Prson Gautam’s dissertation highlights the personalized medicine approach to tackle triple negative breast cancer
Triple negative breast cancer (TNBC) is a highly aggressive type of breast cancer that accounts for 15-20% of breast cancer cases. This cancer type still poses a challenge for clinical treatment since the key genetic events driving the disease are not known and the molecular subtyping approaches have not yet yielded any targeted therapy options.
The main aim of M.Sc. Prson Gautam’s thesis entitled "Chemical Systems Biology Studies of Triple Negative Breast Cancer Cell Lines” was to explore drug vulnerabilities of TNBC cell lines to learn more about the molecular pathology of this cancer and to identify novel, druggable target molecules. His doctoral dissertation will be publically examined on Thursday, 14 December, with the permission of the Faculty of Medicine of the University of Helsinki.
Prson Gautam graduated from the Uppsala University, Sweden in 2011, with biotechnology as his major subject. The Nordplus exchange program brought him to Finland and he started his PhD project in the group of FIMM-EMBL Group Leader Krister Wennerberg in 2013.
Prson’s thesis project is part of FIMM’s “Individualised systems medicine in cancer” Grand Challenge programme. Individualised drug sensitivity data is an essential part of this Grand Challenge research. The high-throughput drug sensitivity and resistance testing approach developed at FIMM provides the means for profiling cancer cells in terms of drug responses to hundreds of oncology compounds and their combinations. However, the currently available high throughput screening-compatible assays for measuring cell viability and toxicity have many limitations.
In his thesis study, Prson focused on setting up better ways of using the existing cell viability and toxicity readouts to determine drug responses using TNBC cell lines as a model. Furthermore, in collaboration with computational scientists from FIMM-EMBL Group Leader Tero Aittokallio’s group, he developed novel drug response metrics and scores. The thesis consists of three publications, two of which have already been published and one is under review.
For the thesis, he studied a panel of 16 TNBC cell lines using a functional profiling approach in which he measured the responses to approximately 300 oncology compounds and 350 kinase inhibitors.
In the first publication of the thesis, Prson established a multiplexed readout for both cell viability and cytotoxicity. In the second publication, he developed a novel drug response metric, called normalized drug response (NDR), which tolerates many kinds of screening artifacts. In this study, Prson was able to categorize TNBC cell lines into sensitive and insensitive groups based on their response to a class of drugs called mitotic inhibitors.
This approach will be a significant asset for future cell-based high throughput drug screening, as it saves time, effort and cost by eliminating the need to perform cytotoxicity assays or replicate screens. It is widely applicable not only for established cell lines but also against technically challenging and slow growing patient derived samples.
- Prson Gautam
In the last study, the team developed a systems network pharmacology approach and a novel kinase inhibition sensitivity score (KISS) to decipher the kinase signal addiction of breast cancer cell lines.
My thesis highlights the need to go beyond the mere cell viability readouts for drug sensitivity assessment of the cell lines or primary cancer cells. Since cell viability does not directly correlate to proliferation or cell death, a simple, multiplexed cell viability and cytotoxicity readout can provide more insights into the drug mode-of-action, hence aiding the design of rational treatment options.
Prson emphasises his positivity and social skills as keys to his successful PhD thesis project. In his free time, he enjoys making new friends, running, going to a gym, cooking and watching movies.
For me, the Wennerberg lab has been like a second family. I want to thank all my colleagues for creating such a supportive and lively environment.
Prson will continue working at FIMM for at least half a year. He is currently screening 30 patient derived xenograft cell lines for a large pancreatic cancer consortium project. In the future, he would be interested in further developing his data handling skills and medical knowledge and to work for example as a clinical trial manager.
He has certainly practised his coordinator skills during the past year by planning a translational medicine conference that will be organized in his home country, Nepal, next February. The conference has developed into a large national event involving local cancer hospitals and ministries and many FIMM Group Leaders and Senior Researchers will travel to Nepal to participate.
The public examination of Prson Gautam’s doctoral dissertation will take place on 14 December at 12 o'clock noon in Lecture hall 3 at Biomedicum Helsinki 1, Haartmaninkatu 8. The thesis has been supervised by FIMM-EMBL Group Leaders, Professor Krister Wennerberg and Professor Tero Aittokallio (FIMM, University of Helsinki). Professor Kjetil Tasken (Center for Molecular Medicine Norway NCMM, University of Oslo) will serve as the opponent and professor Sampsa Hautaniemi as the custos. The dissertation is also available in an electronic form.