Despite impressive therapeutic advances in the treatment of CLL over the past decade, relapsed tumors that are often resistant to known therapies remain a problem. Understanding resistance and developing new treatment strategies will be necessary to turn CLL into a curable disease. With few notable exceptions, responses to chemotherapy typically occur through apoptosis, a form of programmed cell death. Our goal is to identify drugs that sensitize CLL cells to apoptosis, and to identify combinations of drugs that would prevent relapse. While chemical screening of conventional cytotoxicity is an attractive strategy to meet this goal, such an approach is impeded by the inability to reliably culture CLL cells for longer than 48 hours ex vivo. This ultimately reflects a technological gap in our ability to chemically perturb CLL ex vivo, and measure functional and clinically relevant phenotypes. Here, we will use a novel chemical screening approach called dynamic BH3 profiling (DBP), which enables functional measurements of chemically induced apoptotic changes, and requires only 6-24 hours of ex vivo culture, thereby maximizing molecular fidelity and tumor cell viability. Using a panel of over 2000 drugs, not only will we identify novel molecules that sensitize CLL cells for apoptosis, but we will also determine chemical apoptotic sensitivities that are lost or gained on relapse for individual patients. Drugs that uniquely sensitize only relapsed tumors present exciting opportunities for combination chemotherapy. Finally to understand mechanisms of apoptotic vulnerabilities in pre- and post-treatment samples, we will correlate our measurements of functional apoptotic responses with the large molecular datasets in Project 1 and 2 for at least 104 CLL patients. In sum, the successful identification of apoptotic sensitizing drugs in CLL, will not only advance our molecular understanding of CLL, but could result in truly novel therapeutic options.

Public Health Relevance

Dynamic BH3 profiling is a novel approach to identify apoptotic sensitizing chemicals without loss of molecular fidelity or cell viability that occurs with extended ex vivo culture. Using CLL samples at different stages of treatment, this approach will identify novel drugs to selectively kill CLL cells. These drugs will be chose to combine with existing therapies to improve clinical outcomes in CLL.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA206978-05
Application #
10005159
Study Section
Special Emphasis Panel (ZCA1)
Project Start
2016-09-01
Project End
2021-08-31
Budget Start
2020-09-01
Budget End
2021-08-31
Support Year
5
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
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:
Lampson, Benjamin L; Brown, Jennifer R (2018) Are BTK and PLCG2 mutations necessary and sufficient for ibrutinib resistance in chronic lymphocytic leukemia? Expert Rev Hematol 11:185-194
Wang, Lili; Livak, Kenneth J; Wu, Catherine J (2018) High-dimension single-cell analysis applied to cancer. Mol Aspects Med 59:70-84
Wang, Lili; Fan, Jean; Francis, Joshua M et al. (2017) Integrated single-cell genetic and transcriptional analysis suggests novel drivers of chronic lymphocytic leukemia. Genome Res 27:1300-1311
Landau, Dan A; Sun, Clare; Rosebrock, Daniel et al. (2017) The evolutionary landscape of chronic lymphocytic leukemia treated with ibrutinib targeted therapy. Nat Commun 8:2185
Compagno, Mara; Wang, Qi; Pighi, Chiara et al. (2017) Phosphatidylinositol 3-kinase ? blockade increases genomic instability in B cells. Nature 542:489-493
Ten Hacken, Elisa; Gui├Ęze, Romain; Wu, Catherine J (2017) SnapShot: Chronic Lymphocytic Leukemia. Cancer Cell 32:716-716.e1
Murphy, E J; Neuberg, D S; Rassenti, L Z et al. (2017) Leukemia-cell proliferation and disease progression in patients with early stage chronic lymphocytic leukemia. Leukemia 31:1348-1354
Deng, J; Isik, E; Fernandes, S M et al. (2017) Bruton's tyrosine kinase inhibition increases BCL-2 dependence and enhances sensitivity to venetoclax in chronic lymphocytic leukemia. Leukemia 31:2075-2084
Tiao, G; Improgo, M R; Kasar, S et al. (2017) Rare germline variants in ATM are associated with chronic lymphocytic leukemia. Leukemia 31:2244-2247

Showing the most recent 10 out of 11 publications