Identifying and validating novel targets for cancer therapy
Project type
PhD
| Supervisor(s) | Division | |
| (Primary) | Chemical Biology | .(JavaScript must be enabled to view this email address) |
| (Co-supervisor) | Molecular Genetics of Cancer | .(JavaScript must be enabled to view this email address) |
Professor Liam O'Connor (Co-supervisor) |
Personalised Medicine and Systems Biology | .(JavaScript must be enabled to view this email address) |
Details of project
c-myc is a potent oncogene that is overactive in over 70% of human cancers. Directly targeting c-Myc has proven elusive, but recent work from the Huang and Strasser Labs has identified a potential target for tumours driven by amplification of c‑myc: Many models of cancers driven by c‑Myc are highly dependent on the pro-survival protein Mcl-1, a Bcl‑2 family protein. Inactivating Mcl‑1, either genetically or biochemically, led to the rapid killing of cells that overexpress c-Myc, both in tissue culture systems and in a number of mouse models of human cancers. Discovering the molecular mechanism that underpins this striking finding may lead to the development of novel cancer therapeutics, especially for tumours dependent on high levels of c-Myc.
This aims of this PhD project are to:
- understand why c-Myc-overexpressing cells are so reliant on Mcl-1, but not on other pro-survival Bcl‑2 proteins.
- undertake genetic (using RNAi) and chemical screens (e.g. library of kinase inhibitors or other compounds with known mechanism of action) for factors that selectively kill c-Myc overexpressing cells and thus identify potential targets for cancer therapy.
- validate potential targets in model systems both in tissue culture systems and where feasible, by using the whole animal.
The project is well suited to an ambitious student with a background in the relevant biological sciences such as genetics or biochemistry, but interested applicants from other backgrounds are strongly encouraged to discuss the proposed project with the potential supervisors.
In addition to applying the tools of molecular biology, cell biology and biochemistry, the student will have access to high-throughput screening and techniques for large-scale biology, including high-content imaging and proteomics. Upon completion, it is anticipated that the successful student will have outstanding training in cancer biology and systems biology that is relevant for drug discovery and development.
Project references
- van Delft MF, Wei A, Mason KD, Vandenberg CL, Chen L, Czabotar PE, Willis SN, Scott CL, Day CL, Cory S, Adams JM, Roberts AW, Huang DCS. BH3 mimetic ABT‑737 targets selective Bcl‑2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl‑1 is neutralized. Cancer Cell. 2006 Nov;10(5):389-99. PMID: 17097561.
- Roberts AW, Seymour JF, Brown JR, Wierda WG, Kipps TJ, Khaw SL, Carney DA, He SZ, Huang DCS, Xiong H, Cui Y, Busman TA, McKeegan EM, Krivoshik AP, Enschede SH, Humerickhouse R. Substantial susceptibility of chronic lymphocytic leukemia to Bcl-2 inhibition: Results of phase 1 study of navitoclax (ABT-263) in patients with relapsed or refactory disease. J Clin Oncol. 2011; In Press.
- Mason KD, Carpinelli MR, Fletcher JI, Collinge JE, Hilton AA, Ellis S, Kelly PN, Ekert PG, Metcalf D, Roberts AW, Huang DCS, Kile BT. Programmed anuclear cell death delimits platelet life span. Cell. 2007 Mar 23;128(6):1173-86. PMID: 17382885.
- Youle RJ, Strasser A. The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol. 2008 Jan; 9(1):47-59. PMID: 18097445.
- Lessene G, Czabotar PE, Colman PM. BCL-2 family antagonists for cancer therapy. Nat Rev Drug Discov. 2008 Dec;7(12):989-1000. PMID: 19043450.
Research interests
The division of Chemical Biology focuses on developing and applying state-of-the-art chemical approaches for studying important biological and medical problems, and to discover and develop novel therapeutics for the treatment of diseases with unmet medical needs. This research division has infrastructure (e.g. high-throughput screening), expertise (e.g. medicinal chemistry) and a proven track record for drug discovery and development.
A longstanding interest of the Huang and Strasser Labs is to understand how the Bcl‑2 protein family controls the switch that determines whether a cell lives or dies. Their work has contributed much to our understanding of how impairment of cell death, such as by overexpression of Bcl‑2 in leukaemias and lymphomas, contributes to tumour formation - the major research interest of the Molecular Genetics of Cancer division.
More recently, their laboratories have been closely involved in the development and validation of BH3 mimetic compounds, small organic compounds mimicking the BH3-only proteins that are the natural antagonists of Bcl‑2. One such compound, navitoclax (ABT-263), appears promising for treating patients with chronic lymphocytic leukaemia (CLL), whereas a more selective compound, ABT-199 has just entered clinical trials. Professor O’Connor brings extensive experience in drug discovery and development from the biopharmaceutical industry. He is interested in applying the tools of large scale-systems biology to address fundamental scientific questions and for developing better medicines. He heads the newly formed division of Systems Biology and Personalised Medicine.
Together, the co-supervisors of this project bring together expertise in applying the techniques of molecular, cellular, computational and systems biology to studying tumour development and discovering better therapeutics for patients with cancers.
Research theme
Cancer
Scientific discipline
- Biochemistry
- Cell Biology
- Genetics
- Molecular Biology
Keywords
cancer, therapeutic, RNAi, drug discovery, apoptosis,