Lab In The News
Wistar Researchers Garnered More Than $6M in Funding to Support New Discoveries in Cancer & Infectious Disease
Scientists at The Wistar Institute, an international biomedical research leader in cancer, immunology and infectious diseases, received research funds totaling $6 million between the end of 2017 and the first months of 2018.
TP53 Genetic Variant Found in Individuals of African Descent is Linked to Iron Overload but May Improve Response to Malaria
Iron accumulation and defects in the antibacterial function of macrophages caused by the P47S variant result in a less severe inflammatory response.
New Research Highlights a Rare Gene Mutation Linked to Cancer Risk in the Ashkenazi Jewish Population
Dr. Maureen Murphy, Ira Brind Professor and program leader of the Molecular & Cellular Oncogenesis Program of The Wistar Institute Cancer Center, has been investigating the importance of inherited mutations in the gene encoding p53 tumor suppressor protein to determine cancer susceptibility in people of African descent and people of Ashkenazi Jewish descent, for the past twenty-two years.
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, in order 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.
Tim Barnoud, Ph.D.
Jessica Leung, Ph.D.
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; 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 PET-16, 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 improve PET-16 as an anti-cancer compound, with the goal of positioning our HSP70 inhibitors for eventual use in humans.
Sachin Singh, K., Leu, J., Barnoud, T., Vonteddu, P., Gnanapradeepan, K., Lin, C., Liu, Q., Barton, J., Kossenkov, A., George, D., Murphy, M., Dotiwala, F. "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.
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. 2019 Apr 23;116(17):8390-8396. doi: 10.1073/pnas.1821277116. Epub 2019 Apr 8.
Barnoud, T., Budina-Kolomets, A., Basu, S., Leu, J.I., Good, M., Kung, C.P., 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.
Basu, S., Gnanapradeepan, K., Barnoud, T., Kung, C.P., Tavecchio, M., Scott, J., Watters, A., Chen, Q., Kossenkov, A.V., Murphy, M.E., et al. "Mutant p53 controls tumor metabolism and metastasis by regulating PGC-1α." Genes Dev. 2018 Feb 1;32(3-4):230-243. doi:10.1101/gad.309062.117. Epub 2018 Feb 20.
Jennis, M., Kung, C.P., Basu, S., Budina-Kolomets, A., Leu, J.I., Khaku, S., Scott, J.P., Cai, K.Q., Campbell, M.R., Porte, D., et al. "An African-specific polymorphism in the TP53 gene impairs p53 tumor suppressor function in a mouse model." Genes Dev. 2016 Apr 15;30(8):918-30. doi: 10.1101/gad.275891.115. Epub 2016 Mar 31.
Luis J. Montaner, D.V.M., D.Phil.
Vice President, Scientific Operations
Associate Director for Shared Resources, The Wistar Institute Cancer Center
Herbert Kean, M.D., Family Endowed Chair Professor; Director, HIV-1 Immunopathogenesis Laboratory and Leader, HIV Research Program, Vaccine & Immunotherapy Center
Immunology, Microenvironment & Metastasis Program, The Wistar Institute Cancer Center