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Maureen E. Murphy, Ph.D.

  • Deputy Director, Ellen and Ronald Caplan Cancer Center

  • Ira Brind Professor and Program Leader, Molecular and Cellular Oncogenesis Program

  • Associate Vice President for Faculty Affairs

Murphy studies the genetics of the p53 tumor suppressor protein. Her laboratory focuses on genetic variants of p53 that exist in populations of African-descent (P47S and Y107H) and Ashkenazi Jewish descent (G334R). Her work seeks to understand the impact of these genetic variants of p53 on cancer risk and the efficacy of cancer therapy. She also seeks to identify personalized medicine approaches for tumors with these variants. Therefore, her work has direct relevance for improving the cancer prognosis and therapy of African and Ashkenazi Jewish Americans. Murphy also studies the cancer-survival protein HSP70. Her lab employs a novel series of HSP70 inhibitors for melanoma and colorectal cancer therapy.

Murphy obtained a B.S. degree in biochemistry at Rutgers University, followed by a doctorate in molecular biology at the University of Pennsylvania School of Medicine. In 1994, she began postdoctoral research at Princeton University in the laboratory of Arnold J. Levine, Ph.D., the co-discoverer of p53. In 1998, Murphy became an Assistant Professor at Fox Chase Cancer Center, where she was promoted to Associate Professor in 2003, and Full Professor in 2011. She joined The Wistar Institute in 2011 and became Program Leader of the Molecular and Cellular Oncogenesis Program in 2012. Murphy is an adjunct professor at Drexel University College of Medicine and The Perelman School of Medicine at the University of Pennsylvania.

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The Murphy Laboratory

215-495-6870
mmurphy@wistar.org

The Murphy Laboratory

The Murphy laboratory focuses on two cancer-critical proteins involved in tumor cell survival and death: HSP70 and p53. p53 is the most frequently mutated gene in human cancer and is widely regarded as the most important anti-cancer defense protein in the body. The lab studies genetic variants of the p53 gene that exist in different ethnic groups. This work seeks to understand the impact of these genetic variants on the increased cancer burden experienced by these groups. Work in the Murphy lab also aims to identify novel cancer therapies that are more effective on tumors that contain genetic variants of p53 that exist in African Americans and Ashkenazi Jewish populations to improve personalized medicine.

The HSP70 protein is highly expressed in the majority of human tumors but is largely undetectable in normal cells, making it an ideal cancer target. The Murphy lab uses a series of novel HSP70 inhibitors they have created for the therapy of human tumors, with focus on colorectal cancer and melanoma. They also seek to understand why tumors that express high levels of HSP70 are more aggressive and are associated with poorer prognosis.

Staff
  • Postdoctoral Fellows

    Chunlei Shao, Ph.D.
    David Stieg, Ph.D.

  • Predoctoral Fellows

    Maya Foster

  • Research Assistant

    James “Fitz” Dougherty

Research

THE TUMOR SUPPRESSOR P53

p53 is the most important gene in human cancer. Up to 60 percent of human tumors contain mutations in p53, making it the most frequently mutated gene in human cancer. In addition, germline mutations in p53 cause a syndrome called Li Fraumeni disease where people affected develop multiple tumors of the brain, breast, bone, and adrenal cortex before their second decade of life. Therefore, alterations that reduce p53 function have tremendous potential to increase cancer risk.

Unlike other tumor suppressor genes and oncogenes, p53 is unique because it possesses a number of coding region variants that differ in different ethnic populations. Our work has identified two coding region variants in p53 that exist in individuals of African descent. We find that these variants show impaired tumor suppressor function and may contribute to the increased cancer risk and reduced efficacy of cancer therapy, currently experienced by African Americans. Most recently, we have identified chemotherapeutic drugs that preferentially eradicate tumors that contain these African-centric variants of p53. A major goal in the laboratory is to improve the treatment of cancers from individuals of African descent.

HSP70 INHIBITORS FOR CANCER THERAPY

HSP70 is a cancer-critical chaperone protein that allows tumor cells to survive under conditions of stress and aneuploidy by preventing proteotoxic stress. We identified a novel series of inhibitors for HSP70 that are potent and effective anti-cancer agents. More recently, we discovered that a significant fraction of HSP70 in tumors is localized to mitochondria. We modified our inhibitor to target mitochondrial HSP70, and found that this compound, which we call AP-4-139B, can effectively target melanoma tumors in mice, and can inhibit melanoma metastasis, with no evidence for toxicity to normal tissues. We also find that this compound extends the response of melanoma to current therapies like BRAF and MEK inhibitors. Our studies in this area seek to position our HSP70 inhibitors for eventual use in humans. These studies are done in collaboration with the Salvino laboratory at Wistar.

Murphy Lab in the News

Selected Publications

A Rare TP53 Mutation Predominant in Ashkenazi Jews Confers Risk of Multiple Cancers.

Powers, J., Pinto, E.M., Barnoud, T., Leung, J.C., Martynyuk, T., Kossenkov, A.V., Philips, A.H., Desai, H., Hausler, R., Kelly, G., et al. “A Rare TP53 Mutation Predominant in Ashkenazi Jews Confers Risk of Multiple Cancers.” Cancer Res. 2020 Sep 1;80(17):3732-3744.doi: 10.1158/0008-5472.CAN-20-1390. Epub 2020 Jul 16.

African-centric TP53 Variant Increases Iron Accumulation and Bacterial Pathogenesis but Improves Response to Malaria Toxin.

Singh, K.S., Leu, J.I., Barnoud, T., Vonteddu, P., Gnanapradeepan, K., Lin, C., Liu, Q., Barton, J.C., Kossenkov, A.V., George, D.L., et al. “African-centric TP53 Variant Increases Iron Accumulation and Bacterial Pathogenesis but Improves Response to Malaria Toxin.” Nat Commun. 2020 Jan 24;11(1):473. doi: 10.1038/s41467-019-14151-9.

Mechanistic Basis for Impaired Ferroptosis in Cells Expressing the African-centric S47 Variant of p53.

Leu, J.I., Murphy, M.E., George, D.L. “Mechanistic Basis for Impaired Ferroptosis in Cells Expressing the African-centric S47 Variant of p53.” Proc Natl Acad Sci U S A. 2019 Apr 23;116(17):8390-8396. doi: 10.1073/pnas.1821277116. Epub 2019 Apr 8.

Tailoring Chemotherapy for the African-Centric S47 Variant of TP53.

Barnoud, T., Budina-Kolomets, A., Basu, S., Leu, J.I., Good, M., Kung, CP., Liu, J., Liu, Q., Villanueva, J., Zhang, R., et al. “Tailoring Chemotherapy for the African-Centric S47 Variant of TP53.” Cancer Res. 2018 Oct 1;78(19):5694-5705. doi: 10.1158/0008-5472.CAN-18-1327. Epub 2018 Aug 16.

A functionally significant SNP in TP53 and breast cancer risk in African-American women.

Murphy, M.E., Liu, S., Yao, S., Huo, D., Liu, Q., Dolfi, S.C., Hirshfield, K.M., Hong, CC., Hu, Q., Olshan, A.F., et al. “A functionally significant SNP in TP53 and breast cancer risk in African-American women.” NPJ Breast Cancer. 2017 Feb 27;3:5. doi: 10.1038/s41523-017-0007-9. eCollection 2017.

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