Targeting Protein Kinase C Iota for Ovarian Cancer Therapy
The 3q26 region of chromosome 3 is known to be amplified in more than 70 percent of high-grade serous ovarian cancers, the most common and most lethal subtype of ovarian cancer.
In previous work, Mayo Clinic investigators in the Ovarian Cancer SPORE provided the first evidence that protein kinase C iota (PKCɩ), 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 cancers and other malignancies. They demonstrated that ovarian cancer cell proliferation and survival is driven by a PKCɩ-initiated signaling pathway.
This pathway is unique to ovarian cancer as compared with other cancers, such as non-small cell lung cancer, in which PKCɩ is amplified.
In addition, Mayo Clinic investigators partnered with collaborators to identify and characterize highly selective PKCɩ 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, investigators in the Ovarian Cancer SPORE propose to:
- Dissect the mechanism by which PKCɩ regulates ovarian cancer tumor-initiating cell behavior and assess the effect of PKCɩ inhibition on the ovarian cancer tumor-initiating cell phenotype
- Assess the effect of PKCɩ inhibition on signaling and growth of high-grade serous ovarian cancer cell lines and validate potential pharmacodynamic and predictive biomarkers of PKCɩ inhibitors in patient-derived ovarian cancer xenografts in vivo
- Assess the ability of a highly potent and specific PKCɩ inhibitor to inhibit PKCɩ 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
Co-leaders of this Ovarian Cancer SPORE project are: