Assistant Professor, Department of Pharmacology and Therapeutics
University of Manitoba;
Senior Scientist, Manitoba Institute of Cell Biology
Manitoba Institute of Cell Biology, 675 McDermot Ave, ON5010, Winnipeg, MB, R3E 0V9
204-787-2765, fax: 204-787-2190
Brain tumours are devastating to individuals, families and the community. Medulloblastoma (MB) arises from deregulated growth of neuronal precursors (neuroprogenitors) in the developing cerebellum. MBs are highly invasive and the most common pediatric brain tumour. Current MB treatment strategies include surgery, radiation and systemic chemotherapy achieving a 70% cure rate, however; children oftentimes lead a poor long-term quality-of-life which include severe impairment in neurocognitive, neurobehavioral and motor function. As many MB patients are afflicted at a relatively young age, lifelong management of MB post-treatment invokes considerable financial burden to the public health care system (estimated at over $1,000,000 per patient) and the need for continual family support and social assistance. Malignant glioma (MG) arises from glial cells, termed astrocytes, and is a highly aggressive brain tumour that afflicts individuals of all ages. MG prognoses are generally poor and rarely curable with median adult survival of 14 months. Medical intervention is highly invasive and incurs trauma and impairment. Furthermore, the impenitent stealth of patient death is devastating to families and the community-at-large. Progress to further ameliorate outcomes of brain tumour patients has been limited by the toxicity of conventional front-line radio- and chemotherapeutic treatments as they induce highly lethal DNA strand breaks in both normal and tumour cells. As normal brain tissue is fully developed and generally post-mitotic in nature, any cell loss is neurodegenerative. |
DNA repair pathways are guardians of the cellular genome. Every individual human cell is estimated to incur tens of thousands of DNA strand breaks due to environmental stress, oxidation, metabolic function and DNA decay. To preserve genomic integrity, these breaks are resolved by dedicated DNA damage repair (DDR) pathways that ensure faithful transmission of genomes in dividing cells to ensure proper cell function and survival. There are two classes of DNA strand breaks, double-strand breaks (DSBs) and DNA single-strand breaks (SSBs), which are resolved by specific repair pathways, DSBR and SSBR. The inability to properly process and repair SSBs can interfere with the DNA replication and transcriptional machinery resulting in persistent SSBs, formation of the particularly genotoxic DNA double-stranded break (DSB) lesion and aberrant gene expression resulting in a variety of cellular pathology, including: senescence, cancer and apoptosis. It is known that the diverse mechanisms involving cell cycle regulation, DDR pathways, cellular metabolism, and cell death act in concert in response to DNA damage. As such, cellular life and death decisions are balanced by these mechanisms as defective DDR in proliferating cells, including neuroprogenitors, can lead to cancer, while defective neuronal DDR can lead to neurodegeneration.
Anti-tumorigenic agents overwhelm cellular DNA repair responses with lethal levels of genotoxicity. The objective of common front-line radiation and chemotherapeutic strategies used in the treatment of brain tumours is to induce DNA breaks so as to overwhelm the cellular DNA repair machinery thus promoting genomic damage and tumour cell death. However, as the intrinsic cellular DNA repair process counteracts the therapeutic efficacy of this strategy, high radiation and drug doses are required which result in harmful neural and systemic side effects. My research seeks to identify ways to dysregulate cellular DNA repair pathways in tumours and improve therapeutic success. In this regard, DNA damage repair pathways are an ideal clinical target as we can specifically kill cancer cells by lowering the radio- and chemotherapeutic threshold of tumour cell genotoxicity by inhibiting redundant DNA repair pathways.
My research uses advanced molecular, biochemical and genetic techniques to gain insight into the biology of mammalian DNA strand break repair pathways. My goal is to identify ways to manipulate these pathways to develop novel treatment strategies in the clinical management of cancer.
We are seeking very highly motivated graduate students and postdoctoral fellows (with a strong history of previous success) to join our team.
More information on Dr. Katyal is also available on the Manitoba Institure of cell Biology Website at http://www.umanitoba.ca/institutes/manitoba_institute_cell_biology/MICB/Scientists/Katyal.html