SBIR-STTR Award

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 the proposed research is: a newly identified chemical entity YTR107 sensitizes human tumor cells to the lethal effects of ionizing radiation. YTR107 is efficacious in genetically diverse tumor types because its novel intracellular target plays a key role in homologous recombination, a critical DNA repair pathway utilized by dividing cells, including proliferative tumor cells. Targeting a key component of the DNA damage response pathway used by proliferating tumor cells (not quiescent differentiated cells) is a promising, novel therapeutic approach for NSCLCs. Genetic changes in these tumors result in high levels of replication stress and endogenous DNA damage. Constant replication stress renders tumor cells less competent to cope with additional exogenous DNA damage inflicted by therapeutic ionizing radiation. Radiation therapy combined with YTR107 may be ideally used on NSCLCs because ionizing radiation inflicts potentially lethal DNA double strand breaks and because YTR107 interferes with repair of these breaks by interfering with homologous recombination. Our ultimate product is an intravenous formulation of YTR107 used in combination with patients' radiotherapy regimens to effectively control primary tumor growth without promoting normal tissue damage. This outcome is paramount for preserving lung function and decreasing both cachexia severity and the probability of metastatic disease. Phase I goals for this collaborative research program at Cumberland Pharmaceuticals and Vanderbilt University are to: (1) demonstrate that YTR107 is an efficacious radiosensitizing agent in preclinical models of human NSCLC and (2) evaluate normal tissue toxicity by assessing whether YTR107 increases susceptibility to radiation-induced pulmonary fibrosis. YTR107 will change the standard of care for radiotherapy patients and improve therapeutic outcomes for intractable lung cancers, namely improved tumor response to irradiation with minimal drug effects on normal tissues.

Public Health Relevance Statement:


Public Health Relevance:
Lung cancer patients diagnosed as having non-small cell lung cancers have very poor 5-year survival rates (<20%) and fail to benefit from newer targeted therapies used for treating other types of lung cancers. For non- small cell lung cancers, radiation therapy remains a cornerstone of the standard of care. This research aims to develop a safe and effective drug that renders tumor cells more susceptible to the toxic effects of therapeutic ionizing radiation, thereby decreasing tumor growth and increasing patient survival with less damage to surrounding normal tissues.

Project Terms:
Address; Adenocarcinoma; Analytical Chemistry; analytical method; Body Weight; Cachexia; cancer cell; Cancer Patient; cancer radiation therapy; Cell Survival; Cells; Cessation of life; Chemicals; Chest; Clinical; Clinical Trials; coping; Coupled; Curative Surgery; Data; Diagnosis; Disease; DNA Damage; DNA Double Strand Break; DNA Repair; DNA Repair Pathway; Dose; Drug Formulations; effective therapy; Effectiveness; Exhibits; Failure (biologic function); Fibrosis; Future; Goals; Growth; homologous recombination; Human; improved; innovation; Intravenous; Ionizing radiation; irradiation; Lesion; Longevity; Lung; Malignant neoplasm of lung; Malignant Neoplasms; Measures; Mediating; Molecular; mouse model; Mus; Mutation; neoplastic cell; Non-Malignant; Non-Small-Cell Lung Carcinoma; Normal Cell; Normal tissue morphology; novel; novel therapeutic intervention; nucleophosmin; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Play; Pre-Clinical Model; Predisposition; Primary Neoplasm; Probability; product development; programs; Proliferating; Proteins; public health relevance; Pulmonary Fibrosis; Radiation; Radiation Oncology; Radiation therapy; Radiation Therapy Oncology Group; Radiation-Sensitizing Agents; Radiobiology; Radiosensitization; recombinational repair; Regimen; Relative (related person); repaired; Research; respiratory imaging; Respiratory physiology; response; Role; safety study; Severities; Solvents; Squamous cell carcinoma; Staging; standard of care; Stress; Structure of parenchyma of lung; Survival Rate; Synthesis Chemistry; Therapeutic; therapy outcome; Time; Toxic effect; Treatment Protocols; tumor; tumor growth; tumorigenesis; Universities

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.

Public Health Relevance Statement:
NARRATIVE Lung cancer patients diagnosed as having non-small cell lung cancers have very poor 5-year survival rates (<20%) and fail to benefit from newer targeted therapies used for treating other types of lung cancers. For non- small cell lung cancers, radiation therapy remains a cornerstone of the standard of care. This research aims to develop a safe and effective drug that renders tumor cells more susceptible to the toxic effects of therapeutic ionizing radiation, thereby decreasing tumor growth and increasing patient survival, with less damage to surrounding normal tissues.

NIH Spending Category:
Cancer; Genetics; Lung; Lung Cancer; Radiation Oncology

Project Terms:
A549; Academic Medical Centers; Address; Adrenal Glands; Affect; Aftercare; aqueous; Area; Autopsy; base; Biochemical; Biological Assay; Body Weight; Cancer cell line; Cancer Patient; cancer radiation therapy; Cell Death; Cells; Cerebellum; Cessation of life; Chemicals; chemoradiation; Chest; Chest wall structure; Clinical; clinically relevant; Complete Blood Count; Curative Surgery; cytotoxicity; Diagnosis; Dimensions; Disease; Distant; DNA Damage; DNA Double Strand Break; DNA Repair; Dose; Double Strand Break Repair; Drug Formulations; Drug Kinetics; efficacy testing; Exposure to; Failure; Fibrosis; Formulation; Future; Goals; Heart; Histologic; Human; Impairment; improved; innovation; intraperitoneal; Intraperitoneal Injections; Intravenous; Intravenous infusion procedures; Invaded; Ionizing radiation; Irradiated tumor; irradiation; Kidney; Lesion; Leukocytes; Lipids; Liver; Longevity; Lung; Malignant neoplasm of lung; Malignant Neoplasms; Measures; Methods; microCT; mouse model; Mus; Neoplasm Metastasis; neoplastic cell; new therapeutic target; Non-Small-Cell Lung Carcinoma; Normal Cell; Normal tissue morphology; novel; novel therapeutic intervention; NPM1 gene; Organ; Outcome; Pancreas; Pathologist; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Placebos; Plasma; pre-clinical; Primary Neoplasm; programs; Pulmonary Fibrosis; Radiation; radiation response; Radiation therapy; Radiation Therapy Oncology Group; recruit; Regimen; Reporting; Research; research and development; respiratory; Respiratory Diaphragm; response; Route; Severities; Small Business Innovation Research Grant; Small Business Technology Transfer Research; Small Intestines; small molecule; Spleen; Staging; standard of care; Survival Rate; Technology; Therapeutic; Therapeutic Effect; therapy outcome; Threonine; Thymus Gland; Tissues; Toxic effect; Toxicology; Trachea; Treatment Efficacy; tumor; tumor growth; Tumor Tissue; Tumor Volume; tumor xenograft; Xenograft Model; Xenograft procedure