While development of new therapeutic approaches have contributed to the increase in the complete remission rate for CLL patients, relapses and resistance to re-treatment remain a significant problem. Nevertheless, changes that occur in the biology of CLL upon relapse from front-line therapies provide clues to resistance mechanisms that prevent prolonged complete responses. Our overall strategy is to employ three novel approaches that are each directed at an aspect ofthe pathophysiology of CLL and the mechanisms associated with resistance. First, a deletion at 11q22-23, the site of the ATM gene, occurs in half of relapsed/refractory patients. Mutation ofthe residual allele (-50%) inactivates homologous recombination (HR) repair of double strand breaks. Because Sapacitabine causes one-ended double strand breaks, cells that lack ATM are selectively sensitized. We will develop assays to identify patients who's CLL lacks ATM function, and initiate a clinical trial of Sapacitabine therapy to test the hypothesis that their disease will be selectively sensitized. Second, studies in model systems demonstrate that loss of p53 function is a resistance mechanism to cytotoxic therapy. Nearly half of relapsed refractory patients lack p53 function. We postulate that expression of the epigenetically silenced p73 will serve in place of p53 to activate expression of pro-apoptotic proteins. This will be validated in model systems and tested in a clinical trial. Third, a novel mechanism by which the microenvironment sustains CLL cells and increases resistance to chemotherapy appears to act by providing precursors for glutathione. This sustains CLL by neutralizing the destructive action of reactive oxygen species that are innately over-expressed by CLL. By using a small molecule to reduce glutathione we will test this hypothesis to sensitize CLL cells in vitro and in vivo. These investigations will provide mechanism-based rationales for development of combination therapies.

Public Health Relevance

Current first-line therapy for CLL does not target the pathophysiology ofthe disease and is thwarted by resistance mechanisms. This proposal postulates three novel therapeutic approaches aimed at a key genetic lesion, loss of function of a tumor suppressor, and a mechanism of microenvironmental support. Clinical trials are planned to evaluate these strategies in patients with relapsed/refractory CLL. Successful approaches will be combined with induction therapies to improve overall outcome.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-RPRB-0)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Diego
La Jolla
United States
Zip Code
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