Novel inhibitors of oncogenic p53 mutants for lung cancer therapy.

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Project Summary Gain-of-function (GOF) p53 mutations are very frequent in all types of chemo- and radio-resistant intractable lung cancers with poor prognosis. Depletion of endogenous mutant p53 eliminates the tumorigenic phenotype of many human lung cancer cell lines. Therefore, small molecule inhibitors that specifically inactivate the oncogenic function of GOF p53 should have a cancer cell-specific efficient impact on many lung cancer patients. Using genome wide analyses of lung cancer cells, we have traced the oncogenic properties of GOF p53 to its ability to transcriptionally activate expression of cell proliferative genes. Our published genetic data showed that transactivation deficient GOF p53 is defective in tumor formation and proliferation of lung cancer cells. Here we propose to test a hypothesis that small molecule inhibitors of GOF p53-specific transcriptional activation (GOF p53TAIn) specifically inhibit proliferation of lung cancer cells and tumors with GOF p53 mutation. Our short- term goal is to test this hypothesis in cellular and animal models of lung cancer. Our long-term goal is to translate our findings into novel targeted therapies for human lung cancer. In support of our hypothesis, our preliminary studies have identified novel small molecule inhibitors (GOF p53TAIns) that specifically inhibit GOF p53-driven transcriptional activation sparing Wild-type (WT) p53- induced transcription and basal transcription. Pilot experiments identified GOF p53TAIns that preferentially inhibited growth of lung cancer cells with GOF p53, over p53-null lung cancer cells or lung cancer cells with WT 53. One of the GOF p53TAIns, Gloxazone, specifically inhibits GOF p53-induced transcription and cell growth, and in addition specifically inhibits growth of tumors from xenografts of lung cancer cells with mutant p53 but not from that of WT p53. The proposed hypothesis will be further tested via the following specific aims: Aim 1: Examine identified GOF p53TAIns for their ability to specifically inhibit GOF p53-induced growth of lung cancer cells inducing cell death. Human lung cancer cell lines spanning different subtypes (non- small cell, small cell, squamous cell) with or without various GOF p53 mutation (a), matched sets of gene-edited lung cancer cell lines with GOF p53, WT p53 and p53-null alleles (b), and tumor cells isolated from primary or passaged patient lung cancer samples (c) will be employed. Ability of GOF p53TAIns to alter GOF p53 stability will be determined and analysis of mechanism of growth inhibition for selected compounds will be initiated. Aim 2: Examine identified GOF p53TAIns for their ability to specifically inhibit GOF p53-driven tumor growth and induce tumor cell death using mouse models. Three mouse models, tumors from (a) xenograft of lung cancer cells, implanted subcutaneously or orthotopically, and (b) patient-derived xenografts (PDX) in immunocompromised mice will be used and (c) inducible GOF p53-dependent lung cancer mouse models will be examined.