Targeting Protein Kinase C iota for Ovarian Cancer Therapy
In this research project, the Mayo Clinic Ovarian Cancer SPORE is assessing how protein kinase C iota (PKCι) regulates ovarian cancer tumor growth and investigating PKCι inhibitors for treatment.
The 3q26 region of chromosome 3 is known to be amplified in more than 70% of high-grade serous ovarian cancers, the most common and most lethal subtype of ovarian cancer. In previous work, SPORE investigators provided the first evidence that protein kinase C iota, which is located in the middle of this amplicon, is an oncogene.
Investigators worked with both bulk ovarian cancer cells and tumor-initiating cells, which are well established as a source of resistance in ovarian cancer and other malignancies. They demonstrated that ovarian cancer cell proliferation and survival is driven by a PKCι-initiated signaling pathway. This pathway is unique to ovarian cancer as compared with other cancers, such as non-small cell lung cancer, in which PKCι is amplified.
In addition, Mayo Clinic investigators partnered with collaborators to identify and characterize highly selective PKCι inhibitors, including a lead compound that is moving toward a first-in-human trial with an expansion cohort in ovarian cancer.
Building on these results, our investigators propose to:
- Dissect the mechanism by which protein kinase C iota regulates ovarian cancer tumor-initiating cell behavior and assess the effect of PKCι inhibition on the ovarian cancer tumor-initiating cell phenotype
- Assess the effect of PKCι inhibition on signaling and growth of high-grade serous ovarian cancer cell lines and validate potential pharmacodynamic and predictive biomarkers of PKCι inhibitors in patient-derived ovarian cancer xenografts in vivo
- Assess the ability of a highly potent and specific PKCι inhibitor to inhibit PKCι signaling in vivo through analysis of paired pre- and post-treatment biopsies obtained from patients with ovarian cancer enrolled in the expansion cohort of the associated clinical trial