Targeting pro-survival Bcl-2 family proteins for cancer therapy: Exploring and defining new applications

• Applicant: Anne Nolting
• Subject Area: Hematology, Oncology
• Term: from 2013 to 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 246989170

The development of targeted therapies with novel mechanisms-of-action is essential for major improvements in outcomes to occur for patients with cancers that are incurable with current treatment approaches, particularly cytotoxic chemotherapy. For over two decades it has been recognised that Bcl-2 and related proteins that lead to resistance of cancer cells to apoptosis are attractive therapeutic targets given their dual contributions to tumour development and chemoresistance. After several false starts, Bcl-2 can now be inhibited using small molecules that belong to a new class of drugs called BH3 mimetics. Prof. Huang and Prof. Roberts are world leaders in this field and have contributed substantially to the pre-clinical and clinical proof-of-principle data in chemo-refractory chronic lymphocytic leukaemia (CLL) that highlight the exciting potential of the first-in-class BH3 mimetics, navitoclax (ABT-263).In this proposal, we seek to take the next steps towards broadening the application of this class of drug to other tumours, by applying the lessons learnt from CLL and using cutting edge reagents in clinically-informative in vitro and in vivo model systems. We will rationally assess the potential for Bcl-2 selective BH3 mimetic therapy to be extended from CLL to myeloma and acute lymphoblastic leukaemia. We will also determine the mechanism by which these BH3 mimetics lead to cell death after inhibition of Bcl-2 function, and expect to further implicate the Bcl-2-like protein Mcl-1 as a unifying target for further drug development. Using a regulatable system that the Prof. Huang/Prof. Roberts group developed we will define whether Mcl-1 is a bona fide therapeutic target for melanoma, lymphoma, myeloma and ALL, and whether combined inhibition of Bcl-2 and Mcl-1 increases tumour responses without causing prohibitive in vivo toxicity. Arising from this research we expect to be able to initiate clinical trials of the highly specific ABT-199 in patients with relapsed ALL and relapsed multiple myeloma and lymphoma.

• DFG Programme: Research Fellowships
• International Connection: Australia
• Hosts: Professor Dr. David Huang; Professor Dr. Andrew Roberts