Targeting Akt Activation to Prevent Platinum Resistance in Ovarian Cancer
Abstract
Background: Ovarian cancer (OVCa) is the fifth most common cause of death due to cancer in women. There is a very low rate of survival of patients with OVCa (~40%/5 years), a rate that has not improved substantially over the past 30 years. This is due to two factors, diagnosis at late stage and acquired resistance to chemotherapy. Platinum (Pt)-containing chemotherapeutic compounds such as carboplatin are initially efficacious agents for OVCa treatment and are part of the current standard of care; however, resistance to these agents develops in 60%-70% of patients. When resistance to chemotherapy develops, OVCa is essentially incurable. Hence, development of new treatment strategies to overcome Pt resistance and prevent disease recurrence is a critical need. Genomic analysis has identified a set of intracellular enzymes organized in what has been termed the PI3K/PDK1/Akt pathway that is of particular importance for OVCa. In this pathway, the activity of the upstream component (PI3K) maintains the activity of the downstream component Akt, which is a known oncogene (cancer-causing gene). PI3K acts through an intermediary component, PDK1, a kinase that phosphorylates (transfers phosphate to) Akt resulting in Akt activation. Activated Akt controls the growth and survival of OVCa cells and tumors. The importance of this mechanism for OVCa progression from early to advanced stages is indicated by the genetic abnormalities in this pathway that occur in a high proportion of ovarian tumors. Drugs that inhibit the PI3K/PDK1/Akt pathway are currently in multiple clinical trials for OVCa. It is thought that this pathway has particular importance as a mechanism of chemoresistance, and there is evidence that inhibition of the PI3K/Akt pathway reverses the resistance of OVCa cells to Pt compounds. Inhibition of Akt activation may therefore be a promising therapeutic strategy not only for treatment of OVCa as a stand-alone drug but also to "re-sensitize" OVCa tumors to Pt compounds, i.e., to be used in combination chemotherapy with carboplatin. Preliminary Data: We have uncovered a mechanism by which Akt is activated in OVCa cells by another kinase, designated CaMKK2. CaMKK2 activates Akt by phosphorylating it at the same site as does PDK1. In OVCa cells, depletion of CaMKK2 or PDK1 independently produced similar decrements in Akt activation. CaMKK2 therefore plays as similar but independent role as PDK1, leading to the hypothesis that a combination of inhibitors of PI3K and CaMKK2 pathways will produce additive or synergistic inhibitory effects on the growth and survival of OVCa cells and tumors. Specific Aims: Aim 1: To assess synergism or additivity of the effects of inhibitors of CaMKK2 and PI3K and of carboplatin on the growth and survival of OVCa cells. Aim 2: To utilize inhibitors of CaMKK2 and PI3K and carboplatin individually and in combination in tumor xenografts of OVCa cells in mice and assess antitumor efficacies. Conclusions: This study is built on the established importance of the PI3K/Akt pathway for OVCa progression, its likely importance for Pt resistance, and on our strong preliminary data implicating CaMKK2 as an unrecognized, but significant Akt activator in OVCa. It is predicated that, if not inhibited, the activity of the CaMKK2 pathway will lead to suboptimal response rates in clinical studies of PI3K inhibitors for OVCa. Based on this compelling rationale, we will establish proof-of-concept that inhibition of CaMKK2 will be therapeutically efficacious in combination with PI3K inhibition and/or carboplatin, will validate the antitumor activity of the CaMKK2 inhibitor STO-609 in a clinically relevant PDX model of OVCa, and will initiate a process of development of new STO-609-related compounds with optimized anti-tumor efficacies. The significant impact of this project is through enabling a more effective therapeutic option to counter Pt resistance in OVCa patients by enhancing the
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610481
Entities
People
- Arthur Edelman
Organizations
- United States Army
- University at Buffalo