Cancer Science Institute of Singapore
AsianScientist (Oct. 8, 2021) – Eight years ago, actress Angelina Jolie shook the world by publicly announcing her decision to undergo a double mastectomy. In a widely-read piece, Jolie explained how she carried a ‘faulty’ gene that increased her risk of developing breast and ovarian cancer, spurring her to undergo surgery. The name of the gene? BRCA1.
Genes like BRCA1 and BRCA2 are typically responsible for repairing DNA damage and suppressing tumor development. But even BRCA genes can sometimes go haywire, with their mutations leading to a higher risk of breast, ovarian, prostate and pancreatic cancers.
Fortunately, understanding our genetic predisposition to diseases can greatly improve our chances of diagnosing and treating such ailments. Through the efforts of researchers like Professor Ashok Venkitaraman, we know which genes and variants to look out for and how to address their effects.
In 1998, Venkitaraman and his team from the University of Cambridge found that cells with defective copies of BRCA2 undergo large DNA rearrangements when they divide in culture, triggering genomic instability.
Their discovery led to our understanding of why people with BRCA2 mutations have a high risk of developing cancer, driving the emergence of diagnostic kits that detect these mutations to indicate breast cancer risk, and later, effective new therapies.
Today, Venkitaraman holds multiple appointments, including Director of the Cancer Science Institute of Singapore as well as Program Director at the Disease Intervention Technology Laboratory at the Agency for Science, Technology and Research (A*STAR). In this interview with Asian Scientist Magazine, he shares his recent research forays and his vision for the future of cancer research in Singapore and beyond.
- As one of the first to discover BRCA2’s role as a genome guardian, how did you first become interested in studying the impact of genome instability on cancer development?
- Can you share with us any new insights on BRCA2 from your laboratory? How do these insights advance our understanding of cancer?
- As founder and chief scientific adviser of PhoreMost, what are the challenges and opportunities of translating research from bench to bedside?
- What is your vision for the Cancer Science Institute of Singapore (CSI) over the next few years?
- You have recently joined A*STAR as Program Director for the Disease Intervention Technology Laboratory. Can you tell us more about the research projects you are involved with?
- What advice would you like to share for aspiring cancer researchers in Asia?
I never intended to become a cancer researcher. In my postdoctoral research, I defined the molecular components of the antigen receptor on antibody-secreting B lymphocytes. When I started up my own lab, I turned to understanding how programed DNA rearrangements in immunoglobulin genes could generate antigen receptor diversity in the immune system.
The trajectory of my work changed radically when my laboratory first discovered that the breast cancer gene BRCA2 is essential for genome stability. Over the years, our findings have helped not only define how inactivating such genes can cause human cancer, but also to suggest avenues for targeted therapy.
My laboratory found recently that BRCA2 regulates the transcription machinery and that inactivation of this role causes alterations in chromatin structure and gene expression.
We have also identified changes in the localization and function of enzymes that regulate RNA metabolism, like nucleases and helicases, in cells that lack BRCA2. We don’t yet know whether these emerging new roles are relevant to tumor suppression or cancer development in BRCA2 mutation carriers.
But they do highlight an exciting new nexus—between RNA metabolism, genome stability and chromatin structure—that could in the future open new ways to detect, treat or even prevent cancer.
Our understanding of the mechanisms underlying human disease has exploded over the past decade or two, but our ability to translate this knowledge to next-generation medicines has not kept pace. Major challenges remain when it comes to identifying novel therapeutic targets, drugging such previously undrugged targets, and understanding which patients would benefit most from new drugs.
My lab has made inroads into each of these challenges. To give one example, we devised an approach called ‘Protein interference’ or ‘Protein-i’ that harnesses the evolutionary diversity of protein shapes in phenotypic screens to rapidly and efficiently scan disease pathways for new therapeutic targets.
This technology was spun out from my academic lab to PhoreMost and is now being used in partnerships with many leading pharma companies like Novartis, Boehringer-Ingelheim and Otsuka to develop next-generation drugs.
Many new modalities are rapidly emerging, including the recent excitement over RNA vaccines or therapeutics, but just as many fundamental challenges must be overcome before the promise of these new approaches can be delivered. I am quite sure that there will be plenty to do in coming years!
Our mission is simple—we aim to better understand the causes of human cancer across Asia, and thereby improve its detection, treatment and prevention. We are better placed than ever before to make substantial progress.
With the recent revolution in our understanding of the fundamental biology of cancer cells, we are poised for a transformational period in fundamental, translational and clinical understanding—potentially marking what I term ‘the end of the beginning’ for cancer research.
My colleagues and I are determined to look thoughtfully beyond our current efforts to capture important emerging opportunities at the cutting-edge of global cancer research. This realization has equipped us to embark on a program of strategic consolidation and renewal, which will create new research opportunities that capture powerful synergies in the Singapore and global landscapes.
A key step in this program will be to expand our current faculty to complement existing strengths and seed new strategic research directions. Our ambition is to be international leaders in distinctive fields of cancer research that tackle major challenges in Asia and worldwide.
I had the privilege of taking over from Professor Sir David Lane in April 2021 to lead what was previously called the p53Lab. In the Disease Intervention Technology Lab (DITL), we will integrate my lab’s work on novel technologies for therapeutic target discovery and structure-guided lead development, with the work of David and his colleagues on peptide therapeutics.
The DITL will aim to help translate discovery research towards therapeutic or diagnostic application by devising new approaches to identify and validate novel targets, structurally characterize and biologically enable them, and to assess their ‘ligandability’ by peptides, macrocycles or small molecules.
We are also thinking hard about how we can use our collective expertise to make meaningful contributions in emerging areas like nucleic acid therapeutics. Our aim is to remain at the forefront of relevance in developing innovative interventions for human diseases.
Scientifically, I’ve been passionate about understanding how things work, rather than about simply describing them. So, the first piece of advice I would give to an aspiring cancer researcher is to find important questions to work on that could potentially give deep insight into the mechanisms underlying disease.
Secondly, embrace measured risk, rather than avoid risk altogether. This is easier said than done. But the fact is that major scientific breakthroughs often arise from taking measured risks.
Finally, don’t overlook the importance of translating what you discover to societal impact. I trained as a physician and during my work as a scientist, realized that opportunities to translate research to clinical application can open new experiences, learning and collaborations that are refreshing and rewarding.
This is a very exciting time to be an aspiring cancer researcher in Asia. I wish I could turn the clock back!
This article is from a monthly series called Asia’s Scientific Trailblazers. Click here to read other articles in the series.
Copyright: Asian Scientist Magazine; Photo: Ashok Venkitaraman.
Disclaimer: This article does not necessarily reflect the views of AsianScientist or its staff