The mTOR complex 1 lies at the center of proliferation of GS2 non-invasive tumors. mTOR is is the main regulator of protein synthesis, glycolysis, autophagy, and lipid synthesis, all of which lead to cell growth. GS2 tumors do express up-regulation of many of the genes downstream of the mTOR complex, as evidenced by microarray analysis. Dr. Knowles acknowledged that the consequences of mTOR signaling in GS2 cells may be potential targets for therapeutic agents aimed at treating NMIBC. Rapamycin, an mTOR inhibitor, would not likely be a good agent according to Dr. Knowles because it would suppress proliferation without inducing apoptosis, which creates energetic stability, therefore promoting tumor viability.
She next discussed the molecular differences between NMIBC and muscle-invasive bladder cancer (MIBC). Compared to MIBC, NMIBC has more homogeneity of genetic mutations. MIBC has multiple genetic mutations that are similar to NMIBC, however there are higher rates of some mutations in MIBC, namely P53. FGFR3 and PIC3a mutations are very common in NMIBC. Other common mutations include genes that control chromatin modification, such as KDM6a and Stag2, which normally act as tumor suppressor genes.
Dr. Knowles concludes that with further characterization of the molecular profile of NMIBC, we will hopefully be able to identify additional targets for therapeutic intervention. One exciting pathway that is being investigated involves EZH2 inhibition of KDM6A mutant cells.
Presented by: Margaret A. Knowles, PhD, Leeds Institute of Cancer and Pathology
Written by: Brian Kadow, MD, Fox Chase Cancer Center, Philadelphia, PA at the 18th Annual Meeting of the Society of Urologic Oncology, November 20-December 1, 2017 – Washington, DC