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Katherine Borden

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Katherine Borden
Academic background
Alma materYale University
ThesisProtein folding studies on the thioredoxins derived from Escherichia coli and bacteriophage T4 (1990)
Doctoral advisorFred Richards
Academic work
DisciplineMolecular Biology
InstitutionsUniversity of Montreal

Katherine Borden PhD FRSC is a Canadian researcher of Molecular Biology and Biochemistry at the University of Montreal in Quebec, Canada. She has worked on finding new cancer treatments using pre-existing drugs,.[1] She uses a combination of biochemistry, structural biology, cell biological, and clinical studies to study RNA processing. She has received many awards for this work including selected as a Stohlman Scholar of the Leukemia and Lymphoma Society USA (2005), Distinguished Scientist of the Canadian Society for Clinical Investigation (2011), CSMB Canadian Science Publishing Senior Investigator Award (2022) and was inducted as a fellow of the Royal Society of Canada in 2022.

Research

Her work provided a series of transformative revelations into the role of dysregulated RNA metabolism in cancer using the eukaryotic translation initiation factor eIF4E as an exemplar. Her studies demonstrated that dysregulation of this factor influenced multiple steps in RNA processing of thousands of RNAs simultaneously thereby reprogramming the cell to become more oncogenic.[2][3][4] eIF4E impacts the extent of m7G RNA capping, splicing, export and/or translation of these RNAs based on the presence of cis-acting elements within the RNAs as well as induction of wide scale changes to the production of factors substantially modulated the RNA processing landscape within cells. Her work showed that modulating of many of these factors influence cell survival and cell motility contributing to cancer.[5]

Her studies also led to the finding that a substantial number of Acute Myeloid Leukemia (AML) patients were characterized by elevated eIF4E.[6] This coupled to the discovery that eiF4E could bind to and be inhibited by an antiviral drug ribavirin[7][8][9] led to the first clinical trials targeting eIF4E in patients.[10] Indeed, these were also the first studies to target RNA translation or RNA export (and likely related RNA processing events) in humans. Targeting of eIF4E was safe and corresponded to objective clinical responses including remissions in patients.[10][11] These studies also led to the discovery of a new form of drug resistance in patients, inducible drug glucuronidation. Drug glucuronidation impacts 50% of drugs usually through liver mediated drug deactivation. However, this work revealed that cancer cells could turn on the enzymes involved in this process.[12]

Her lab developed the means to target this inducible drug glucuronidation, with Vismodegib, and showed in patients this reduced levels of glucuronidation enzymes which corresponded to ribavirin activity, targeting of eIF4E and objective clinical responses.[12][13] However, eventually patients become resistant to the Visomdegib and thus, new modalities are required to overcome this form of drug resistance long term.

References

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  1. ^ "Researchers pairing antiviral, chemotherapy drugs to fight leukemia". CTVNews. 2013-04-11. Retrieved 2023-07-11.
  2. ^ Culjkovic, Biljana; Topisirovic, Ivan; Skrabanek, Lucy; Ruiz-Gutierrez, Melisa; Borden, Katherine L. B. (2006-11-06). "eIF4E is a central node of an RNA regulon that governs cellular proliferation". The Journal of Cell Biology. 175 (3): 415–426. doi:10.1083/jcb.200607020. ISSN 0021-9525. PMC 2064519. PMID 17074885.
  3. ^ Ghram, Mehdi; Morris, Gavin; Culjkovic-Kraljacic, Biljana; Mars, Jean-Clement; Gendron, Patrick; Skrabanek, Lucy; Revuelta, Maria Victoria; Cerchietti, Leandro; Guzman, Monica L.; Borden, Katherine L. B. (2023-04-03). "The eukaryotic translation initiation factor eIF4E reprograms alternative splicing". The EMBO Journal. 42 (7): e110496. doi:10.15252/embj.2021110496. ISSN 1460-2075. PMC 10068332. PMID 36843541.
  4. ^ Volpon, Laurent; Culjkovic-Kraljacic, Biljana; Sohn, Hye Seon; Blanchet-Cohen, Alexis; Osborne, Michael J.; Borden, Katherine L. B. (June 2017). "A biochemical framework for eIF4E-dependent mRNA export and nuclear recycling of the export machinery". RNA. 23 (6): 927–937. doi:10.1261/rna.060137.116. ISSN 1469-9001. PMC 5435865. PMID 28325843.
  5. ^ Borden, Katherine L. B. (2023-11-05). "The eukaryotic translation initiation factor eIF4E unexpectedly acts in splicing thereby coupling mRNA processing with translation: eIF4E induces widescale splicing reprogramming providing system-wide connectivity between splicing, nuclear mRNA export and translation". BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology: e2300145. doi:10.1002/bies.202300145. ISSN 1521-1878. PMC 11021180. PMID 37926700.
  6. ^ Topisirovic, Ivan; Guzman, Monica L.; McConnell, Melanie J.; Licht, Jonathan D.; Culjkovic, Biljana; Neering, Sarah J.; Jordan, Craig T.; Borden, Katherine L. B. (December 2003). "Aberrant eukaryotic translation initiation factor 4E-dependent mRNA transport impedes hematopoietic differentiation and contributes to leukemogenesis". Molecular and Cellular Biology. 23 (24): 8992–9002. doi:10.1128/MCB.23.24.8992-9002.2003. ISSN 0270-7306. PMC 309660. PMID 14645512.
  7. ^ Kentsis, Alex; Topisirovic, Ivan; Culjkovic, Biljana; Shao, Ling; Borden, Katherine L. B. (2004-12-28). "Ribavirin suppresses eIF4E-mediated oncogenic transformation by physical mimicry of the 7-methyl guanosine mRNA cap". Proceedings of the National Academy of Sciences of the United States of America. 101 (52): 18105–18110. Bibcode:2004PNAS..10118105K. doi:10.1073/pnas.0406927102. ISSN 0027-8424. PMC 539790. PMID 15601771.
  8. ^ Kentsis, Alex; Volpon, Laurent; Topisirovic, Ivan; Soll, Clifford E.; Culjkovic, Biljana; Shao, Ling; Borden, Katherine L. B. (December 2005). "Further evidence that ribavirin interacts with eIF4E". RNA. 11 (12): 1762–1766. doi:10.1261/rna.2238705. ISSN 1355-8382. PMC 1370864. PMID 16251386.
  9. ^ Volpon, Laurent; Osborne, Michael J.; Zahreddine, Hiba; Romeo, Andrea A.; Borden, Katherine L. B. (2013-05-10). "Conformational changes induced in the eukaryotic translation initiation factor eIF4E by a clinically relevant inhibitor, ribavirin triphosphate". Biochemical and Biophysical Research Communications. 434 (3): 614–619. doi:10.1016/j.bbrc.2013.03.125. ISSN 1090-2104. PMC 3659399. PMID 23583375.
  10. ^ a b Assouline, Sarit; Culjkovic, Biljana; Cocolakis, Eftihia; Rousseau, Caroline; Beslu, Nathalie; Amri, Abdellatif; Caplan, Stephen; Leber, Brian; Roy, Denis-Claude; Miller, Wilson H.; Borden, Katherine L. B. (2009-07-09). "Molecular targeting of the oncogene eIF4E in acute myeloid leukemia (AML): a proof-of-principle clinical trial with ribavirin". Blood. 114 (2): 257–260. doi:10.1182/blood-2009-02-205153. ISSN 1528-0020. PMID 19433856.
  11. ^ Assouline, Sarit; Culjkovic-Kraljacic, Biljana; Bergeron, Julie; Caplan, Stephen; Cocolakis, Eftihia; Lambert, Caroline; Lau, Cara J.; Zahreddine, Hiba Ahmad; Miller, Wilson H.; Borden, Katherine L. B. (January 2015). "A phase I trial of ribavirin and low-dose cytarabine for the treatment of relapsed and refractory acute myeloid leukemia with elevated eIF4E". Haematologica. 100 (1): e7–9. doi:10.3324/haematol.2014.111245. ISSN 1592-8721. PMC 4281321. PMID 25425688.
  12. ^ a b Zahreddine, Hiba Ahmad; Culjkovic-Kraljacic, Biljana; Assouline, Sarit; Gendron, Patrick; Romeo, Andrea A.; Morris, Stephen J.; Cormack, Gregory; Jaquith, James B.; Cerchietti, Leandro; Cocolakis, Eftihia; Amri, Abdellatif; Bergeron, Julie; Leber, Brian; Becker, Michael W.; Pei, Shanshan (2014-07-03). "The sonic hedgehog factor GLI1 imparts drug resistance through inducible glucuronidation". Nature. 511 (7507): 90–93. Bibcode:2014Natur.511...90Z. doi:10.1038/nature13283. ISSN 1476-4687. PMC 4138053. PMID 24870236.
  13. ^ Assouline, Sarit; Gasiorek, Jadwiga; Bergeron, Julie; Lambert, Caroline; Culjkovic-Kraljacic, Biljana; Cocolakis, Eftihia; Zakaria, Chadi; Szlachtycz, David; Yee, Karen; Borden, Katherine L. B. (2023-11-01). "Molecular targeting of the UDP-glucuronosyltransferase enzymes in high-eukaryotic translation initiation factor 4E refractory/relapsed acute myeloid leukemia patients: a randomized phase II trial of vismodegib, ribavirin with or without decitabine". Haematologica. 108 (11): 2946–2958. doi:10.3324/haematol.2023.282791. ISSN 1592-8721. PMC 10620574. PMID 36951168.
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