Maureen Murphy, Ph.D.
Manipulating Cell Death Pathways for Improved Cancer Therapy
1. The tumor suppressor p53
p53 is the most important gene in human cancer. Up to sixty percent of human tumors contain mutations in p53, making it the most frequently mutated gene in human cancer. In addition, there are families that have germline mutations in p53, in a syndrome called Li Fraumeni disease; these people develop multiple tumors of the brain, breast, bone, and adrenal cortex before the 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). We 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. Further, we find 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.
Figure 1. Tumors that arise in S47 mice. Left panel: Hepatocellular carcinoma. Right panel: B cell lymphoma infiltrating the kidney (arrows)
2. HSP70 inhibitors for cancer therapy
We have obtained data that the pathway of autophagy is critical for tumor survival. We find that inhibiting this pathway using chemical or genetic inhibitors greatly impedes tumor progression, suggesting that this pathway is an Achilles heel for cancer. Recently we discovered a novel inhibitor of the chaperone protein HSP70 that is a potent and effective anti-cancer agent. This inhibitor, which we call PES, can successfully eradicate multiple tumor types, including melanoma and acute myeloid leukemia, while normal cells are not affected.
We have created a novel series of HSP70 inhibitors based upon the PES scaffold, and identified several that markedly prolong survival in a mouse model of melanoma, and also inhibit melanoma metastasis. One of these, called PET-16, shows the ability to target cancer cell mitochondria, thus impeding energy pathways. Current efforts are focused on the ability of PES and PET-16 to target tumor cell proteostasis pathways in melanoma and other tumors.