P50CA269022

Molecularly targeted radiosensitization of locally advanced cancers - project summary (overall)

Cancer cannot be cured unless the primary tumor is cured. For patients with locally advanced or unresectable disease for whom initial surgery is not an option, radiation therapy (RT) combined with a systemic agent has become the standard treatment. This is because systemic therapy alone can rarely cure gross disease, but can significantly improve the efficacy of RT and eliminate microscopic disease.

Therefore, as systemic therapies continue to improve, the need for effective local control becomes increasingly important. Although technical improvements in planning and delivery have decreased the toxicity of RT, RT dose escalation trials have, in general, failed to improve outcome.

The overarching hypothesis of this SPORE proposal is that combining RT with systemic therapy that targets the molecular drivers of locally advanced cancers will improve the outcome of treatment. The goal of this SPORE proposal is to test this hypothesis through in vitro and in vivo preclinical studies targeting key mechanisms of radiation resistance.

Our studies will motivate pilot clinical trials that will define the conditions for phase II trials, yield an initial assessment of response, and test the preclinical hypotheses through correlative studies. This goal will be achieved through three specific aims.

Aim 1 will determine if primary radiation resistance, the presence of occult metastatic disease, and a lack of immunogenicity can be targeted by increasing radiation-induced DNA damage using a PARP inhibitor with immune checkpoint blockade (ICB). We test this strategy in preclinical and clinical studies combining olaparib, RT, and durvalumab in pancreatic cancer.

Aim 2 will determine if the radiation resistance due to unique tumor metabolism, specifically, elevated purine levels, can be targeted. We test this hypothesis in preclinical and clinical studies of glioblastoma using the purine depleting CNS-penetrant FDA approved agent mycophenolate mofetil (MMF).

Aim 3 will determine if the radiation resistance due to aberrant cell cycle control and activated DNA repair can be targeted in tumor cells with intact retinoblastoma protein (RB) using CDK4/6 inhibitors. We test this hypothesis in preclinical studies and in a clinical trial treating women with locally advanced ER+ (and, in the future, if supported by preclinical data, triple negative) breast cancer using RT with concurrent abemaciclib.

These projects will be supported by the five cores: administrative, translational pathology, biostatistics & computational biology, clinical trials, and radiosensitization. We have a strong history of vertical translation: our prior early phase trials in these three diseases have progressed to multi-institutional trials.

We do not know of another group that can carry out integrated preclinical and clinical studies which have a significant chance of decreasing the morbidity and mortality of three common and difficult to treat cancers by increasing the RT sensitivity and immunogenicity of tumors through targeting their molecular drivers using clinically available agents.

Regents Of The University Of Michigan

TO PROVIDE AN ORGANIZATIONAL FOCUS AND STIMULUS FOR THE HIGHEST QUALITY CANCER RESEARCH THAT EFFECTIVELY PROMOTES INTERDISCIPLINARY CANCER RESEARCH AIMED TOWARD THE ULTIMATE GOAL OF REDUCING CANCER INCIDENCE, MORTALITY AND MORBIDITY. THE CANCER CENTER SUPPORT GRANT (CCSG) PROVIDES THE RESOURCES AND INFRASTRUCTURE TO FACILITATE THE COORDINATION OF INTERDISCIPLINARY PROGRAMS ACROSS A BROAD SPECTRUM OF RESEARCH FROM BASIC LABORATORY RESEARCH TO CLINICAL INVESTIGATION TO POPULATION SCIENCE. THE CCSG SUPPORTS SALARIES FOR SCIENTIFIC LEADERSHIP OF THE CENTER, SHARED RESOURCES FOR FUNDED CENTER INVESTIGATORS, CERTAIN ADMINISTRATIVE COSTS, PLANNING AND EVALUATION, AND DEVELOPMENTAL FUNDS FOR NEW RECRUITMENTS AND FEASIBILITY STUDIES.

93.397 - Cancer Centers Support Grants

National Cancer Institute (NCI) [HHS - NIH]

Ann Arbor, Michigan 481091276 United States

Single Zip Code

Specialized Programs of Research Excellence (SPOREs) in Human Cancers for Years 2021, 2022, and 2023 (P50 Clinical Trial Required) (PAR-20-305)

Amendment Since initial award the total obligations have increased 94% from $2,066,150 to $4,012,214.