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.
|Hasan, M K; Yu, J; Chen, L et al. (2017) Wnt5a induces ROR1 to complex with HS1 to enhance migration of chronic lymphocytic leukemia cells. Leukemia 31:2615-2622|
|Patel, V M; Balakrishnan, K; Douglas, M et al. (2017) Duvelisib treatment is associated with altered expression of apoptotic regulators that helps in sensitization of chronic lymphocytic leukemia cells to venetoclax (ABT-199). Leukemia 31:1872-1881|
|Patel, Viralkumar; Balakrishnan, Kumudha; Bibikova, Elena et al. (2017) Comparison of Acalabrutinib, A Selective Bruton Tyrosine Kinase Inhibitor, with Ibrutinib in Chronic Lymphocytic Leukemia Cells. Clin Cancer Res 23:3734-3743|
|Edelmann, J; Tausch, E; Landau, D A et al. (2017) Frequent evolution of copy number alterations in CLL following first-line treatment with FC(R) is enriched with TP53 alterations: results from the CLL8 trial. Leukemia 31:734-738|
|Miller, Cecelia R; Ruppert, Amy S; Fobare, Sydney et al. (2017) The long noncoding RNA, treRNA, decreases DNA damage and is associated with poor response to chemotherapy in chronic lymphocytic leukemia. Oncotarget 8:25942-25954|
|Vangapandu, Hima V; Jain, Nitin; Gandhi, Varsha (2017) Duvelisib: a phosphoinositide-3 kinase ?/? inhibitor for chronic lymphocytic leukemia. Expert Opin Investig Drugs 26:625-632|
|Vangapandu, Hima V; Chen, Huiqin; Wierda, William G et al. (2017) Proteomics profiling identifies induction of caveolin-1 in chronic lymphocytic leukemia cells by bone marrow stromal cells. Leuk Lymphoma :1-12|
|Rassenti, Laura Z; Balatti, Veronica; Ghia, Emanuela M et al. (2017) MicroRNA dysregulation to identify therapeutic target combinations for chronic lymphocytic leukemia. Proc Natl Acad Sci U S A 114:10731-10736|
|Kipps, Thomas J; Stevenson, Freda K; Wu, Catherine J et al. (2017) Chronic lymphocytic leukaemia. Nat Rev Dis Primers 3:16096|
|Vangapandu, Hima V; Havranek, Ondrej; Ayres, Mary L et al. (2017) B-cell Receptor Signaling Regulates Metabolism in Chronic Lymphocytic Leukemia. Mol Cancer Res 15:1692-1703|
Showing the most recent 10 out of 552 publications