Monday, April 29, 2024
4/29/2024
PROJECT SUMMARY / ABSTRACT Cisplatin is frequently used to treat squamous cell carcinoma (SCC), frequently in combination with other drugs or ionizing radiation (IR). Tumor recurrence due to therapeutic failure occurs in approximately 8% of patients within 5 years of treatment, and the 5-year survival for individuals with recurrent disease remains around 55% despite the recent introduction of targeted immunotherapies. The mechanisms regulating cisplatin resistance remain poorly understood, representing a significant gap in knowledge with high clinical relevance. This proposal will elucidate novel mechanisms of cisplatin resistance in SCC, thus opening new avenues for much needed treatment strategies for chemoresistant HNSCC and enabling rapid advancements in the field. ¿Np63a is a proto-oncogene implicated in cisplatin resistance and overexpressed in SCC of the skin, head and neck, cervix, and lung. We previously published that the TIP60 acetyltransferase directly acetylates and stabilizes ¿Np63a to promote SCC cell proliferation. Our preliminary data indicate that (a) chemoresistance to cisplatin correlates with high ¿Np63a and TIP60 levels in HNSCC tumors and skin SCC cell lines, (b) TIP60 inhibits the ubiquitination and degradation of ¿Np63a while increasing its acetylation, (c) silencing TIP60 or inhibiting its HAT activity using TH1834 downregulates ¿Np63a, reduces its acetylation, increases cell apoptosis, and sensitizes cells to cisplatin, and (d) we demonstrated an increased efficacy of cisplatin-IR treatment and the IR-TH1834 combination demonstrating that TIP60 inhibition increases sensitivity to IR. We hypothesize that TIP60 promotes cSCC and HNSCC proliferation and cisplatin resistance via enhanced stability of ¿Np63a and function. To test this hypothesis, we will (Aim 1) determine how acetylation of ¿Np63a by TIP60 impacts the ubiquitination and proteasomal degradation of ¿Np63a, (Aim 2) investigate how TIP60 mediated acetylation of ¿Np63a alters transcriptional activity to impact apoptosis, the DDR and ultimately cisplatin resistance, and (Aim 3) elucidate the role of the TIP60/¿Np63a axis in SCC progression and therapeutic response utilizing cell derived xenograft models and efficacy studies in HNSCC PDX models to determine the effectiveness of a TIP60 inhibitor as a potential therapeutic adjunct to standard of care chemoradiation (cisplatin and IR) treatment. Together, the combined use of gain- and loss-of-function in vitro analyses, in vivo xenograft and PDX models of cisplatin-resistant SCC will provide a statistically rigorous characterization of TIP60/¿Np63a signaling in cisplatin resistance, apoptosis, and the DNA damage response in SCC; and will assess a potential novel therapy. This will aid in the identification of additional potential therapeutic targets for the treatment of SCC and other epithelial cancers, including nasopharyngeal and lung carcinomas and provide critical insights into the therapeutic potential of acetyltransferase inhibitors.
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