PROJECT 6 : Pharmacologic Inhibitors of Cellular Kinases and Signal Transduction Chronic lymphocytic leukemia (CLL) is currently initially treated with chemoimmunotherapy (CIT). Despite this advance, virtually all patients receiving CIT relapse and ultimately die from their disease. Recent identification of targets central to the biology of B-cell transformation provides an opportunity to set a new treatment paradigm in CLL, as has been done in chronic myeloid leukemia. In this regard, we are investigating clinically active kinase inhibitors that target cyclin-dependent kinases (CDK;flavopihdol and SCH727965) and phosphoinositide 3-kinase delta (PlSK-delta;CAL-101). Flavopiridol, SCH727965, and CAL-101 each have demonstrated signficant clinical activity in patients with relapsed and refractory CLL. The mechanisms by which each ofthese agents kill CLL cells and interfere with microenvironmental protection, as well as pathways by which resistance develops, are uncertain. Through detailed mechanistic interrogation we will confirm and extend our strong prelimitiary data. In conjunction, we will also perform translational studies accompanying CRC phase l/ll trials with each agent.
Specific Aim 1 : To perform mechanistic studies of flavopiridol and SCH727965 to study: a) The contribution of ER stress to cell death promoted by these agents, b) The contribution of autophagy to CDK inhibitor drug resistance;c) The influence of microenvironment on promoting resistance to CDK inhibitors in CLL cells and strategies to overcome these with novel targeted agents, and d) performance of pharmacodynamic studies with completed and planned CDK inhibitor clinical trials in the CRC.
Specific Aim 2 : To interrogate the PI3K-delta pathway with particular focus on: 1) Identification ofthe mechanism by which CAL-101 promotes direct cytotoxicity toward CLL cells;2) Relevance of external signals antagonized by CAL-101 in the microenvironment to the survival of CLL cells;3) Pre-clinical testing of PI3K-delta inhibitors in the TCLI mouse model of CLL to further validate optimal combination studies with this agent, and 4) performance of pharmacodynamic studies in concert with the planned CAL-101 clinical trials in the CRC.
Entirely new therapeutic strategies are crucial to make headway the successful treatment of chronic lymphocytic leukemia. This project continues to be extremely active in the identification and development of novel CLL therapies. The therapeutic agents to be studied (flavopiridol, SCH727965, and CAL-101) all have demonstrated clinical activity in CLL, and are part of past or current clinical trials to be pursued in the CRC.
|Mani, R; Mao, Y; Frissora, F W et al. (2015) Tumor antigen ROR1 targeted drug delivery mediated selective leukemic but not normal B-cell cytotoxicity in chronic lymphocytic leukemia. Leukemia 29:346-55|
|Veronese, A; Pepe, F; Chiacchia, J et al. (2015) Allele-specific loss and transcription of the miR-15a/16-1 cluster in chronic lymphocytic leukemia. Leukemia 29:86-95|
|Woyach, Jennifer A; Furman, Richard R; Liu, Ta-Ming et al. (2014) Resistance mechanisms for the Bruton's tyrosine kinase inhibitor ibrutinib. N Engl J Med 370:2286-94|
|Stephens, D M; Ruppert, A S; Jones, J A et al. (2014) Impact of targeted therapy on outcome of chronic lymphocytic leukemia patients with relapsed del(17p13.1) karyotype at a single center. Leukemia 28:1365-8|
|Chen, Wenbing; Han, Yanyan; Peng, Xiaohua (2014) Aromatic nitrogen mustard-based prodrugs: activity, selectivity, and the mechanism of DNA cross-linking. Chemistry 20:7410-8|
|Strati, Paolo; Ferrajoli, Alessandra; Lerner, Susan et al. (2014) Fludarabine, cyclophosphamide and rituximab plus granulocyte macrophage colony-stimulating factor as frontline treatment for patients with chronic lymphocytic leukemia. Leuk Lymphoma 55:828-33|
|Cheney, Carolyn M; Stephens, Deborah M; Mo, Xiaokui et al. (2014) Ocaratuzumab, an Fc-engineered antibody demonstrates enhanced antibody-dependent cell-mediated cytotoxicity in chronic lymphocytic leukemia. MAbs 6:749-55|
|Riches, John C; Gribben, John G (2014) Hanging tough: CMV-specific CD8+ T cells in CLL. Blood 123:608-9|
|Cui, Bing; Chen, Liguang; Zhang, Suping et al. (2014) MicroRNA-155 influences B-cell receptor signaling and associates with aggressive disease in chronic lymphocytic leukemia. Blood 124:546-54|
|Beckwith, K A; Frissora, F W; Stefanovski, M R et al. (2014) The CD37-targeted antibody-drug conjugate IMGN529 is highly active against human CLL and in a novel CD37 transgenic murine leukemia model. Leukemia 28:1501-10|
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