PROJECT 2: Molecular Inhibition of Apoptosis Inhibitors B-cell chronic lymphocytic leukemia [B-CLL] arises primarily because of failures in apoptosis mechanisms. Aberrant over-expression of anti-apoptotic Bcl-2 family proteins contributes greatly to the long lifespan of CLL cells, and also thwarts attempts to eradicate these leukemic cells by chemotherapy. The human genome contains six genes encoding anti-apoptotic Bcl-2 family proteins (Bcl-2, BCI-XL, Mcl-1, Bfl-1, Bcl-W, Bcl-B), several of which are often highly expressed in CLLs. Expression of Mcl-1 or Bfl-1 accounts for resistance to chemical antagonists of Bcl-2, such as ABT263 analogs. Moreover, expression of these pro survival proteins increases in CLL cells thriving in microenvironmental niches. We hypothesize that redundancy caused by multiple anti-apoptotic Bcl-2 family members is a critical barrier to effective treatment of CLL. We propose to test this hypothesis through 3 complementary approaches. First. ABT263 and other small molecule Bcl-2 antagonists currently in clinical development bind a regulatory site on Bcl-2, mimicking endogenous antagonists that contain the BH3 domain. We have generated novel BH3 mimicking compounds with broad-spectrum inhibitory activity against all anti-apoptotic Bcl-2 family proteins. These compounds will be tested for preclinical activity against primary human CLL cells in culture and against murine CLL cells in transgenic mouse models. Second, we have identified a non-BH3 regulator of Bcl-2 in the Nur77/TR3 protein, an orphan nuclear receptor that binds to Bcl-2, Bfl-1, and Bcl-B, converting these proteins from antito pro-apoptotic. Using Nur77/TR3, we have discovered a novel non-BH3 regulatory site on Bcl-2 family proteins that will be targeted with small molecules as an alternative approach to Bcl-2 antagonism. Third. expression of many anti-apoptotic Bcl-2 family proteins (including Mel-1, BCI-XL, and Bfl-1) is upregulated when CLL cells are influenced by microenvironment. Hence, agents from Aims 1 and 2 will be evaluated for activity against CLL cells using in vitro culture models of microenvironment interactions. Altogether, our goal is to extend preclinical studies of novel Bcl-2 family antagonists towards the ultimate goal of bringing these concepts and new agents into the clinic via the CLL Research Consortium (CRC).

Public Health Relevance

CLL is the most common type of leukemia in the Western world, remaining incurable with currently available therapies. In this project, we propose to generate novel pro-apoptotic drugs and to elucidate synergistic drug combinations, creating novel strategies for the improved treatment of CLL.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA081534-14
Application #
8733426
Study Section
Special Emphasis Panel (ZCA1-RPRB-0)
Project Start
Project End
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
14
Fiscal Year
2014
Total Cost
$449,324
Indirect Cost
$65,766
Name
University of California San Diego
Department
Type
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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

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