Friday, December 27, 2024
12/27/2024
ABSTRACT There is an urgent, unmet need for novel therapeutic approaches that are efficacious against lung cancer. Ranking first among cancer deaths in the U.S., this disease has 5-year relative survival rates of < 20%. Most lung cancers are non-small cell (NSCLC, 85% of cases). Curative surgery is not an option for the 80% of NSCLC patients who present with advanced stage III cancer. For these patients chemo/radiation therapy remains the standard of care, and presently there is no effective strategy to improve radiation therapy outcomes. The central innovative theme of this proposal is that the novel chemical entity YTR107 inhibits recruitment of pT199 NPM1 (nucleophosmin1 phosphorylated at threonine 199) to DNA double strand breaks (DSBs), thereby improving tumor response to radiation. Failure to recruit pT199 NPM1 to DSB repair foci significantly impairs DSB repair and increases radiation-induced tumor cell death. Importantly we have shown that YTR107 preferentially impairs pT199 NPM1 function in tumor cells, compared to normal cells. We successfully completed all Phase 1 STTR (R41) milestones. We developed a sensitive bioanalytical method to quantitate YTR107 concentrations in mouse plasma. We showed that 1 nM YTR107 inhibits repair of DNA DSBs in irradiated tumor cells and significantly increases radiation cytotoxicity in seven genetically distinct NSCLC cell lines. In an A549 xenograft mouse model, intraperitoneal (IP) injection of YTR107 followed by tumor irradiation (q.d.x 7) increased the survival of tumor-bearing mice: 60% of mice treated with YTR107 + 2.2-Gy were alive 70 days after treatment whereas only 20% of mice treated with placebo + 2.2-Gy lived 70 days post-treatment. We developed an intravenous (IV) YTR107 formulation suitable for use in mice. We measured 20 nM YTR107 in plasma after a single IV dose, a level matching that measured after an efficacious IP dose, and 60 nM YTR107 in plasma at the end of a 5-day IV dosing regimen. The goals for our collaborative SBIR Phase 2 research program at Cumberland Pharmaceuticals Inc. and Vanderbilt University Medical Center are to: (1) demonstrate that systemic exposure to YTR107 after IV administration results in dose- dependent therapeutic benefit, measured as increased tumor response to radiation and increased survival of tumor-bearing mice; and (2) demonstrate that the IV drug product intended for human use is of acceptable quality, is suitable to deliver a therapeutic human dose of YTR107, and supports a future New Investigative Drug application for YTR107. Our ultimate product is a safe and effective IV YTR107 drug product intended for use in conjunction with NSCLC patients' (chemo)radiotherapy regimens to effectively control primary tumor growth, without promoting normal tissue damage--an outcome not achieved by the current standard of care therapy.
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