secondary role in disease progression and should be further evaluated for their clinical significance and influence on therapeutic approaches in patients with MDS/AML carrying del(5q) and/or -7/del(7q) in large-scale, patient population study.

Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: AML, clinical trial
This phase II trial studies the side effects and how well clofarabine works when given together with low-dose total-body irradiation (TBI) in treating patients with acute myeloid leukemia (AML) undergoing donor peripheral blood stem cell transplant (PBSCT). Giving chemotherapy and TBI before a donor PBSCT helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: AML, MDS
This clinical trial studies liposomal cytarabine-daunorubicin CPX-351 in treating patients with untreated myelodysplastic syndrome or acute myeloid leukemia. Drugs used in chemotherapy, such as liposomal cytarabine-daunorubicin CPX-351, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: AML, MDS, clinical trial
This phase I/II trial studies the side effects and best dose of mitoxantrone hydrochloride when given together with filgrastim, cladribine, and cytarabine and to see how well they work in treating patients with acute myeloid leukemia or high-risk myelodysplastic syndromes that is newly diagnosed, has returned, or does not respond to treatment. Drugs used in chemotherapy, such as filgrastim, cladribine, cytarabine, and mitoxantrone hydrochloride, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: AML, 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, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: AML, clinical trial
This first-in-human (FIH) clinical trial is a Phase 1/1b, open-label, sequential-group, dose-escalation and cohort expansion study evaluating the safety, PK, PD, and antitumor activity of FLX925 in subjects with relapsed or refractory AML.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: AML, clinical trial
- The study is a multicenter, open label Phase I/II trial. - The goal of the Phase I part of this study is to find the highest tolerable dose of Lintuzumab-Ac225 that can be given with cytarabine to patients with AML. - The goal of the Phase II part of this study is to learn if Lintuzumab-Ac225 and cytarabine can control AML. The safety of this drug combination will also be studied. - Lintuzumab-Ac225 is designed to deliver radiation therapy directly inside leukemia cells without giving any radiation to the surrounding normal cells - Cytarabine is designed to insert itself into DNA (genetic material) of cancer cells and stop the DNA from repairing itself.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: AML, clinical trial
This study will examine the safety profile of SGN-CD33A by itself (monotherapy) or in combination with other standard treatments. The main purpose of this study is to find the best dose and schedule for SGN-CD33A when given in combination with standard induction treatment, in combination with standard consolidation treatment, or by itself for maintenance treatment. This will be determined by observing the dose-limiting toxicities (the side effects that prevent further increases in dose) of SGN-CD33A. In addition, the pharmacokinetic profile and anti-leukemic activity of the study treatment will be assessed.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: AML, clinical trial
The purpose of this study is to evaluate the efficacy, safety and tolerability of ibrutinib alone or in combination with either cytarabine or azacitidine in the treatment of subjects with Acute Myeloid Leukemia (AML) who have failed standard treatment, or subjects without prior therapy who refuse standard chemotherapy.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: FLT, AML
This pilot study is designed to evaluate the safety and tolerability of oral crenolanib besylate given sequentially during standard induction and consolidation chemotherapy in patients with newly diagnosed AML with FLT3 activating mutations.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: AML, clinical trial
This study will examine the safety and anti-leukemic profile of SGN-CD33A (vadastuximab talirine) in patients with relapsed chemo-resistant AML, who are given vadastuximab talirine in sequence with standard treatments before a planned stem cell transplant, or as maintenance therapy after a stem cell transplant. The main purpose of the study is to find the best dose and determine the anti-leukemic activity of vadastuximab talirine, given either pre- or post-allogeneic stem cell transplant (alloSCT) for adults with relapsed or refractory AML. This will be determined by assessing the safety and tolerability of vadastuximab talirine. In addition, the pharmacokinetic profile and anti-leukemic activity of the study treatment will be assessed.
Wednesday, September 14, 2016 5:40 AM|Akifumi Endo, Daisuke Tomizawa, Yuki Aoki, Tomohiro Morio, Shuki Mizutani, Masatoshi Takagi|Cancer Science|Labels: P53, AML
The Ewing sarcoma breakpoint region 1 (EWSR1) gene is known to fuse with various partner genes to promote the development of the Ewing sarcoma family of tumors and other sarcomas. In contrast, the association of EWSR1 chimeric fusion genes with leukemia has been rarely reported. We identified a novel EWSR1 associated chimeric fusion gene in a patient with acute myeloid leukemia (AML) harboring 46, XY, t (11; 22) (p13; q12) karyotype abnormality. The patient was refractory to intensified chemotherapy including hematopoietic stem cell transplantation. Total RNA paired-end sequencing identified a novel chimeric fusion gene as EWSR1/ELF5, a member of the E26 transformation-specific (ETS) transcription factor family. Transduction of EWSR1/ELF5 to NIH3T3 cells induced transformation by attenuating with the p53/p21-dependent pathway. The injection of EWSR1/ELF5-transduced NIH3T3 cells into NSG-SCID mice systematically induced the development of tumors in vivo. These results revealed the oncogenic potency of EWSR1/ELF5. This article is protected by copyright. All rights reserved.
Thursday, September 1, 2016 10:05 PM|S. Soderquist, R., Eastman, A.|Molecular Cancer Therapeutics current issue|Labels: Bcl-2, AML, CLL

Antiapoptotic BCL2 proteins play a major role in tumor cell survival. Hence, BCL2 inhibitors have been developed as direct inducers of apoptosis. ABT-199 (venetoclax) received breakthrough therapy designation from the FDA due to its apparent efficacy in CLL and AML. However, resistance to ABT-199 is mediated by other BCL2 proteins including BCLXL and MCL1. Considerable effort has been expended seeking novel "BH3 mimetics" that inhibit all of these BCL2 proteins. While many BH3 mimetics inhibit BCL2 proteins in vitro, they fail to directly inhibit them in intact cells. Many BH3 mimetics induce the unfolded protein response culminating in induction of the proapoptotic protein NOXA, which in turn inhibits MCL1. We propose simple experiments to validate BH3 mimetics in cells. A true BCL2 inhibitor will rapidly induce apoptosis in chronic lymphocytic leukemia cells ex vivo. A BCLXL inhibitor will rapidly induce apoptosis in platelets. Finally, a BH3 mimetic targeting MCL1 will inhibit its degradation thereby inducing rapid MCL1 accumulation. Compounds that fail these tests should no longer be called BH3 mimetics. We now have a toolbox of selective inhibitors for most of the BCL2 proteins, and we hope these new tools will lead to effective treatment options for many cancers. Mol Cancer Ther; 15(9); 2011–7. ©2016 AACR.

Monday, August 22, 2016 6:00 PM|Anna Dart|Nature Reviews Cancer - Issue - nature.com science feeds|Labels: AML

Nature Reviews Cancer 16, 551 (2016). doi:10.1038/nrc.2016.94

Author: Anna Dart

Mutations in the genes isocitrate dehydrogenase 1 (IDH1) and tet methylcytosine dioxygenase 2 (TET2) are common drivers in myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML), which has led to the assumption that mutant IDH1 might drive alterations in DNA methylation

Sunday, August 14, 2016 10:05 PM|Farge, T.|Clinical Cancer Research recent issues|Labels: ROS, AML

The major therapeutic barrier in acute myeloid leukemia (AML) is chemotherapy resistance. AML cells resistant to conventional chemotherapy targeting DNA synthesis are thought to be enriched in quiescent leukemic stem cells (LSCs). In order to better understand chemotherapy resistance in AML, we analyzed the response to cytarabine (AraC) through patient-derived xenograft (PDX) models with 20 primary AML patient specimens from two clinical sites and in the context of a French "Innovative models initiative" (IMODI) program. After confirming AML engraftment, highly immunodeficient NOD/LtSz-scid IL2Rc null (NSG) mice were treated with AraC administered IP for 5 days as a single agent at 60 mg/kg daily, which correlates with human dosing. In all mice treated with this regimen, there was a significant but variable cytoreductive effect (4- to 46-fold reduction of tumor cell burden; 2- to 13-fold induction of apoptosis) at 3 days post-treatment. This in vivo AraC response in PDX models has been compared to clinicobiological data of their matched patients (including overall survival, FAB classification, and age at diagnosis). Furthermore, residual leukemic cells (RLCs), surviving after in vivo AraC treatment, have been characterized for their cell surface phenotype, stem cell frequency, cell cycle and metabolic status. Gene expression of RLCs from three different PDX models showed an enrichment of genes involved in inflammatory, immune and stress/ROS responses. When tested in three independent cohorts of AML patients (Verhaak et al. 2009; TGCA. 2011; Metzeler et al. 2011), the down-regulated gene signature is associated with an unfavorable prognosis in patients treated with intensive chemotherapy. Altogether, these results suggest a novel model of AraC chemotherapy resistance uncovering the control of the oxidative and mitochondrial energy metabolism in vivo and the relevance of PDX models for clinical investigations and new preclinical drug assessment. Further studies of the role of immune and stromal microenvironment will be assessed in this model to extend our findings in a more relevant setting.

Citation Format: Thomas Farge{Authors}. Studying cytarabine resistance through PDX models in acute myeloid leukemia. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr B06.

Sunday, August 14, 2016 3:00 PM|Cancer|Cancer via MedWorm.com|Comments|Labels: AML
CONCLUSIONSAltogether, with the exclusion of infants, a significant decrease in the proportion of favorable cytogenetic subtypes and an increase in unfavorable cytogenetics were observed with increasing age. These findings indicate different mechanisms for the pathogenesis of AML; these different mechanisms also suggest directions for etiological research and contribute to the more unfavorable prognosis with increasing age. Cancer 2016. © 2016 American Cancer Society. (Source: Cancer)
Friday, August 12, 2016 12:35 AM|News-Medical.Net Apoptosis News Feed|Comments|Labels: Bcl-2, AML, 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 10:00 PM|EurekAlert! - Cancer Research News|Labels: Bcl-2, AML, clinical trial
(American Association for Cancer Research) 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.
CONCLUSIONSThe type of treatment received did not improve outcomes in younger or older patients with TP53‐mutated AML. These data suggest that novel therapies are needed to improve the outcome of patients with AML who have TP53 mutations. Cancer 2016. © 2016 American Cancer Society. (Source: Cancer)
Thursday, July 14, 2016 10:05 PM|Lai, T.-H., Ewald, B., Zecevic, A., Liu, C., Sulda, M., Papaioannou, D., Garzon, R., Blachly, J. S., Plunkett, W., Sampath, D.|Clinical Cancer Research recent issues|Labels: HDAC, AML

Purpose: The double-strand breaks elicited by sapacitabine, a clinically active nucleoside analogue prodrug, are repaired by RAD51 and the homologous recombination repair (HR) pathway, which could potentially limit its toxicity. We investigated the mechanism by which histone deacetylase (HDAC) inhibitors targeted RAD51 and HR to sensitize acute myelogenous leukemia (AML) cells to sapacitabine.

Experimental Design: Chromatin immunoprecipitation identified the role of HDACs in silencing miR-182 in AML. Immunoblotting, gene expression, overexpression, or inhibition of miR-182 and luciferase assays established that miR-182 directly targeted RAD51. HR reporter assays, apoptotic assays, and colony-forming assays established that the miR-182, as well as the HDAC inhibition–mediated decreases in RAD51 inhibited HR repair and sensitized cells to sapacitabine.

Results: The gene repressors, HDAC1 and HDAC2, became recruited to the promoter of miR-182 to silence its expression in AML. HDAC inhibition induced miR-182 in AML cell lines and primary AML blasts. miR-182 targeted RAD51 protein both in luciferase assays and in AML cells. Overexpression of miR-182, as well as HDAC inhibition–mediated induction of miR-182 were linked to time- and dose-dependent decreases in the levels of RAD51, an inhibition of HR, increased levels of residual damage, and decreased survival after exposure to double-strand damage-inducing agents.

Conclusions: Our findings define the mechanism by which HDAC inhibition induces miR-182 to target RAD51 and highlights a novel pharmacologic strategy that compromises the ability of AML cells to conduct HR, thereby sensitizing AML cells to DNA-damaging agents that activate HR as a repair and potential resistance mechanism. Clin Cancer Res; 22(14); 3537–49. ©2016 AACR.

Friday, July 8, 2016 6:19 AM|Leukemia News -- ScienceDaily|Labels: FLT, AML
Researchers have identified a set of genes, including DNMT3A, that could potentially be used to predict clinical outcomes of patients who suffer from a type of Acute Myeloid Leukemia (AML) associated with an FLT3 internal tandem duplication (FLT3-ITD) mutation.
Thursday, June 30, 2016 1:53 PM|Leukemia News -- ScienceDaily|Labels: telomerase, AML
The chemotherapy treatments necessary to treat Acute Myeloid Leukemia (AML) in children can be grueling on the body, and can cause health-related complications during therapy, as well as long down the road after remission. Children receiving chemotherapy for AML receive 4 to 5 intensive chemotherapy courses, and while some children recover quickly from each course, others may take several months or more, which increases their risk for life-threatening infections.
Wednesday, June 29, 2016 6:00 PM|Hong-Sheng Zhou, Bing Z. Carter, Michael Andreeff|Cancer Biology & Medicine|Labels: WNT, AML, preclinical
Acute myeloid leukemia (AML) is characterized by the accumulation of circulating immature blasts that exhibit uncontrolledgrowth, lack the ability to undergo normal differentiation, and have decreased sensitivity to apoptosis. Accumulating evidenceshows the bone marrow (BM) niche is critical to the maintenance and retention of hematopoietic stem cells (HSC), includingleukemia stem cells (LSC), and an increasing number of studies have demonstrated that crosstalk between LSC and the stromalcells associated with this niche greatly influences leukemia initiation, progression, and response to therapy. Undeniably, stromalcells in the BM niche provide a sanctuary in which LSC can acquire a drug-resistant phenotype and thereby evade chemotherapyinduceddeath. Yin and Yang, the ancient Chinese philosophical concept, vividly portrays the intricate and dynamic interactionsbetween LSC and the BM niche. In fact, LSC-induced microenvironmental reprogramming contributes significantly toleukemogenesis. Thus, identifying the critical signaling pathways involved in these interactions will contribute to targetoptimization and combinatorial drug treatment strategies to overcome acquired drug resistance and prevent relapse followingtherapy. In this review, we describe some of the critical signaling pathways mediating BM niche-LSC interaction, includingSDF1/CXCL12, Wnt/β-catenin, VCAM/VLA-4/NF-κB, CD44, and hypoxia as a newly-recognized physical determinant ofresistance, and outline therapeutic strategies for overcoming these resistance factors.
Wednesday, June 29, 2016 9:30 AM|Ranganathan, P., Kashyap, T., Yu, X., Meng, X., Lai, T.-H., McNeil, B., Bhatnagar, B., Shacham, S., Kauffman, M., Dorrance, A. M., Blum, W., Sampath, D., Landesman, Y., Garzon, R.|Clinical Cancer Research Online First Articles|Labels: AML

Purpose: Selinexor, a selective inhibitor of XPO1, is currently being tested as single agent in clinical trials in acute myeloid leukemia (AML). However, considering the molecular complexity of AML, it is unlikely that AML can be cured with monotherapy. Therefore we asked whether adding already established effective drugs such as Topoisomerase (Topo) II inhibitors to selinexor will enhance its anti-leukemic effects in AML. Experimental Design: The efficacy of combinatorial drug treatment using Topo II inhibitors (Idarubicin, Daunorubicin, Mitoxantrone, Etoposide) and selinexor was evaluated in established cellular and animal models of AML. Results: Concomitant treatment with selinexor and Topo II inhibitors resulted in therapeutic synergy in AML cell lines and patient samples. Using a xenograft MV4-11 AML mouse model, we show that treatment with selinexor and idarubicin significantly prolongs survival of leukemic mice compared to each single therapy. Conclusions: Aberrant nuclear export and cytoplasmic localization of Topo IIα has been identified as one of the mechanisms leading to drug resistance in cancer. Here, we show that in a subset of AML patients that express cytoplasmic Topo IIα, selinexor treatment results in nuclear retention of Topo IIα protein, resulting in increased sensitivity to idarubicin. Selinexor treatment of AML cells resulted in a c-MYC dependent reduction of DNA damage repair genes (Rad51 and Chk1) mRNA and protein expression, and subsequent inhibition of homologous recombination repair and increased sensitivity to Topo II inhibitors. The preclinical data reported here support further clinical studies using selinexor and Topo II inhibitors in combination to treat AML.

CONCLUSIONSThe current data indicate that FLT3 mutation status did not adversely impact overall survival after HCT, and about 50% of patients with this mutation who underwent HCT were long‐term survivors. Cancer 2016. © 2016 American Cancer Society. (Source: Cancer)
Tuesday, May 17, 2016 9:25 AM|Reusch, U., Harrington, K., Gudgeon, C., Fucek, I., Ellwanger, K., Weichel, M., Knackmuss, S., Zhukovsky, E., Fox, J. A., Kunkel, L. A., Guenot, J., Walter, R. B.|Clinical Cancer Research Online First Articles|Labels: AML

Purpose: Randomized studies with gemtuzumab ozogamicin have validated CD33 as a target for antigen-specific immunotherapy of acute myeloid leukemia (AML). Here, we investigated the potential of CD33/CD3-directed tandem diabodies (TandAbs) as novel treatment approach for AML. These tetravalent bispecific antibodies provide two binding sites for each antigen to maintain the avidity of a bivalent antibody and have a molecular weight exceeding the renal clearance threshold, thus offering a longer half-life compared to smaller antibody constructs. Experimental design: We constructed a series of TandAbs comprised of anti-CD33 and anti-CD3 variable domains of diverse binding affinities and profiled their functional properties in CD33+ human leukemia cell lines, xenograft models, and AML patient samples. Results: Our studies demonstrated that several CD33/CD3 TandAbs could induce potent, dose-dependent cytolysis of CD33+ AML cell lines. This effect was modulated by the effector-to-target cell ratio and strictly required the presence of T-cells. Activation and proliferation of T-cells and maximal AML cell cytolysis correlated with high avidity to both CD33 and CD3. High-avidity TandAbs were broadly active in primary specimens from patients with newly diagnosed or relapsed/refractory AML in vitro, with cytotoxic properties independent of CD33 receptor density and cytogenetic risk. Tumor growth delay and inhibition were observed in both prophylactic and established HL-60 xenograft models in immunodeficient mice. Conclusion: Our data show high efficacy of CD33/CD3 TandAbs in various preclinical models of human AML. Together, these findings support further study of CD33/CD3 TandAbs as novel immunotherapeutics for patients with AML.

Wednesday, April 6, 2016 8:30 AM|tpatton@lhwh.com (Taylor Patton)|Cancer|Labels: AML

Medically reviewed by Michael D. Pavy, MD

“Where’s coach?” several players asked. His absence from the regular Monday meeting struck the attendees as more than unusual. It was extraordinary for their NFL head coach to miss this critical weekly team meeting.

Indianapolis Colts Coach Chuck Pagano “skipped” that meeting in 2012 because he was in the hospital being treated for leukemia.

WHAT IS LEUKEMIA?

Leukemia – like all cancers – results from the wrong kind of cells growing in the body.  Unlike normal cells, these cancer cells don’t die, they continue to divide and eventually crowd out the healthy cells.

Instead of creating tumors, leukemia cells generally stay in the blood stream. Although, the unhealthy cancer cells can build up in bone marrow or the brain, as well as the body’s organs that act as filters (liver, spleen).

Myeloid leukemia affects blood and bone marrow cells. Lymphocytic leukemia primarily affects blood, bone marrow and lymph nodes. Either can be acute (harsh, immediate) or chronic (slow growing, long-lasting).  

Acute Myeloid Leukemia (also know as AML) occurs in both adults and children. It’s the most common form of acute leukemia.

Chronic Myeloid Leukemia (CML) mainly affects adults.

Acute Lymphocytic Leukemia (ALL) is most a common among children, although adults can also be diagnosed with it.

Chronic Lymphocytic Leukemia (CLL) almost never strikes children and usually is found in people over 55. It’s the most common form of leukemia.

WHO IS AT RISK

Although researchers believe that smoking, high doses of radiation or exposure to benzene are related, no specific cause has been identified.  People with a family history or children with Down’s syndrome seem to be at risk, as are some patients who received chemotherapy or radiation therapy for other cancers.

LEUKEMIA SYMPTOMS

Coach Pagano didn’t see his doctor until his wife noticed some odd bruising – one of the key symptoms of acute leukemia. Other symptoms of acute leukemia include:

  • Abnormal bleeding,
  • Enlarged lymph nodes in the neck and underarms,
  • A continuing low-grade fever,
  • Aching back, limbs, and stomach area,
  • Fatigue, low energy, and shortness of breath,
  • Pale skin or small red spots under the skin and
  • Vomiting.

The chronic forms of leukemia may not trigger noticeable symptoms.  You may not even be aware of it until the cancer is discovered during a routine physician visit.

LEUKEMIA TREATMENT

Chemotherapy is often the main treatment for most types of leukemia,” says McLeod Oncologist Dr. Michael D. Pavy.  “Radiation therapy is used to prevent leukemia from spreading to the central nervous system or to prepare for a stem cell transplant.

Stem Cell Therapy. Treatment with chemotherapy and radiation can kill healthy cells along with the cancer cells, leaving the patient with a weakened immune system. All cells grow from stem cells. Patients can receive their own stem cells or from a twin or close family member. The healthy stem cells reinforce the immune system, and allow bone marrow recovery from the high dose chemotherapy.

Biological Therapy. Chronic lymphocytic leukemia can be treated by injecting man-made proteins (monoclonal antibodies) that bind to the leukemia cells, helping the body kill them. This is usually used in addition to chemotherapy.

The specific treatments you receive will depend on the type of leukemia, your general health, age and whether the cancer cells are found in your brain or spinal fluid.

Patients, who don’t respond to these traditional therapy can explore clinical trials underway for people with leukemia.

FINAL NOTE

In case you don’t follow the NFL, Coach Pagano is doing well and continues to lead his team. So, leukemia – this cancer of the blood – can be placed in remission.

Have a question for a cancer specialist?  Click here to ask us.

 

Sources include:  McLeod Health, National Institutes of Health, Leukemia & Lymphoma Society, American Society of Clinical Oncology

Wednesday, January 13, 2016 4:00 PM|Cancer Research|MedWorm: Cancer Therapy|Comments|Labels: AML
Acute myeloid leukemia (AML) is a hematologic malignancy with a 5-year survival rate of under 30%. We recently identified the bromodomain and extraterminal (BET) protein Brd4 as a therapeutic target in AML, and several trials are currently evaluating the clinical utility of BET inhibitors for this disease. BET inhibitors displace Brd4 from chromatin and subsequently reduce the expression of key oncogenes, such as Myc, leading to AML blast differentiation and cell death. However, the mechanism by which Brd4 maintains oncogene expression in AML is still unclear. We hypothesized that Brd4 functions by working with other coactivators in AML to promote expression of oncogenes. One such coactivator is the Mediator complex, which is comprised of ~30 subunits and directly contacts RNA Polymerase I...