Michael Weinfeld, PhD

Pronouns: he, him, his

Contact Overview Publications

Contact

Faculty of Medicine & Dentistry - Oncology Dept

Email: mweinfel@ualberta.ca
Phone: (780) 432-8438
Address: Cross Cancer Institute
11560 University Avenue

Edmonton AB

T6G 1Z2

Overview

Area of Study / Keywords

Drug development DNA damage DNA repair Cancer

About

Dr. Michael Weinfeld is currently appointed as Professor in the Department of Oncology in the Faculty of Medicine & Dentistry.

Research

The focus of the research in my laboratory is the cellular response to chemical and radiation-induced stress. We are particularly interested in DNA damage and repair, and cell death and survival.

Characterization of polynucleotide kinase and other DNA repair enzymes that act at strand break termini
Several years ago we cloned human polynucleotide kinase/phosphatase (PNKP), an enzyme that has the ability to phosphorylate 5'-hydroxyl termini and dephosphorylate 3'-phosphate termini, thus rendering the DNA termini suitable for the subsequent action of DNA polymerases and/or DNA ligases. With colleagues in the UK, US, France and Canada, we have shown that the protein is involved in several DNA repair pathways including base-excision repair, single-strand break repair and the nonhomologous end joining double-strand break repair pathway. Stable RNAi-mediated down-regulation of PNKP in human cells increases their sensitivity to ionizing radiation and camptothecin, a topoisomerase I inhibitor, and leads to a significant elevation in their spontaneous mutation frequency. In collaboration with Dallan Young (University of Calgary), we similarly observed that a PNK knockout mutant of S. pombe is hypersensitive to both agents.

Together with Drs. Mark Glover (University of Alberta) and Susan Lees-Miller (University of Calgary), we have initiated a detailed biophysical examination of the protein and its interaction with DNA and other DNA repair enzymes, such as XRCC1 and XRCC4. We are also collaborating with Frank Jirik (University of Calgary) to generate transgenic mice to define the physiological function(s) of and to dissect the importance of kinase and phosphatase activities. Recently, in collaboration with Dennis Hall (University of Alberta), we have identified a small molecule inhibitor of the phosphatase activity of PNKP and shown that it sensitizes cells to ionizing radiation and camptothecin. In collaboration with Edan Foley ( of we have identified synthetic lethal partners of PNKP including SHP-1 and PTEN.

Investigation of the carcinogenic properties of arsenic
Arsenic is a major environmental carcinogen, but it has been shown to be very difficult to induce tumours in laboratory animals with arsenic. This has led to the hypothesis that arsenic is a co-carcinogen that enhances the carcinogenicity of other agents. In collaboration with X. Chris Le (University of Alberta), we are examining the influence of arsenic on the formation and repair of DNA adducts generated by the carcinogenic polycyclic aromatic hydrocarbon benzo[a]pyrene and its metabolites.

DNA repair in initiating cells
Recent evidence has led to the proposal that normal stem cells may be the key cells in a tissue or organ that undergo mutation and transformation giving rise to “cancer stem cells”. Because normal adult stem cells are slowly dividing, long-lived cells and the precursors to differentiated cells, DNA repair and mutation avoidance in these cells should be critical. The cancer stem cells, however, undergone mutation, may have dysregulated DNA repair activity in one or more repair pathways, and/or reduced potential to undergo apoptosis or senescence. How normal and cancer stem cells deal with DNA damage and its consequences a fundamental question related to cancer and therapy. We are currently examining the DNA repair profile of breast cancer stem cells.

Analysis of low-dose radiation hypersensitivity
Exposure to environmental radiation and the application of new clinical modalities, such as radioimmunotherapy, have heightened the need to understand cellular responses to low dose and low-dose rate ionizing radiation. Many human cell lines exhibit a hyper-radiosensitivity (HRS) to radiation doses < 20 cGy, which manifests as a significant deviation from the clonogenic survival response predicted by a linear-quadratic fit to higher doses. This is followed by increased radioresistance (IRR) at slightly higher doses. Using a variety of cellular and molecular approaches, we have established that the phenomenon of low-dose radiation hypersensitivity is due to p53 and caspase-3 dependent apoptosis. We are further investigating the molecular mechanisms underlying both HRS and IRR.

Featured Publications

Cellular mechanism of action of 2-nitroimidazoles as hypoxia-selective therapeutic agents

Rashed F.B., Diaz-Dussan D., Mashayekhi F., Macdonald D., Nation P.N., Yang X.H., Sokhi S., Stoica A.C., El-Saidi H., Ricardo C., Narain R., Ismail I.H., Wiebe L.I., Kumar P., Weinfeld M.

Redox Biology. 2022 June; 52 10.1016/j.redox.2022.102300

Zika Virus Induces Mitotic Catastrophe in Human Neural Progenitors by Triggering Unscheduled Mitotic Entry in the Presence of DNA Damage While Functionally Depleting Nuclear PNKP

Rychlowska M., Agyapong A., Weinfeld M., Schang L.M.

JOURNAL OF VIROLOGY. 2022 May; 96 (9) 10.1128/jvi.00333-22

Hydrazonoyl chlorides possess promising antitumor properties

El Gendy M.A.M., Hassanein H., Saleh F.M., Karimi-Busheri F., Fanta M., Yang X., Tawfik D., Morsy S., Fahmy M., Hemid M., Abdel Azeiz M., Fared A., Weinfeld M.

LIFE SCIENCES. 2022 April; 295 10.1016/j.lfs.2022.120380

Biodistribution and Activity of EGFR Targeted Polymeric Micelles Delivering a New Inhibitor of DNA Repair to Orthotopic Colorectal Cancer Xenografts with Metastasis

De Paiva I.M., Vakili M.R., Soleimani A.H., Tabatabaei Dakhili S.A., Munira S., Paladino M., Martin G., Jirik F.R., Hall D.G., Weinfeld M., Lavasanifar A.

MOLECULAR PHARMACEUTICS. 2022 March; 19 (6):1825-1838 10.1021/acs.molpharmaceut.1c00918

Modulation of ERCC1-XPF Heterodimerization Inhibition via Structural Modification of Small Molecule Inhibitor Side-Chains

Weilbeer C., Jay D., Donnelly J.C., Gentile F., Karimi-Busheri F., Yang X., Mani R.S., Yu Y., Elmenoufy A.H., Barakat K.H., Tuszynski J.A., Weinfeld M., West F.G.

Frontiers in Oncology. 2022 March; 12 10.3389/fonc.2022.819172

Mutations of the DNA repair gene PNKP in a patient with microcephaly, seizures, and developmental delay (MCSZ) presenting with a high-grade brain tumor

Jiang B., Murray C., Cole B.L., Glover J.N.M., Chan G.K., Deschenes J., Mani R.S., Subedi S., Nerva J.D., Wang A.C., Lockwood C.M., Mefford H.C., Leary S.E.S., Ojemann J.G., Weinfeld M., Ene C.I.

Scientific Reports. 2022 March; 12 (1) 10.1038/s41598-022-09097-w

Nano-Delivery of a Novel Inhibitor of Polynucleotide Kinase/Phosphatase (PNKP) for Targeted Sensitization of Colorectal Cancer to Radiation-Induced DNA Damage

Sadat S.M.A., Wuest M., Paiva I.M., Munira S., Sarrami N., Sanaee F., Yang X., Paladino M., Binkhathlan Z., Karimi-Busheri F., Martin G.R., Jirik F.R., Murray D., Gamper A.M., Hall D.G., Weinfeld M., Lavasanifar A.

Frontiers in Oncology. 2021 December; 11 10.3389/fonc.2021.772920

Pnkp is required for maintaining the integrity of progenitor cell populations in adult mice

Shin W., Alpaugh W., Hallihan L.J., Sinha S., Crowther E., Martin G.R., Scheidl-Yee T., Yang X., Yoon G., Goldsmith T., Berger N.D., de Almeida L.G.N., Dufour A., Dobrinski I., Weinfeld M., Jirik F.R., Biernaskie J.

Life Science Alliance. 2021 September; 4 (9) 10.26508/LSA.202000790

Gold Nanorods are Selective Cytotoxic Agents

El Gendy M., Weinfeld M., Abdoon A.

Anti-Cancer Agents in Medicinal Chemistry. 2021 July; 22 (5):991-998 10.2174/1871520621666210726130028

A synthetically lethal nanomedicine delivering novel inhibitors of polynucleotide kinase 3'-phosphatase (PNKP) for targeted therapy of PTEN-deficient colorectal cancer

Sadat S.M.A., Paiva I.M., Shire Z., Sanaee F., Morgan T.D.R., Paladino M., Karimi-Busheri F., Mani R.S., Martin G.R., Jirik F.R., Hall D.G., Weinfeld M., Lavasanifar A.

Journal of Controlled Release. 2021 June; 334 10.1016/j.jconrel.2021.04.034

Design, synthesis and in vitro cell-free/cell-based biological evaluations of novel ERCC1-XPF inhibitors targeting DNA repair pathway

Elmenoufy A.H., Gentile F., Jay D., Karimi-Busheri F., Yang X., Soueidan O.M., Mani R.S., Ciniero G., Tuszynski J.A., Weinfeld M., West F.G.

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. 2020 October; 204 10.1016/j.ejmech.2020.112658

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