THE KOH LABORATORY
Innovating tomorrow's therapies
Themes
We study genetic and signalling aberrations in cancer cells.
Our goal is to turn their molecular features into their liabilities.
Targeting the DNA damage response
Defects in the DNA damage response (DDR) pathway render some cancer cells vulnerable to exogenous insults, a concept that underpins the use of chemotherapy. However, because of their lack of target selectivity, many chemotherapeutic agents operate within a narrow therapeutic window. A strategy to redress this issue is the development of molecularly targeted agents that exploit cancer-specific abnormalities. Our work shows that inhibiting cell cycle kinases such as ATR, CHK1 and WEE1 is an effective way to capitalise on DDR defects in cancer cells.
Reversing drug resistance
While tumours may respond to treatment initially, drug resistance often occurs, leading to disease progression or relapse. We propose two complementary strategies. First, from analyses of primary and preclinical specimens, our work shows that identifying potential predictive biomarkers can reveal rational therapy options right from the outset. Second, through in silico and in vivo validation, we show that mechanism-led multidrug regimens given at low infrequent doses can achieve durable tumour inhibition without inducing toxicities.
Building better tools
The success of science relies on the availability and advances of research tools. We are interested in creating experimental molecules, models and methods that are applicable to the pipeline of drug discovery and development. Our work so far has generated predictive approaches for lead optimisation, dose-response effects and drug-drug interactions, as well as high-content microscopy systems and analytical platforms. These tools continue to help us discover new details about cancer behaviours and drug mechanisms of action.
