Abstract 4940: Proteasome and survivin inhibitors synergize to inhibit the growth of oral cancer organoids

Abstract

Abstract Oral squamous cell carcinoma (OSCC) is the most prevalent subtype of head and neck cancers that has a disproportionately high incidence and mortality in developing countries in South-Central Asia, including Pakistan. The standard treatment for OSCC generally consists of surgery combined with radiotherapy or chemotherapy; however, the overall survival rates have not improved, and only ~50% of patients survive the disease. Therefore, identifying and validating new drug targets can provide new therapeutic options for improved treatment and better prognosis for OSCC patients. The present study aimed to develop an organoid model from patient-isolated primary tumour cells and determine their drug sensitivity profile coupled with mutational analysis. New combinations of targeted drugs with synergistic activity in oral cancer cells were identified through high-throughput screening followed by validation of their activity in oral cancer cells in 2D monolayer and 3D organoid cultures. Results indicate a synergistic activity of proteasome (PR-171) and survivin (YM155) inhibitors in all tested patient-derived tumour cells and four oral cancer cell lines. Moreover, chitosan-based nanocapsules harboring these drugs showed therapeutic efficacy comparable to free drug combinations, indicating a potential for efficient and targeted delivery. Next-generation sequencing data identified missense mutations in eleven cancer-related genes that encode BRAF, EGFR, KRAS, NRAS, HRAS, MEK1, PIK3CA, PTEN, NOTCH1, TP53 and TERT. The ongoing research aims to correlate the drug sensitivity data with the mutational profile of patient-derived tumour cells to find novel targets. In conclusion, we have developed 3D organoids from patient-derived primary tumours and utilized them to validate the synergistic combination between screen-identified proteasome and survivin inhibitors. Our preclinical study provides a rationale for further evaluation of the novel drug combination in vivo and in clinical settings. Citation Format: Muhammad Furqan, Iffat Aleem, Muhammad Tahseen, Raza Hussain, Asif Loya, Muhammad Tariq Mahmood, Philippe Gautier, Kevin Myant, Saira Saleem, Amir Faisal. Proteasome and survivin inhibitors synergize to inhibit the growth of oral cancer organoids. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4940.