Washington, DC (UroToday.com) In today’s state of the art lecture at the Society of Urologic Oncology meeting, Dr. Lewis Cantley discussed Targeting PI3-Kinase (PI3K) Cancer therapy. He began the discussion with a review of the PI3K pathway. PI3K was discovered in the 1980s when it was found that its production correlated with cell transformation. PI3K was associated with glucose uptake and metabolism, which leads to cell survival and growth. In cancer, loss of PTEN leads to cancer cell survival and
cancer cell growth. In soft tissue diseases that feature localized hypertrophy, PI3K expression was identified through sequencing of hyperplastic tissue, and it was found to take up glucose at a faster rate than normal tissue. Based on this finding, investigators looked at many common cancers, including uterine, glioblastoma, colorectal, lung cervical, ovarian, breast, and prostate, and identified mutations in genes in the PI3K signaling network (oncogenes = PI3K, Ras, Raf, AKT; suppressors = NF1, PTEN, INPP4B, LKB1, TSC2).
The second portion of Dr. Cantley’s talk was on the rationale for combining PI3K-I with PARP in tumors with high DNA damage levels. In a mouse model involving PTEN loss and BRCA mutation, investigators found that those treated with BKM120 alone had a delay in tumor progression, but no shrinkage or cure. Those treated with alpha specific PI3K BYL719 had no effect at all. This prompted the search for combination agents, which started with breast cancer explants. Those treated with PI3K alone showed some DNA damage via high gamma H2ax, which is active in DNA repair pathway activation. A large increase in polyADP ribosylation was also identified, indicating the progression of DNA repair. Olaparib, a PARP inhibitor used as monotherapy, similarly showed little effect. This prompted the theory that PI3K-I would induce DNA damage, and the addition of Olaparib would prevent DNA repair. This was supported when pan- and alpha-specific PI3K-I were added to Olaparib, and complete cure was seen.
Finally, Dr. Cantley turned to a discussion of pre-clinical prostate models for testing PI3K-I in prostate cancer. With a relative paucity of cell lines there are currently no good clinical models; however explants and organoids can prove to be useful. Mouse models currently in use include PTEN deletion, PTEN/p53 deletion, PTEn/p53 deletion + ERG transgene, INPP4B/PTEN/p53 deletion, and AKT transgene. Early studies demonstrate similar results to the breast models, where PTEN- P53- cancers are vulnerable to PARP-PI3K inhibition. Again, PI3K-I induces genetic instability that puts cell on edge of ability to keep up w DNA repair. Olaparib alone and BKM120 alone resulted in shrinkage, but in combination complete tumor regression was seen.
Dr. Cantley concluded that tumors with defects in p53 and defects in either PTEN or PARP have high rates of DNA damage. Inhibiting PI3K in these tumors further enhances DNA damage by limiting nucleotide synthesis needed for DNA repair. Combination of PARP-I and PI3K-I provides synergistic killing in these tumors.
Presented By:
Lewis Cantley, PhD
Weill Cornell Medical College
Reported by:
Dr. Nikhil Waingankar, MD. from the Society of Urologic Oncology Meeting - December 2 - 4, 2015 – Washington, DC.
Fox Chase Cancer Center, Philadelphia, PA.