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New molecular targets for anticancer therapies

Chit Fang Cheok


Chit Fang Cheok
IFOM p53 Joint Research Lab
c/o A*STAR, Singapore
8A Biomedical Grove Immunos #06-37, Singapore 138648

Research project

Our group's research is focused on exploring therapeutic strategies that exploits the defects in DNA repair in cancer cells.

The concept of targeted therapy and personalized medicine is fast becoming important in the light of reports of tumor/patient subtypes that respond differentially to the same therapeutic treatment. Learning the genetic or molecular alterations that underlie these differential responses is critical for the success of therapeutic approaches. Correlating the genotype of tumors to drug susceptibility will help to predict successful therapeutic outcomes and establish guidelines for the use of chemotherapeutics more effectively. This should also guide methods and concepts to achieve specificity of drugs for tumor cells over normal cells. The DNA damage response pathways is an attractive target for therapeutic intervention since it is clear that tumor cells suffer from invariant defects in the DNA repair pathways which contributes to the increased genomic instability and drug resistances in tumor cells. Furthermore, targeting DNA repair defects in tumor cells has shown to be successful in the clinics for the treatment of BRCA- deficient tumors. In addition, reducing the ability of tumor cells to repair DNA breaks/adducts is successful in sensitizing tumor cells to chemotherapy.


Chemical Biology: effects of anticancer drugs on cancer signaling network

Currently, many cytotoxic cancer therapeutics that cause different types of DNA lesions are regarded as "general cytotoxics" against proliferating tumor cells even though their mechanisms of action may be vastly different. This approach may change with more reports demonstrating marked sensitivity of some cell lines to a subset of DNA damaging agents. We aim to perform genetic "reprofiling" of anticancer drugs to identify pathways that modulate cellular sensitivity/resistance to these drugs. These relationships will be defined by a systematic approach using cell lines with targeted genetic knockouts in human somatic cells. Our strategic platforms include

  • A fast-throughput imaging platform for the screening of anticancer drugs in a cell based assay
  • Isogenic cell lines carrying targeting mutations as cellular model systems for interrogating drug responses. These are generated using Zinc Finger nucleases or adeno-associated virus-mediated homologous recombination to introduce causative cancer mutations in somatic cells.

These studies will ultimately create a drug-genetic interaction map that defines the relationship between drug outcome and genetic loss/gain and will allow principles regarding pathway alteration and drug susceptibility to be established, setting guidelines for the stratification of patients in clinical trials.


Targeting synthetic lethality in DNA repair pathways

We aim to discover synthetic lethal relationships in DNA damage and repair pathways as an approach for targeting molecular defects in cancer cells.

Certain cancers are known to harbor deficiencies in one or more major DNA repair pathways, which render them highly dependent on other repair pathways for survival. Targeting these alternative pathways is potentially a highly specific anticancer approach since only tumor cells, but not normal cells, would be susceptible. The concept of synthetic lethality in DNA damage repair pathways has been best described in yeast but less work has been performed in mammalian cells due to technological challenges. However, evidence of synthetic lethal relationships in BRCA-deficient human tumors that translated to clinical successes has generated renewed interest in this approach. Extending this concept to other causative mutations in the key tumor suppressor pathways in mammalian cells will address if mutations in other DNA repair pathways and apoptotic pathways can be targeted.

update: July 2011
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