1102 Engineering cellular backpacks to deliver therapies to ‘undruggable’ p53 in lung cancer
Year: 2024
Type: conference-abstract
Abstract: Background We have developed novel therapeutics using mechanistic insights that we have unveiled over the last several years. TP53 has long been known as an ‘undruggable’ target due to its fundamental roles in controlling key cellular functions and its role as a transcription factor. We have shown that one way to therapeutically target p53 deficient and mutant tumors is through the down regulation of ∆Np63 using genetically engineered mouse models and xenograft models that down regulation of ∆Np63 in thymic lymphomas deficient for p53, lung adenocarcinomas and squamous cell carcinomas mutant for p53, and cutaneous squamous cell carcinomas resulted in rapid tumor regression. Methods Based on these data, we developed a screen to identify compounds to inhibit ∆Np63 expression. Using this approach, we identified HDAC inhibitors and pramlintide (an FDA-approved for diabetes therapy in combination with insulin) as potent inhibitors of ∆Np63 expression and induced tumor regression. Results We have shown that systemic administration of these compounds results in tumor regression in p53 deficient and mutant cuSCC and LuAD and LuSC through mechanisms present in the tumor and its microenvironment. More recently, we have found that systemic delivery of pramlintide results in regression of p53-deficient and p53-mutant cuSCC and Rb/p53 deficient and Myc mutant preclinical models of small cell lung cancer (SCLC). Pramlintide modulates the immune microenvironment by reducing myeloid-derived suppressor cell (MDSC) differentiation and suppressive function in vivo and in vitro. Based on this data, we have engineered targeted cellular backpacks using several innate immune cell types to test their ability to home to tumor beds in the above preclinical models and to correspondingly modulate the microenvironment and ultimately sensitize tumors to immunotherapy. MDSCs migrated spontaneously to the lungs and tumor beds. Conclusions We conclude that targeting ∆Np63 is a useful strategy to target its oncogenic function and to modulate the tumor microenvironment. In addition, our data show that MDSCs can be targeted to tumor beds and represent a novel therapeutic approach to develop novel drug delivery vehicles by engineering cellular backpacks. With our expertise in basic biology of p53, DNp63, and preclinical models, translational work in cuSCC, the design and engineering of cellular backpacks, and multi-omics analysis, we have developed a deep molecular understanding of p53 mutant/∆Np63 biology and have engineered targeted cellular backpacks for targeted drug delivery. We will present our findings in non-small cell (NSCLC) and SCLC. Ethics Approval The animal studies involved in this study were approved by the IACUC at USF. IS 10550.
Authors: Marco Napoli, Suehelay Acevedo, Karol Prieto, Aynur Yilmaz, Michael Dunne, Kenneth Y Tsai, Elsa R Flores
Institution: Moffitt Cancer Center
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
OpenAlex ID: W4404065287