Hypothesis: Simultaneous inhibition of multiple resistance pathways in a tumor-targeted manner will synergistically sensitize renal cancer tumors towards radiation therapy and also reduce the growth of non-irradiated metastatic tumors by enhancing the abscopal effect when combined with systemic cytokine therapy.

Scientific Rationale: Kidney cancer is well known for its resistance to radiation therapy. However, recent advances in radiation therapy procedures have rejuvenated interests in using radiation therapy for the treatment of kidney cancer. These new procedures have also increased the growth inhibitory effect of radiation therapy on non-irradiated metastatic tumors present in other organs by enhancing the abscopal effect. In addition, the combination of various chemotherapy agents and other molecular targeted therapies as radiosensitizers has been shown to enhance the response to radiation therapy. Among them, everolimus (E) and YM155 (Y) are of special interest since they target multiple resistance mechanisms responsible for radiation therapy resistance of kidney cancer. Interestingly, Y has been shown to reduce the acquired resistance towards E in kidney cancer. Additionally, Y acts synergistically with cytokine therapy to make the tumor microenvironment more immunogenic. Hence, a combination of E and Y in a single tumor-targeted formulation is expected to induce higher radiosensitization than individual treatments and also enhance the abscopal effect by making the tumor microenvironment more immunogenic when combined with cytokine therapy. The tumor-targeted formulation will also be beneficial in improving the pharmacokinetic parameters and reducing treatment-induced toxicities. Supporting evidence: Previously we developed a proprietary tumor-targeted liposomal formulation and used it successfully to deliver multiple drugs for the treatment of RCC in both immune-deficient and immune-competent mouse models. Our preliminary data shows that a similar formulation containing E and Y (EY-L) was able to contain the primary tumor growth and improve survival in an immunocompetent syngeneic mouse model of RCC. EY-L leads to significantly higher sensitization of RCC cells towards radiation in vitro than E-L or Y-L, the single drug-loaded formulations. Collectively, the published studies and our preliminary data support our proposal.

Career Goals: My long-term career goal is to become a tenured professor in a top-tier research institute or university that will allow me to perform research in kidney cancer and teach graduate students. My short-term career goal is to become an independent kidney cancer researcher by securing funds for my research. The career development plan formulated with the help of my mentors will help me improve my research skills, communications skills, and management skills. Development of new innovative proposals based on the results obtained from proposed experiments and improved knowledge and skills acquired from the regular interactions with my mentors and the Academy will help me obtaining new independent funding and achieve my goals.

Participation and Contribution to Academy of Kidney Cancer Investigators (AKCI): I will attend the Annual DoD Kidney Cancer Research Program (KCRP) 1-day AKCI Workshop and Biennial DoD KCRP multi-day AKCI Workshop on a regular basis to meet with the Dean and other Academy members to share data, discuss innovative ideas for future research plans, and extend my network for future collaborative works. I would be thrilled to be a part of AKCI and would remain committed to the development of the Academy after reaching my dream of becoming an established kidney cancer researcher as a mentor for future generations of Early-Career Investigators.

Applicability: The proposed research will focus on the development of a novel therapeutic strategy for the treatment of kidney cancer patients, especially those with advanced metastatic disease not responding to immunotherapy. The experiments outlined in our proposal will assess the effect of our proposed therapy on the irradiated primary tumor as well as non-irradiated metastatic tumors, so patients with advanced metastatic tumors would benefit from our research provided we obtain satisfactory results and translate them into the clinic. We are certainly not very close to that mark as of now, however, if the preclinical data from our proposal are inspiring, the transition to the next phase will be rapid.

Knowledge Gap: This proposal will assess the role of various immune cell populations in circulation and tumor microenvironment on the radiation-induced growth inhibition of irradiated primary tumors as well as non-irradiated metastatic tumors. This will increase the understanding of the role of the immune system in response to radiation therapy and help us to design better therapeutic strategies for kidney cancer patients.

Impact: Kidney cancer is the fourth most common cause of malignancies in patients from the VA healthcare system, accounting for approximately 4% of all cancers. In the general population, kidney cancer is the sixth and eighth most common cancer in men and women, respectively, in the United States. In 2020, roughly 73,750 new kidney cancer diagnoses are estimated in the United States. The success of our proposed research is anticipated to have potential impact on the health and well-being of all of these kidney cancer patients.