Determining modifiers of cdk inhibitor sensitivity
Supervisor(s): Professors Sibylle Mittnacht and Paul Workman
Section of Cell and Molecular Biology (CRUK Programme on Tumour Cell Signalling Networks) and Section of Cancer Therapeutics (including the Cancer Research UK Centre for Cancer Therapeutics)
Teams: Antioncogene and Signal Transduction and Molecular Pharmacology
View full details of this PhD Studentship in PDF format
Summary
Genetic alterations that disable control of progression from G1 into S phase of the cell cycle are extremely frequent in cancers [1]. Components of this control are the cyclin D-dependent kinases (CDK4 and CDK6) and the cyclin E-associated kinase, CDK2, which phosphorylate and thereby inactivate the retinoblastoma tumour suppressor protein (pRB). The high frequency of cancers in which signalling though these kinases is deregulated has provided impetus for the development of cdk-targeted agents as promising agents for anticancer treatment [1, 2]. However, and although highly potent agents have been generated, these have shown poor effectiveness in clinical trials [3]. Recent work has demonstrated increased sensitivity of cancers with VHL loss to cdk inhibiton [4], indicating herethereto unappreciated signalling cues which sensitize cells to cdk inhibition and hence could be therapeutically exploited. A systematic search for predictive biomarkers and opportunities for combination therapy that increase sensitivity to cdk-targeted agents has not been undertaken.
The aim of this studentship proposal is to develop a cell-based screen for the discovery of biomarkers and druggable modifiers to increase the response to these inhibitors. Concept of the screen will be the treatment of tester cells with cdk inhibiting agent following manipulation of the cells using small interfering RNA (siRNA) libraries. Key objective will be the gathering of information able to inform clinical use of agents and to take this through to proof of concept validation and preclinical assessment. To maximize yield of translatable information, i.e information that can inform the clinic, we plan to bias the selection of siRNA targets, which will be determined in consultation with the team of Computational Biology & Chemogenomics in Cancer Therapeutics. The Mittnacht laboratory has considerable expertise in devising and running RNAi screens and a long-standing interest, and ample expertise in studying G1/S checkpoint control. Hence devising the screening assay and running of the screen and hit deconvolution will be supervised using the facilities of this team. Preclinical assessment will be supervised by the Workman team, who are highly experienced in the assessment of drug interactions using new and conventional technologies in molecular pharmacology. The Workman team will also be involved in RNAi library design and provide consultation on screen and hit evaluation.
The proposed study design is geared towards “translational outcome”, with the primary aim of enhancing clinical utility of cdk targeting therapeutics. However it is likely that the work will also yield principle conceptual information that can be used to identify nodes and generate network predictions as to signalling that determines dependency of cells on cdk activity. Lastly the project establishes methodology and generates resources that will have utility in conjunction with other targeted agents or cell models, thus providing value beyond the experimental work described in the proposal.
References
- Mittnacht, S. (2005) The retinoblastoma protein-from bench to bedside. Eur J Cell Biol Vol 84, No 2-3, p97-107
- Benson, C., et al. (2005) Clinical anticancer drug development: targeting the cyclin-dependent kinases. Br J Cancer, Vol 92, No 1, p7-12
- Lapenna, S., Giordano, A. (2009) Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov Vol 8, No 7, p547-66
- Bommi-Reddy, A., et al. (2008) Kinase requirements in human cells: III. Altered kinase requirements in VHL-/- cancer cells detected in a pilot synthetic lethal screen. Proc Natl Acad Sci U S A Vol 105, No 103, p16484-9
