R01CA262530

Developing CDK12 Inhibitors to Overcome Therapy Resistance in HER2+ and KRAS-Driven Breast and Lung Cancers - Project Summary

Although the development of targeted therapies has improved overall cancer patient survival, adaptive responses by tumor cells can render these treatments ineffective. The development of agents that block adaptive responses, thereby increasing treatment durability, is desperately needed. We and others have demonstrated that inhibitors of the transcriptional cyclin-dependent kinases 12 (CDK12) and 13 (CDK13) are strong candidates to combat acquired drug resistance.

The long-term goal of this proposal is to develop a highly effective CDK12/13 inhibitor with an aggregate set of properties suitable to advance as a safety assessment candidate to overcome therapy resistance in both TNBC and HER2+ breast cancers and KRAS inhibitor-resistant NSCLCs. The overall objective in this application is to identify targets and pathways altered by treatment-directed CDK12/13 rewiring and develop new therapeutics that render this rewiring an exploitable vulnerability.

The central hypothesis is that CDK12/13 acts as a driver of transcriptional and post-transcriptional adaptation and that targeting CDK12/13 will block drug-induced escape and improve treatment response in breast and lung cancer. The rationale for this project posits that: (I) multiple malignancies hijack CDK12/13 to provoke transcriptional and signaling plasticity as an adaptive stress resistance mechanism, and (II) elucidation of mechanisms underpinning compound action will offer a strong scientific framework that will facilitate future clinical development of these new agents for improved patient outcome.

The central hypothesis will be tested by pursuing three specific aims: (1) optimize the drug-like properties of in-house CDK12/13 specific inhibitors; (2) define and validate the mechanisms whereby CDK12/13 inhibition prevents or reverses treatment resistance in TNBC and HER2+ breast cancers; and (3) define and validate the mechanisms whereby CDK12/13 inhibition prevents or reverses KRASG12C inhibitor resistance in NSCLC.

Accordingly, using a battery of approaches, we will: A) optimize key CDK12/13 inhibitor parameters to deliver a safety assessment candidate; B) define and validate the transcriptional and translational mechanisms whereby SR-4835 provokes resensitization to chemotherapy; and C) validate cell-based observations in pre-clinical xenograft models.

The research approach of our multi-PI application is innovative, as our team has developed exceptionally selective and novel small molecule CDK12/13 in vivo active molecular probes that will enable (I) interrogation of the roles of CDK12/13 during adaptation to treatment resistance; (II) evaluation that disrupting transcriptional control will counter-resistance mechanisms providing lasting, more durable anti-cancer responses or even cures; and (III) understanding of the critical signaling nodes that drive drug resistance.

The proposed research is highly significant and provides a strong scientific rationale for the continued development of novel CDK12/13 inhibitors. We submit that insight into the molecular underpinnings of the master effectors of CDK12 and CDK13-driven signaling, together with an optimized CDK12/13 inhibitor, will offer new opportunities for improved combination treatments for breast and lung cancer.

H. Lee Moffitt Cancer Center And Research Institute Hospital

TO DEVELOP THE MEANS TO CURE AS MANY CANCER PATIENTS AS POSSIBLE AND TO CONTROL THE DISEASE IN THOSE PATIENTS WHO ARE NOT CURED. CANCER TREATMENT RESEARCH INCLUDES THE DEVELOPMENT AND EVALUATION OF IMPROVED METHODS OF CANCER TREATMENT THROUGH THE SUPPORT AND PERFORMANCE OF BOTH FUNDAMENTAL AND APPLIED LABORATORY AND CLINICAL RESEARCH. RESEARCH IS SUPPORTED IN THE DISCOVERY, DEVELOPMENT, AND CLINICAL TESTING OF ALL MODES OF THERAPY INCLUDING: SURGERY, RADIOTHERAPY, CHEMOTHERAPY, AND BIOLOGICAL THERAPY INCLUDING MOLECULARLY TARGETED THERAPIES, BOTH INDIVIDUALLY AND IN COMBINATION. IN ADDITION, RESEARCH IS CARRIED OUT IN AREAS OF NUTRITIONAL SUPPORT, STEM CELL AND BONE MARROW TRANSPLANTATION, IMAGE GUIDED THERAPIES AND STUDIES TO REDUCE TOXICITY OF CYTOTOXIC THERAPIES, AND OTHER METHODS OF SUPPORTIVE CARE THAT MAY SUPPLEMENT AND ENHANCE PRIMARY TREATMENT. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.395 - Cancer Treatment Research

National Cancer Institute (NCI) [HHS - NIH]

Tampa, Florida 336129497 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 418% from $679,205 to $3,519,313.