Raffles Institute student awarded top accolades from MIT for cancer research titled "In-Vitro Resistance Modeling of B-RAF Inhibition in Colorectal Cancer"

his speech was broadcasted from the White House press conference on the day the first draft of the human genome project was published in the year 2000. That day marked a truly significant leap forward in the fight against cancer. And the fight against cancer continues to this day, gaining fresh ammunition from the involvement of youths in their tireless battles against cancer research. Their fresh perspectives and energetic enthusiasm invigorate a renewed rigour in the fight with this new generation of young scientists. The question is “What is our next generation of budding scientists in Singapore doing in the area of cancer research?"

One such 17 years old student from Raffles Institution, Low Kay Yi conducted an original clinical research in colorectal cancer at state-of-the-art university laboratories, hospitals and corporate research facilities. She had been carefully selected, counting among some of the world’s most accomplished students, to be involved in a research internship opportunity at Massachusetts Institute of Technology (MIT). The amalgamation of over 70 highly passionate math and science students from over 50 nations in the MIT campus during the internship proved to be one of the most memorable experiences in her life. Her peers and her would sit by the hallway and engage in lively debates on a plethora of topics, from current affairs, recent discoveries, to their life aspirations. It was truly an overwhelming experience connecting so many like-minded individuals and experts together.

A Day in the Life of a Research Student

Low Kay Yi conducted her research at Tufts Medical Center, Boston, USA, under the stewardship of Dr Kenneth Hung, in the department of Gastroenterology. The research project demanded grilling hours of intensive research which tested her resilience and multi-disciplinary skill. The more time she dedicated to her research, the more she fell in love with it. Her alarm would set off at 6.30am, signifying the start of her daily routine- Grab a sandwich, hop onto the bus and to the lab. Having to report back to the dormitory by 10.30pm, she would race down Tufts Medical Street to catch the 10.05pm train back to MIT. Lunch was a luxury, and so were toilet breaks. Time permitting, she would indulge in a salmon bagel at the hospital cafeteria before her last train. She embraced this routine, and this built up her determination, mental strength and independence. Never did she envisage that this would turn out to be one of her most memorable and dearly missed research experience at the MIT internship!

Why Cancer Research?

Cancer research has always excited and intrigued her. An indefinite number of signal transduction pathways are implicated in cancer and two people suffering from the same type of cancer may have very different mutations. This was the inspiration for her research topic as she was very interested to find out the possible resistance mechanisms to GDC-0879 drug treatment in colon cancer, so as to better map out possible signal pathways implicated in colon cancer, contributing towards the eventual goal of effective combinatorial cancer therapy.

An area of cancer research that she hopes to explore in the future is miRNAs. Up to 30% of our protein coding genes may be regulated by miRNAs. miRNAs, having a crucial role in diverse biological processes such as cell development and proliferation, have potentially immense implications for cancer. The levels of mature miRNAs from the mir-17-92 locus have been proven to be substantially increased in B-cell lymphoma. It has also been found that c-myc activates the expression of a cluster of six miRNAs on human chromosome 13. miRNAs therefore have significant tumour suppression and oncogenic potential, presenting an extremely promising research path for cancer therapy! Tumours derived from tissues with common embryonic precursors also share similar miRNA expression patterns. miRNA profiling could therefore prove effective in cancer diagnosis and allow for better-informed treatment choices. She hopes to further her research in this area by looking into transcription factors that regulate miRNAs, and explore the precise targets of each miRNA.

"Low Kay Yi's acumen in biology studies, outstanding academic talent and profound understanding of her research work, will serve her well as she pursues a scientific career in future"

"My inspiration for doing cancer research stems from my belief that personalized and combinatorial medicine should be the eventual goal for cancer therapy. Just look around you and witness how many people suffer from cancer in our country. This should be the very motivation for your zest in cancer research!"

Key Research Contributions

Oncogenic mutations in the serine/threonine kinase B-RAF (BRAFV 600E) are found in 15% of colorectal cancers (CRC), and result in constitutive activation of the mitogen-activated protein kinase (MAPK) pathway. Therefore, B-RAF, being a frequently mutated protein in cancer, is an attractive target for colorectal cancer (CRC) drug treatment. However, resistance to B-RAF inhibitor drugs has been a significant clinical challenge. Effective strategies to overcome B-RAF inhibitor drug resistance are therefore urgently needed. Clinical trials examining the ATP-competitive B-RAF inhibitor, PLX4032, demonstrated unprecedented tumor regression in 81% of BRAFV 600E melanoma patients, but resulted in poor and mixed responses amongst BRAFV 600E CRC, suggesting the presence of resistance mechanisms that circumvent pharmacologic B-RAF inhibition. In our work, we demonstrated that resistance to B-RAF inhibition in CRC was perpetrated by the development of a novel negative feedback loop system intercalating the MAPK and PI3K/AKT pathways, as shown in figure 1. Furthermore, a combinatorial B-RAF inhibition with concurrent cMET, PI3K, or Tpl2 blockade was identified as a promising therapeutic strategy for overcoming B-RAF resistance. The results of the various combinatorial inhibitor-based therapies are illustrated in figures 2-4. Hence, mechanisms of drug resistance in CRC cells were firmly established in our work, and robust strategies to overcome the drug resistance were proposed. These findings, in turn, contributed to the concerted progress towards a cure for CRC.

Deaths from cancer worldwide are projected to continue to rise to over 11 million in 2030. Both her paternal grandparents passed away in 2004 from lung cancer. This is and will continue to be the very inspiration for her present and future efforts in cancer research. It is in the hope of Kay Yi that more students can take up cancer research. She has this advice to say to her fellow students, “To our students in Singapore, just look around you and witness how many people suffer from cancer in our country. This should be the very motivation for your zest in cancer research!”

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