Racing against tumor evolution
Developing effective targeted therapies to dispatch tumors before they evolve resistance requires knowledge of available escape pathways. This is especially critical given that resistant clones are likely present in small numbers at the time of treatment initiation. Given the pathway and compensatory alterations in Hh-dependent tumors thus far, dual targeting of the most downstream component of the pathway, and the compensatory pathways, will likely generate optimal therapies. Gli transcription factors ultimately transduce the signal from the Hh ligand; moreover, escape pathways that bypass Smo still activate Gli. Targeting Gli directly or the signaling components that activate Gli could prove quite successful as the next level of therapy.
Several Gli inhibitors have been identified that have impressive efficacy. Through a screen of the National Institutes of Health compound library, molecules such as GANT58 and GANT61 were found to block Gli transcriptional activity (Lauth et al., 2007
). These drugs inhibit Hh signaling with a similar IC50 to cyclopamine and suppress Gli1-positive human prostate cancer xenografts. Moreover, similar screens using a library of previously FDA-approved drugs identified arsenic trioxide (ATO) as a Gli antagonist (Kim et al., 2010
). ATO blocks accumulation of Gli2 to primary cilia, with longer incubation times reducing steady-state Gli2 protein levels, resulting in suppression of medulloblastoma growth in mouse models. As ATO is already in clinical use for acute promyelocytic leukemia, this may be a useful therapy for resistant BCCs in the near future.
Identifying and targeting modulators of Gli activity may also show promise in preventing or treating resistant tumors. New pathways that regulate Gli such as the aforementioned S6K1 may hold the key to delay tumor resistance. Because S6K1 appears to regulate Gli1 activity downstream of mTOR, and Smo inhibitors regulate Gli activity and nuclear localization, combination therapy may prevent tumor cells containing this compensatory alteration from growing. Indeed, in vitro data from esophageal adenocarcinoma xenografts suggest that combination therapy with mTOR inhibitors and vismodegib work synergistically (Wang et al., 2012
). These data provide strong preclinical support for the use of combined therapy to delay growth of Smo antagonist–resistant tumors.
The blueprint to develop the first Hh pathway inhibitors came from impressive efforts from the Hh and cancer communities, beginning with identification of Hh pathway components and their roles in cancer and continuing with intense screening and medicinal chemistry that refined drug targets for optimal human use. The challenge for the future is to better understand common pathway-dependent genetic and compensatory escape pathways that evolve from clonal populations within tumors and design combination therapies to block them before further evolution takes place. Through improved genomics, cell biology, and medicinal chemistry, this may be a race medical research can win.