Abstract IA08: Personalizing HNSCC treatment based on TP53 mutational status

Abstract

Abstract Head and neck squamous cell carcinoma (HNSCC) is a leading cause of cancer deaths worldwide, and resistance to standard treatments with radiation/chemotherapy accounts for the majority of HNSCC deaths. Mutation of TP53 occurs in 60-85% of non-HPV-associated HNSCC cases, and some mutant p53s display oncogenic properties, termed “gain-of-function (GOF),” which are independent of wild-type (WT) p53 functions. These GOF p53 mutant proteins can enhance cell transformation, increase tumor formation, and confer cellular resistance to chemo- and/or radio-therapy. Therefore, we are interested in the development of innovative therapeutic approaches to overcome this resistance. Pre-clinical studies both in vitro and in vivo have shown the promise of some novel targeted agents including Chk-1, Wee-1, and PARP inhibitors used alone or in combination with HDAC inhibition. In addition, COTI-2 is a novel drug with striking single-agent and radio-/chemo-sensitizing activity in pre-clinical models of HNSCC bearing TP53 mutations. Our preliminary data demonstrate that COTI-2 markedly decreases cell growth in vitro and induces p21, noxa, and puma expression in HNSCC cells. COTI-2 also negatively modulates the PI3K/AKT/mTOR survival pathway, which is constitutively activated in many types of cancer including HNSCC. In vitro studies in our laboratory have shown that COTI-2 has a nanomolar (IC50: 1.3-13.2 nm) activity in nine human HNSCC cell lines. Additionally, GOF mutant p53-bearing HNSCC cells are significantly delayed in outgrowth in an orthotopic nude mouse model of tongue cancer when treated with COTI-2. Current clinical studies are evaluating the safety and efficacy of the combination of COTI-2 alone and in combination with cisplatin in phase I/II studies of patients with refractory HNSCC and whether response is associated with TP53 mutational status of the tumor determined from sequencing of circulating cell free DNA. If this combination is found to safely provide sensitization of HNSCC to cisplatin-based chemotherapy in the majority of human patients who have TP 53 mutant tumors, this should make a major impact on the survival of individuals suffering from HNSCC, and potentially other p53 driven epithelial malignancies. Citation Format: Jeffrey Myers. Personalizing HNSCC treatment based on TP53 mutational status [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; April 23-25, 2017; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(23_Suppl):Abstract nr IA08.