Research Discipline(s): Basic, Translational
Primary Title: Senior Scientist, Paul Albrechtsen Research Institute, CancerCare Manitoba
Additional Titles & Affiliations: Director, Manitoba Tumour Bank, CancerCare Manitoba; Associate Professor, Dept. of Pharmacology and Therapeutics, University of Manitoba
RESEARCH TOPICS
Blood Disorders, Brain Cancer, Breast Cancer, Tumour Banking, Biorepositories, DNA Damage Repair, Chemoresistance, Drug Resistance, Drug Combination Therapy
CancerCare Manitoba
675 McDermot Ave, ON5010
Winnipeg, MB R3E 0V9
Canada
“Research is seeing what everybody else has seen and thinking what nobody else has thought.” - Albert Szent-Györgyi
Research Summary
DNA strand breaks occur on a daily basis in cells due to cell stress, environmental factors, oxidation and metabolism. Damaged DNA is resolved by dedicated DNA damage response (DDR) and repair mechanisms in order to preserve genomic integrity and cell function. The goal of conventional chemotherapeutic drugs and radiotherapy is to elicit DNA damage to overwhelm the tumour’s innate DDR and induce cell death. However, tumour cells have remarkable ability to respond to DNA damage, repair and adapt thus allowing survival and eventual drug resistance. It is predicted that >90% of all tumours incur at least one defect in the DNA damage response (DDR), thus tumour cell survival relies upon enhanced activity of other compensatory DNA repair pathways. The aggressive and deadly brain tumour, glioblastoma multiforme (GBM) shows a very high level of recurrence due to emergence of chemo/radio-resistant tumour cell populations; patients usually only live about 1 yr from their date of diagnosis.
My research seeks to identify the “back-up” DNA repair pathways in these deadly brain tumours in order to enhance patient treatment success and quality-of-life. Recently, this work has been extended to the analysis of CLL, a form of adult-onset leukemia. In collaboration with clinical research laboratories (brain tumors: Dr. Sheila Singh – McMaster; CLL: Dr. James Johnston – UM/CCMR), we use functional assays to identify and dysregulate DNA repair enzymes underlying chemoresistance. This work has enabled several basic, pre-clinical and clinical analyses pertaining to CNS tumour and leukemia research, particularly in, i) developing and analyzing novel chemotherapeutics and, ii) identifying new ways to characterize chemoresistance in the context of tumour heterogeneity.
In addition, in my role as the Director of the Manitoba Tumour Bank, I strive to expand the remit of this invaluable biorepository resource so as to link basic and clinical cancer researchers, engage in patient partners and the Manitoba public health system so as to create and expand translational research capacity and teams.
The research I am invested in continually evolves but now wholly involves clinical collaborations locally, nationally and internationally. These links have fomented translational team-based research approaches focused on understanding molecular mechanisms of treatment-resistance and tumour recurrence using primary patient-derived tumour materials/samples in fundamental and pre-clinical experimental studies.
Goals
The goal of my research is to perform fundamental scientific experiments on clinical/patient-derived samples in order to gain mechanistic insights into drug resistance mechanisms. These findings can lead to new drugs and/or drug combinations to help patients with refractory disease.
Research Biography
I received my B.Sc. (Biochemistry) from the University of Alberta and received my Ph.D. (Oncology) at the Cross Cancer Institute and the University of Alberta in the lab of Dr. Roseline Godbout. My post-doctoral training, at St. Jude Children’s Research Hospital, in the area of DNA damage and repair in neurodevelopment and neuro-oncology was done in the lab of Dr. Peter McKinnon. In 2013, I began my independent academic research position at the University of Manitoba and CancerCare Manitoba within the Department of Pharmacology and Therapeutics (D-PT) and the Paul Albrechtsen Research Institute CancerCare Manitoba. In Sept 2022, I took on the role as Director of the Manitoba Tumour Bank.
My translational research program is focused on DNA damage and repair in neuro-oncology and CLL. I am an a Senior Scientist within CCMR, Director of the Manitoba Tumour Bank and an Associate Professor within the Department of Pharmacology and Therapeutics (D-PT). I was the recipient of the CIHR Institute of Cancer Research 2014 Early Career Award in Cancer Research and a CIHR New Investigator award. I have also established industrial partnerships, which have facilitated the development of innovative methodological platforms to accelerate my DNA damage repair research program. These were instrumental in obtaining my CFI JELF award to develop an innovative high-throughput genotoxicity and drug screening facility to interrogate DNA repair biology and to identify new therapies against neurological and lymphoproliferative malignancy. With this platform in-hand and my research program maturing, I was awarded a TFRI Terry Fox New Investigator Award to study deficiency/hyperactivity of DNA damage repair pathways underpinning resistant/recurrent disease. In total, I have garnered over $3.9M in funding from various local and international funding agencies including CIHR, CFI, Research Manitoba, CCMF and the Terry Fox Research Institute. I have published 41 peer-reviewed journal articles, book chapters and/or reviews. This body of work has garnered over 1500 citations and accrued an h-index of 19. I am also actively involved in trainee development, mentorship and career progression through various University-wide initiatives, courses and workshops.
Achievements
- Merit Award for Service (2022) – University of Manitoba and University of Manitoba Faculty Association.
- Terry Fox New Investigator Award, Terry Fox Research Institute, 2018-2022, (Principal Investigator), “Targeting Resistant Glioblastoma Multiforme (rGBM) Through Suppression of Overactive DNA Repair Activity”. $450,000, 3 yrs
- CIHR Early Career Investigator Observer Program (2018) – Cancer Biology and Therapeutics panel, Canadian Institutes of Health Research.
- CIHR New Investigator Salary Award (2015), Canadian Institutes of Health Research, 2015-2020, “Modulation of the DNA damage repair (DDR) response in the treatment of brain tumours.” $300,000, 5 yrs.
- CIHR Institute of Cancer Research Early Career Award in Cancer (2015). Highest ranking (by percent rank) by a new principal investigator in the 2014 CIHR Operating Grant competition for “ATM and TDP1 coordinate neurodevelopment and modulate Top1-mediated anti-cancer therapeutic outcome.” $25,000, 1 yr.
- CIHR Institute of Cancer Research and CIHR ICS (2016) - Travel Award to attend 2016 IARC 50th Anniversary Meeting in Lyon, France. $3000, 1 yr.
- Canadian Cancer Society Research Institute Junior Investigator Award (2013) - Travel Award to Observe 2013 CCSRI Innovation Grant Panel. $1000, 1 yr.
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Featured Publications
- Kost, S.E.F., Saleh, A., Yuan, S.H., Kuzio, B., Gibson, S. B., Yang, L., Banerji, V. Johnston, J.B. and KATYAL, S. (2023). DNA-PK hyperactivation occurs in deletion 11q chronic lymphocytic leukemia and is both a biomarker and therapeutic target for drug-resistant disease. Blood Cancer Journal. 13:20. IF: 11.68
- Kwak Y.D., Shaw, T., Downing, S.M., Tewari, A., Aditi, Jin, H., Li, Y., Dumitrache, L.C., KATYAL, S., Khodakhah, K., Russell, H.R. and McKinnon, P.J. (2021). Chromatin architecture at susceptible gene loci in cerebellar Purkinje characterize DNA damage-induced neurodegeneration. Science Advances. 7: eabg6363. IF: 14.14
- Sinha, A., Saleh, A., Endersby, R., Yuan S.H., Chokshi, C.R., Brown, K.R., Kuzio, B., Kauppinen, T.K., Singh, S.K., Baker, S., McKinnon, P.J. and KATYAL, S. (2020). RAD51-mediated DNA homologous recombination is independent of PTEN. Cancers. 12: E3178. IF: 6.64
- Kost, S., Saleh, A., Meija, E.M., Mostafizar, M., Bouchard, E.D.J., Banerji, V., Marshall, A.J., Gibson, S.B., *Johnston, J.B. and *KATYAL, S. (2019). Transcriptional modulation by Idelalisib synergizes with bendamustine in chronic lymphocytic leukemia. Cancers. 11: E1519. * denotes co-corresponding authors. IF: 6.64
- "#KATYAL, S., Lee, Y., Nitiss, K., Downing, S., Zhao, J., Li, Y., Russell, H.R., Petrini, J.H.J, Nitiss, J.L., #McKinnon, P.J. (2014). Aberrant topoisomerase-1 DNA lesions are pathogenic in neurodegenerative genome instability syndromes. Nat. Neurosci. 17: 813-21. IF 28.8 # co-corresponding"
- Lee, Y., KATYAL, S., Downing, S., Zhao, J., Russell, H.R., McKinnon, P.J. (2012). Neurogenesis requires TopBP1 to prevent catastrophic replication-associated DNA damage in early progenitors. Nat. Neurosci. 15: 829-826. IF 28.8
- "*Gao, Y., * KATYAL, S., Lee, Y., Zhao, J., Rehg, J.E., Russell, H.R. and McKinnon, P.J. (2011). Ligase III is critical for mtDNA integrity but not Xrcc1-mediated nuclear DNA repair. Nature. 471: 240-244. IF 64.8 *Equal Contribution"
- Lee, Y., KATYAL, S., Li, Y., El-Khamisy, S.F., Russell, H.R., Caldecott, K.W. and McKinnon, P.J. (2009). Genesis of cerebellar interneurons and the prevention of neural DNA damage require Xrcc1. Nat. Neurosci. 12: 973-980. IF 28.8
