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Directly targeting the Cell Death Machinery to Treat Hematopoietic Malignancies

Andreas Strasser

Andreas Strasser

PhD, MSc, FAA

Walter & Eliza Hall Institute of Medical Research

Project Term: October 1, 2017 - September 30, 2022

These multidisciplinary, collaborative grants bring together teams of researchers to solve difficult challenges in the blood cancers. We are working to understand why and how it is that if cells in the body don’t die when they should, cancer is able to develop,” This SCOR paves the way for therapies that harness the body's own cell death machinery, called apoptosis, the normal process that causes impaired cells to self-destruct. When the process goes awry, cancer cells do not die as readily. The team was instrumental in the discovery of the first approved apoptosis-targeted agent called venetoclax (Venclexta) for use in chronic lymphocytic leukemia and, more recently, for elderly patients with acute myeloid leukemia (AML). The team is now testing multiple new approaches to boost apoptosis in other leukemias, as well as lymphoma and myeloma.

Lay Abstract

The link between malignant cell growth and evasion of cell death was first forged by our seminal discovery that BCL2, a gene commonly translocated in human follicular center B cell lymphoma, contributed to neoplasia by preventing programmed cell death 1. It is now widely accepted that evasion of cell death (apoptosis) is a key attribute that cells must acquire for neoplastic transformation, particularly for leukemia, lymphoma and multiple myeloma. Long support from the LLS (4 SCOR grants) has allowed our team to help develop such drugs that yielded the BCL2-specific inhibitor Venetoclax (VENCLEXTA®). A milestone in cancer research came in April 2016 when the US FDA approved venetoclax for treatment of refractory CLL.

Our genetic studies established that several hematological malignancies, including AML, MYC driven B lymphomas, T cell lymphoma and multiple myeloma, were maintained primarily by MCL, for which no suitable inhibitor existed until recently. Since 2014, however, we have collaborated with the French pharmaceutical company Servier to develop a potent and tolerable MCL1-specific BH3 mimetic. Notably, a recent study in Nature, on which six of our proposed SCOR leaders are authors, revealed its striking efficacy and tolerability in multiple myeloma, lymphomas and AML. Pertinently, patients are being enrolled for its first clinical trials, including a pioneering AML trial headed by Wei (Project 3). Collectively, these findings convince us that the potential for BH3 mimetic therapy in hematopoietic malignancies is enormous, and we are superbly positioned to advance it. That is the major focus of our proposal.

Program
Specialized Center of Research Program
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