Abstract 4659: Intratumoral sirolimus injection for prostate cancer

Abstract

Abstract A key unmet need in the field of prostate cancer treatment is the lack of targeted therapy for local control of tumor burden, that circumvents the systemic adverse events related to currently available systemic therapy. Our clinical stage, sterile injectable 2% sirolimus formulation acts by inhibiting the activity of mTOR, a central signaling molecule with multiple mechanism of actions. mTOR functions downstream of two of the key driver mutations associated with prostate cancer namely PTEN (30%) and AR (63%) and affects downstream processes like proliferation, survival, protein synthesis, cell growth, EMT transition regulating metastasis as well as angiogenesis. Additionally, a feedback loop also exists between mTOR and AR, which aids in the development of androgen resistance, resulting in hormone resistant prostate cancer. Therefore, inhibiting mTOR activity can not only inhibit tumor growth but can potentially prevent metastasis and development of resistance. However, all current mTOR inhibitors are administered systemically leading to unwanted systemic adverse events in addition to poor tissue availability, which prevents achievement of optimal efficacy of the molecule. In our preclinical study, athymic nude mice were injected with prostate cancer line 22Rv1 and PC3 cells to generate xenografted prostate tumors. The mice were randomized into 4 groups and each tumor was injected with either vehicle control, weekly or biweekly intratumoral injection of 2% sirolimus, while an oral 0.1% Rapamycin group was fed the drug daily for a period of 1 month at the end of which, all the mice were sacrificed, and the residual tumors were sectioned and probed for various markers to determine the specificity and molecular mechanism of action of our formulation. Unlike Rapamycin, injectable sirolimus forms a depot at the site of injection that results in increased tissue availability and sustained local delivery of the drug over time. The tumors in the injectable sirolimus weekly and biweekly treatment groups showed significant decrease in tumor burden compared to oral Rapamycin and vehicle treated groups in both 22Rv1 and PC3 cell generated tumors. Blood PSA in the injectable sirolimus treated groups also showed a faster decrease than treatment with Rapamycin. Immunohistochemistry showed a decrease in the phosphorylation of both mTOR targets, S6K and 4EBP with no change in the protein levels of mTOR confirming that injected sirolimus acts by inhibiting the mTOR activity. Proliferation marker Ki-67 showed a decrease while apoptosis marker cleaved caspase-3 showed an increase upon treatment with sirolimus substantiating the underlying molecular mechanism of the observed tumor shrinkage. Interestingly, anti-metastasis marker E-cadherin levels increased with sirolimus treatment as well. These results show the clinical potential of local sirolimus injection for the treatment of prostate cancer and underscores the need for next stage human trials. Citation Format: Aishwarya Kundu, Sri Mudumba. Intratumoral sirolimus injection for prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4659.