The Experimental Therapeutics Program collaborates with numerous Mayo Clinic researchers on four areas of cancer research:
- Signaling pathways. The program is studying signaling pathways involved in cell survival and proliferation to better define cellular responses to existing anti-cancer treatments and to identify potential new therapeutic targets.
- Anti-cancer drugs. The program is clarifying biological, biochemical and pharmacological aspects of the action of new anti-cancer drugs and identifying biochemical and genetic changes that allow tumor cells to resist these agents.
- Response differences. The program is identifying genetic and genomic contributions to individual differences in response (efficacy and toxicity) to established and investigational anti-cancer treatments.
- Early-phase clinical trials. The program is evaluating the toxicity and activity of selected treatments in early-phase clinical trials, including assessment of the pharmacokinetics, pharmacogenetics, and biological effects of agents in tumor cells in situ, before transitioning these treatments to appropriate disease-specific clinical programs for phase II testing.
Research advances related to signaling pathways include:
- Demonstrating that signaling by the oncogenic kinase PKCι activates a Notch3-dependent signaling pathway in lung adenocarcinoma and a Hippo/YAP signaling pathway in ovarian cancer, providing a rationale for targeting PKCι in multiple cancers
- Demonstrating that the pro-apoptotic BCL2 family member BAK undergoes concentration-dependent autoactivation in malignant hematopoietic cells and is then held in check by various anti-apoptotic BCL2 family members, providing new insight into the anti-neoplastic action of BH3 mimetics currently undergoing clinical testing
- Identifying mitochondrial creatine kinase 1 (MtCK1) as a unique metabolic target of amplified HER2 that is required for proliferation of HER2+ breast cancer cells
Research advances related to new anti-cancer drugs include:
- Demonstrating that activities of the tumor suppressor proteins BRCA1 and BRCA2 are regulated by deubiquitinases, providing new insight into PARP inhibitor sensitivity and identifying potential new targets for sensitizing cancer cells to DNA-damaging agents
- Demonstrating that ATR inhibitors sensitize cancer cells to various DNA-damaging agents, leading to National Cancer Institute-sponsored early-phase clinical trials in ovarian cancer
- Demonstrating that CDK4/6 inhibitors regulate the deubiquitinase DUB3, providing new insight into the action of these agents in breast cancer
Research advances related to response differences include:
- Completing a 33,000-sample genome-wide association study and subsequent mechanistic analysis. This analysis identified single nucleotide polymorphisms in ZNF423, a previously unrecognized regulator of BRCA1 expression, as a critical determinant of selective estrogen receptor modulator efficacy in the adjuvant setting. It also identified CALML3 as a co-regulator of estrogen receptor action that binds the polymorphic site, providing new insight into selective estrogen receptor modulator action.
Early-phase clinical trials
Research advances related to early-phase clinical trials include:
- Accruing participants to early-phase clinical trials, especially those based on preclinical findings
- A phase I trial initiated by the Mayo Clinic Ovarian Cancer SPORE of the floxuridine/veliparib combination that resulted in responses lasting more than 18 months in nine of 18 currently evaluable patients
- A phase II trial sponsored by the Experimental Therapeutics Clinical Trials Network of an ATR inhibitor/gemcitabine/platinum combination with a safety run-in
- Several first-in-human studies, including phase I trials of endoxifen and copanlisib