Since my years as a Harvard faculty member, I have focused a sustained effort toward cancer biology, and my initial most significant contribution was the first to discover that pro-survival pathway activation is directly associated with p53-dependent genotoxic responses in cancer cells, and have provided a unique and significant contribution in this area. As an Assistant and then as an Associate Professor at the BIDMC and the MGH/Harvard Medical School, I pursued my major interest in how tumor suppressor p53-mediated transcriptional regulation influences cell fate decisions: live or die. Based on my contribution concerning the dark side of p53 in cancer therapeutics that wt-p53 can function as a guardian of cancer genome for their survival against therapeutic stress, I have established close collaborations with the Broad Institute utilizing their technological, computational and chemical biological tools under their Chemical Genetics Platform. Together with Broad scientists, I have identified several promising small molecules with anti-cancer activity through the activation of tumor suppressor p53 apoptotic pathway. Specifically, we have identified a small molecule to induce apoptosis selectively in cells having a cancer genotype by targeting a non-oncogene co-dependency acquired by the expression of the cancer genotype in response to transformation-induced oxidative stress. This highlights a novel strategy for cancer therapy that preferentially eradicates cancer cells by targeting the ROS stress-response pathway. My experience in this area has played a major role in the development of a Chemical Genetics Core facility at CBRC in collaboration with the Broad Institute. My group now possesses considerable experience in systematic small molecule technologies. I will continue to assist with the design, validation, execution and interpretation of investigator initiated chemical genetic screens.
"A neomycin cassette replaces exons 2-6, including the start codon, of Trp53 (transformation related protein 53). Mice homozygous for the mutation show no visible phenotype but most develop tumors (principally lymphomas and sarcomas) at three to six months of age. Heterozygous mice develop tumors at about 10 months of age. These mice model some of the features of human Li-Fraumeni syndrome, a form of familial breast cancer with mutations in TRP53. Homozygous mice may produce a litter before succumbing to tumors. "
"These mice contain a point-mutant allele of Trp53 that can be activated by Cre-mediated recombination. The conditional allele, containing LoxP sites and a transcriptional/translational STOP sequence, is functionally equivalent to a null mutation."