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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA081534-12A1
Application #
8235355
Study Section
Special Emphasis Panel (ZCA1-RPRB-0 (O1))
Project Start
2011-12-01
Project End
2017-08-31
Budget Start
2012-09-24
Budget End
2013-08-31
Support Year
12
Fiscal Year
2012
Total Cost
$235,469
Indirect Cost
$39,449
Name
University of California San Diego
Department
Type
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Vangapandu, Hima V; Chen, Huiqin; Wierda, William G et al. (2018) Proteomics profiling identifies induction of caveolin-1 in chronic lymphocytic leukemia cells by bone marrow stromal cells. Leuk Lymphoma 59:1427-1438
Yu, Jian; Chen, Yun; Chen, Liguang et al. (2018) Cirmtuzumab inhibits ibrutinib-resistant, Wnt5a-induced Rac1 activation and proliferation in mantle cell lymphoma. Oncotarget 9:24731-24736
Barr, Paul M; Robak, Tadeusz; Owen, Carolyn et al. (2018) Sustained efficacy and detailed clinical follow-up of first-line ibrutinib treatment in older patients with chronic lymphocytic leukemia: extended phase 3 results from RESONATE-2. Haematologica 103:1502-1510
Kondo, K; Shaim, H; Thompson, P A et al. (2018) Ibrutinib modulates the immunosuppressive CLL microenvironment through STAT3-mediated suppression of regulatory B-cell function and inhibition of the PD-1/PD-L1 pathway. Leukemia 32:960-970
Hasan, Md Kamrul; Yu, Jian; Widhopf 2nd, George F et al. (2018) Wnt5a induces ROR1 to recruit DOCK2 to activate Rac1/2 in chronic lymphocytic leukemia. Blood 132:170-178
Ten Hacken, Elisa; Valentin, Rebecca; Regis, Fara Faye D et al. (2018) Splicing modulation sensitizes chronic lymphocytic leukemia cells to venetoclax by remodeling mitochondrial apoptotic dependencies. JCI Insight 3:
Gribben, John G (2018) How and when I do allogeneic transplant in CLL. Blood 132:31-39
Sivina, Mariela; Werner, Lillian; Rassenti, Laura et al. (2018) Dynamic changes in CCL3 and CCL4 plasma concentrations in patients with chronic lymphocytic leukaemia managed with observation. Br J Haematol 180:597-600
Ott, Christopher J; Federation, Alexander J; Schwartz, Logan S et al. (2018) Enhancer Architecture and Essential Core Regulatory Circuitry of Chronic Lymphocytic Leukemia. Cancer Cell 34:982-995.e7
Balatti, Veronica; Tomasello, Luisa; Rassenti, Laura Z et al. (2018) miR-125a and miR-34a expression predicts Richter syndrome in chronic lymphocytic leukemia patients. Blood 132:2179-2182

Showing the most recent 10 out of 562 publications