We are interested in the molecular basis of cell death and proliferation control during the genotoxic stress response. Our laboratory is primarily using two human tumor models: (i) Chronic lymphocytic leukemia (CLL) for leukemia, and (ii) prostate cancer, for epithelial tumors. For leukemia, we seek to understand therapeutic resistance and how the BCL-2 family and autophagy regulation contributes to it. Overcoming such resistance with rational, targeted approaches, is a desired outcome for translation of these findings into clinical setting. Specifically: 1) We study the role of BCL-xL and MCL-1 in resistance to and sensitization to BCL-2 homology domain 3 (BH3) mimetics, 2) We study autophagy as a mechanism of resistance, and 3) We seek to lay the foundations for optimizing the use of BCL-2 targeting agents by integrating gene expression data obtained from cell lines with that from patients treated in the clinic or ex vivo. Understanding the critical BCL-2 family protein associations according to differing cell sensitivities will allow development of molecular and pharmacologic approaches for their effective targeting. By characterizing apoptotic and autophagy pathways in lymphoid malignancies, we seek to ultimately use them to predict response and thus personalize the selection of targeted therapeutic agents. For prostate, we are pursuing in addition to similar studies in autophagy also how it impact on repair of DNA damage, and ultimately to the outcome of radiotherapy. We seek to understand the DNA damage signals incurred by mammalian cells following ionizing radiation (IR). We are interested in IR-regulated genes, with a focus on those that have an important role in cell cycle checkpoints, cell proliferation, apoptosis (Bcl-2 family), and autophagy (ATG family, Beclin, mTOR). A third project focuses on a tumor-specific cell death ligand, Apo2L/TRAIL and its role in apoptosis, autophagy and potential for cancer therapy.
One area of focus has been to determine the molecular basis of cell death and proliferation control during the genotoxic stress response, such as encountered during chemotherapy or radiotherapy (RT) in leukemia and prostate cancer. We have been examining the DNA damage signals incurred by mammalian cells following RT. We are interested in IR-regulated genes, with a focus on those that have an important role in apoptosis, autophagy, checkpoints, and cell cycle control. Another area of interest has been the understanding of how the three fundamental cellular responses to RT: cell cycle control, DNA repair, and cell death, are integrated.
Al-harbi S, Choudhary GS, Sabith J, Vivekananthan N, Hill BT, Radivoyevitch T, Smith MR, Ting A, Shukla G, Almasan A. Mir-377-dependent Bcl-xL regulation drives chemo-therapeutic resistance in B-cell lymphoid malignancies. Mol Cancer, 2015, 14:185. (PMID: 26537004).
Chatterjee P, Choudhary GS, Alswillah T, Xiong X, Heston WD, Magi-Galuzzi C, Zhang J, Klein EA, Almasan A. The TMPRSS2-ERG gene fusion blocks XRCC4-mediated non-homologous end joining repair and radiosensitizes prostate cancer cells to PARP inhibition. Mol Cancer Ther, 2015, 14:1896-1906. (PMID: 26026052)
Choudhary GS, Tat T, Misra S, Hill BT, Smith MR, *Almasan A, *Mazumder S. Cyclin E/Cdk2-dependent phosphorylation of Mcl-1 determines its stability and cellular sensitivity to BH3 mimetics. Oncotarget, 2015, 6:16912-16925. (PMID: 26219338; Priority Research Paper). *corresponding authors.
Choudhary GS, Al-Harbi S, Mazumder S, Hill BT, Smith MR, Bodo J, Hsi ED, Almasan A. MCL-1 and BCL-xL-dependent resistance to the BCL-2 inhibitor ABT-199 can be overcome by preventing PI3K/AKT/ mTORC activation in lymphoid malignancies. Cell Death & Disease, 2015, 6: e1593 (PMID: 25590803).
Klionsky DJ, …Almasan A, et al. Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy, 2016 (in press).
Sharma A, Janocha TA, Hill BT, Smith MR, Erzurum SC, Almasan A. Targeting mTORC1-mediated metabolic addiction to overcome fludarabine resistance in malignant B cells. Molecular Cancer Res, 2014; 12:1205-1215, 2014 (article featured as a Highlight; PMC4163513).
Singh K, Sharma A, Mir MC, Drazba JA, Heston WD,Magi-Galuzzi C, Hansel D,Rubin BP, Klein EA, Almasan A. Autophagic flux determines cell death and survival in response to Apo2L/TRAIL (dulanermin). Molecular Cancer, 2014; 13:70 (highly cited; PMC3998041).
Chatterjee P, Plesca D, Mazumder S, Boutros J,Yannone SM, Almasan A. Defective chromatin recruitment and retention of NHEJ core components in human tumor cells expressing a Cyclin E fragment. Nucleic Acids Res, 2013; 41: 10157-69. (PMC3905870).
Sharma A, Singh K,Mazumder S, Hill BT, Kalaycio M, Almasan A. BECN1 and BIM interactions with MCL-1 determine fludarabine resistance in leukemic B cells. Cell Death & Disease, 2013; L4: e628 (PMC3674362).
Chatterjee P, Choudhary G, Sharma A, Singh K, Heston WD, Ciezki J, Klein EA, Almasan A. PARP inhibition radiosensitizes most effectively to low dose-rate radiation PTEN-deficient and TMPRSS2-ERG fusion gene-expressing prostate cancer cells. PloS One, 2013; 8: e60408 (PMC3614551).
Mazumder S, Choudhary GS, Al-harbi S, Almasan A. Mcl-1 phosphorylation defines ABT-737 resistance that can be overcome by increased NOXA expression in leukemic B-cells. Cancer Res, 2012; 72: 3069-3079 (PMC3626291).
Singh K, Matsuyama S, Drazba JA, Almasan A. Autophagy-dependent senescence in response to DNA damage and chronic apoptotic stress. Autophagy, 2012; 8: 236-51 (PMC3336077).
Al-harbi S, Hill BT, Mazumder S, Singh K, DeVecchio J, Choudhari G, Rybicki LA, Kalaycio M, Maciejewski JP, Houghton JA, Almasan A. An anti-apoptotic Bcl-2 family expression index predicts the response of CLL to ABT-737. Blood, 2011; 118: 3579-90 (Featured in: Blood; Expert Rev. Hematology, Expert Rev. of Anticancer Therapy; PMC3186334).