Targeting p53 conformational defects to arrest carcinogenesis

p53 mutations are believed to arise at a very early stage in carcinogenesis (Leitao et al, 2004) and were reported in tubal intraepithelial carcinoma (TIC) which is a common early precursor lesion for high-grade serous carcinoma of the ovaries (Kindelberger et al, 2007). TIC and ovarian serous carcinoma from the same patient most frequently share the same p53 mutation (Kindelberger et al, 2007). Moveover, p53 mutations are also identified in pre-neoplastic subpopulations of cells in the benign fallopian tube mucosa, termed “p53 signature” (Lee et al, 2007). Both p53 signatures and TIC lesions are found in the distal end of the fallopian tube, which is considered as a possible site of origin for ovarian cancer (Lee et al, 2007; Kurman et al, 2010). p53 mutants have the capability to promote its aggregation, which is a mechanism of inactivating the protein. Here we will determine whether aggregation of newly acquired p53 mutations in pre-neoplastic and early lesions is a defined molecular event that favors cancer progression through p53 inactivation. Our first aim is to whether aggregation of mutant p53 is present in clinical samples of p53 signatures or TICs in archival ovarian cancer specimens. Results of this aim will determine whether p53 aggregation is a feature that can be used to discriminate pre-malignant tissue from normal tissue, and can be targeted for early therapy and prevention of ovarian cancer. We previously demonstrated that p53 aggregation is an actionable event, and developed a peptide drug, ReACp53, currently in clinical development as an anti-cancer therapy. Next, we will test the hypothesis that ReACp53 can be efficacious on preventing conversion of pre-malignant lesions to full blown ovarian cancer. ReACp53 is a cell-penetrating peptide that was rationally designed to arrest p53 aggregation and results in rescue of p53 function and induction of cell death in cancers bearing aggregated mutant p53. Here we will test whether early administration of ReACp53 can prevent progression of pre-malignant lesions to ovarian cancer. Lastly we will attempt to identify a gene expression signature for ovarian tumors that carry p53 aggregates and respond to ReACp53. This will enable the rapid identification of cases for which ReACp53 will be effective and will allow us to fully estimate the fraction of tumors that are likely to respond to this therapy.