|Prof Venkitaraman holds a joint appointment as distinguished professor at the NUS Yong Loo Lin School of Medicine, a member of the National University Health System and Director of the Cancer Science Institute of Singapore. His laboratory is recognized for discovering the biological functions of the inherited breast cancer gene, BRCA2, and developing new technologies for drug discovery that have led to serial spinouts including PhoreMost. |
Cancer will affect about 1 in 3 humans at some stage in our lives. But not everyone is equally at risk of developing cancer. Some of us will experience a higher risk, either because of exposure to cancer-causing substances like cigarette smoke, or because of faulty genes that we inherit. Our research seeks to understand what makes some people more susceptible to cancer than others, and to use this new knowledge to find transformative new ways to detect, treat and eventually prevent cancer.
We aspire to understand the mechanisms underlying human cancer susceptibility, in order to find innovative means to diagnose, treat or prevent (‘intercept’) cancer early in its evolution. To this end, my laboratory operates in three closely inter-linked spheres. Our uniquely multi-disciplinary research bridges from bench to bedside, subtending a wide range of techniques from molecular cell biology to single-cell/single-molecule imaging to structural biology, biophysics and chemistry. The aim is to develop actionable insights from which novel therapeutics and diagnostic entities can emerge.
People who inherit mutations affecting the ‘breast cancer gene’ BRCA2 become highly susceptible to many different epithelial cancers. My lab was amongst the first to discover that BRCA2 suppresses cancer by guarding genome integrity. We have since elucidated essential roles of BRCA2 in genome maintenance through its functions in DNA repair by homologous recombination, in stabilizing stalled DNA replication forks, and in accurate chromosome segregation during mitosis. Our work has broken technological silos to enable scientific advances, by combining structure determination by X-ray or cryo-EM, with somatic cell genetics and molecular cell biology, with biophysical approaches including advanced imaging.
Use-inspired basic research (UIBR):
Our fundamental discoveries have provoked UIBR for translation to clinical impact. For example, we have discovered (combining innovative transgenic murine models & studies in patients) that cancer suppression by BRCA2 contravenes the classical Knudson ‘two-hit’ model, engendering new approaches for precision medicine now being applied in the clinic. We have identified new functions of the mitotic kinases PLK1 and AURKA, and their role in cancer drug resistance, now being targeted by pharma. We have recently discovered a novel cellular mechanism that links a ubiquitous class of environmental and endogenous substances – the aldehydes – with genome instability, opening new avenues for cancer therapy as well as prevention.
Technology development & commercialization:
To translate our UIBR, we have developed 3 new technology platforms for commercialization. Allo-targeting – a new concept to selectively target important cellular enzymes via their regulatory interactions rather than catalytic sites – will reach validation in 2021 through FTIM clinical trials (with our Cambridge Uni spin-out, Sentinel Oncology). Protein-interference (Protein-i) – a novel technology to rapidly identify & validate new drug targets – was spun out by Cambridge Uni into PhoreMost, a rapidly growing company with major pharma deals. Hyper-dimensional imaging microscopy (HDIM) – a high-dimensional photophysical method for biochemical imaging developed with Alessandro Esposito – has yielded prototype instruments. Together, these 3 platforms promise to accelerate drug discovery for many human diseases including cancer.