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 populations, in order to identify therapeutic protocols that work best in tumor cells that contain these variants. Her studies have relevance for understanding ethnic disparities in cancer risk and survival, and it makes use of cell lines, mouse models and human data.
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 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.
Subhasree Basu, Ph.D.
Anna Budina-Kolomets, M.D., 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.
Wild type p53 encodes proline at amino acid 47, but in 1:40 African Americans and 1:50 Hispanic Americans, this amino acid encodes serine (S47). The Murphy group found that the S47 variant has reduced phosphorylation on serine 46, and up to three-fold decreased apoptotic function. We also discovered that this variant has impaired ability to work as a transcription factor, regulating the expression of p53 target genes. We recently created a mouse model for the S47 variant, and compared this protein to normal (wild type) p53. We found that the S47 variant functioned very poorly in the transcription of a subset of p53 target genes. Moreover, the S47 mice get multiple types of cancer, including colorectal cancer, B cell lymphoma, pancreatic adenocarcinoma and histiocytic sarcoma. In addition, these mice develop mammary and prostate lesions.
In human studies, we have found that the S47 variant is associated with increased risk for pre-menopausal breast cancer in African American women and that African American men who have one S47 allele show earlier age of onset for prostate cancer. Currently we are seeking to better understand the function of the S47 variant. We are also testing the hypothesis that cancer therapy should be tailored for individuals who are S47. We seek to identify compounds that successfully eradicate S47 tumors. We believe that the proposed research will have direct impact on our understanding of disparities in cancer risk and efficacy of therapy in African and Hispanic Americans, which is a very important scientific goal.
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. In 2009 we discovered a novel inhibitor of HSP70 that is a potent and effective anti-cancer agent. 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.
Basu, S., Gnanapradeepan, K., 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.
Basu, S., Barnoud, T., Murphy, M.E., et al. "The African-specific S47 polymorphism of p53 alters chemosensitivity." Cell Cycle. 2016 Oct;15(19):2557-2560. Epub 2016 Aug 2.
Jennis M., Kung, C.P., Murphy, M.E., 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.
Budina-Kolomets, A., Webster, M.R., Murphy, M.E., et al. "HSP70 Inhibition Limits FAK-Dependent Invasion and Enhances the Response to Melanoma Treatment with BRAF Inhibitors." Cancer Res. 2016 May 1;76(9):2720-30. doi: 10.1158/0008-5472.CAN-15-2137. Epub 2016 Mar 16.
Kung, C.P., Leu, J.I., Murphy, M.E., et al. "The P72R Polymorphism of p53 Predisposes to Obesity and Metabolic Dysfunction" Cell Rep. 2016 Mar 15;14(10):2413-25. doi: 10.1016/j.celrep.2016.02.037. Epub 2016 Mar 3.
Luis J. Montaner, D.V.M., D.Phil.
Vice President, Scientific Operations
Herbert Kean, M.D., Family Endowed Chair Professor
Director, HIV-1 Immunopathogenesis Laboratory
Professor, Immunology, Microenvironment & Metastasis Program
Associate Director for Shared Facilities, Wistar Cancer Center
Scientific Director, Biomedical Research Support Facility
Scientific Director, Flow Cytometry Facility