Identification of Novel Targets for Cancer Therapy
Project type
Honours
| Supervisor(s) | Division | |
| (Primary) | Chemical Biology | .(JavaScript must be enabled to view this email address) |
Dr Hendrik Falk (Co-supervisor) |
Chemical Biology | .(JavaScript must be enabled to view this email address) |
| (Co-supervisor) | Chemical Biology | .(JavaScript must be enabled to view this email address) |
Details of project
In this project, we seek to identify new targets for cancer therapy. Many current cancer therapies relying on small molecules cannot provide long-term cure because of resistance development in primary tumors or metastases. A common mechanism that renders cells more resistant to cytotoxic therapies is the de-regulation of the expression or mutation of proteins in the apoptotic pathways. For example, the p53 tumor suppressor protein is often inactivated allowing cells to evade cell death initiated through treatment.
In this project we will test known therapeutic drugs in their potential to overcome resistance on cell lines representing different tissue types (fibroblasts, T cells, and B cells). We have a library of known small molecule drugs, many of them kinase inhibitors, which are in clinical trials or approved for therapeutic application. Many of these drugs exert their activity through partly unknown mechanisms of action. We will treat matched cell lines of p53 wild type and mutant status to identify differential drug effects where as yet unknown activities of the drugs render the cells more susceptible to cell death. The effects will be initially studied by an assay format amenable to high-throughput, e.g. cell proliferation or cell viability. Upon identification of effective combinations the mechanism of action of these will be further investigated through high content imaging.
Research interests
Programmed cell death (apoptosis) is an important control mechanism in multicellular organisms to allow development of organs and tissues, and remove damaged and dangerous cells. Deregulation of apoptosis gives rise to cancer in particular. Apoptosis is regulated through intrinsic and extrinsic pathways, leading to the association of the pro-apoptotic Bcl-2 family members Bak or Bax, puncturing the mitochondric membrane and release of Cytochrome C, ultimately leading to activation of the caspase cascade.
We aim to develop and exploit chemical approaches for studying important biological and medical problems, thereby discovering and developing novel therapeutics to treat diseases with unmet needs. Our group has long-standing experience in applying chemical approaches to biological problems, helping both to understand the underlying biology of cancerous cells and develop new therapies. We intertwine high-throughput chemical screening (HTCS), medicinal chemistry as well as cellular & molecular biology.
Selected publications
- Baell JB, Huang DC. Prospects for targeting the Bcl-2 family of proteins to develop novel cytotoxic drugs. Biochem Pharmacol 2002 64(5-6):851-63. PMID:12213579
- van Delft MF, Huang DC. How the Bcl-2 family of proteins interact to regulate apoptosis. Cell Res 2006 16(2):203-13. PMID: 16474435
- Cory S and Adams JM. The Bcl2 family: regulators of the cellular life-or-death switch. Nat Rev Cancer 2002 2(9): 647-56. PMID: 12209154
Research theme
Cancer
Scientific discipline
- Biochemistry
- Cell Biology
- Medicinal Chemistry
Keywords
High Throughput Screening, Kinases, Therapeutic Drugs, Apoptosis