Uveal melanoma (UM) is the most common intraocular tumor in adults. Nearly half of UM patients
develop metastatic disease and survive one year or less. No effective therapy exists. Current interventions
impair or destroy vision, yet do not improve morbidity or mortality caused by metastatic disease. Clinical trials
of cytotoxic chemotherapeutics and immune checkpoint inhibitors have shown little efficacy. Mutant
constitutively active forms of Gaq/11 that drive oncogenesis in ~90% of UM patients thus far have been
undruggable. Inhibitors of signaling molecules downstream of these oncoproteins have failed to demonstrate
significant clinical benefit. Effective therapy may require breakthroughs that enable direct targeting of
constitutively active Gaq/11 or necessary but as yet unidentified downstream signaling cascades.
This project fills these gaps by showing for the first time that constitutively active Gaq/11 can be
trapped pharmacologically in the inactive GDP-bound state, thereby attenuating downstream signaling. The
inhibitor causes Gaq/11-driven UM cells to arrest growth, die, or re-differentiate into melanocytic cells,
whereas it has no effect on BRAF-driven UM cells. Inhibitor-treated UM cells has revealed a novel
oncogenesis mechanism in which signaling by constitutively active Gaq/11 antagonizes epigenetic silencing
mediated by polycomb repressive complex 2 (PRC2) to drive de-differentiation.
Based on these breakthroughs, the following Aims will be pursued: 1) Identify novel druggable targets
that mediate signaling between constitutively active Gaq/11 and PRC2 in UM cells; 2) Determine whether the
Gaq/11 inhibitor provides vision-sparing therapeutic benefit in mouse models of primary and metastatic UM;
and 3) Set the stage for clinical trials by determining which clinical subclasses of human primary UM tumors
respond ex vivo to the Gaq/11 inhibitor. In summary, this project provides unprecedented opportunity to
determine whether direct pharmacological inhibition of mutant constitutively active Gaq/11 could provide the
first effective and potentially vision-sparing therapeutic option for treating UM.