Arf6 inhibitors for the treatment of uveal melanoma

DESCRIPTION provided by applicant Activating mutations in G proteins are the drivers of oncogenesis in numerous cancers Therefore identifying drugs that block the signaling pathways controlled by these mutations could have enormous therapeutic consequences Uveal melanoma is a prototypical G driven cancer in which about of tumors have activating mutations in one of two G encoding genes GNAQ and GNA Although progress has been made in the treatment of primary uveal melanoma tumors metastasis occurs in approximately of patients and once the tumor has spread to other tissues and organs usually the liver no current treatments are effective and the disease is invariably fatal Therefore finding a treatment that reduces metastasis or can reduce tumor establishment or growth of metastatic uveal melanomas is of utmost importance especially if the treatment also has therapeutic potential for several other cancers Activating mutations in GNAQ and GNA control at least two major signaling pathways that are important for melanocyte transformation and uveal melanoma growth These signaling pathways activate mitogen activated protein kinase extracellular signal regulated kinases MAPK ERK and YAP to control AP and YAP TEAD mediated transcription that leads to transformation and tumor growth We and our collaborators at the University of Utah have identified the small GTPase ADP ribosylation factor ARF as a primary immediate effector of constitutively activated GNAQ Knocking down ARF expression or inhibiting its activation with the small molecule compound SecinH has the same effect as knocking down constitutively activated GNAQ We have demonstrated that ARF knockdown inhibits the establishment and growth of tumors in an orthotopic xenograft mouse model of uveal melanoma and have preliminary data suggesting that small molecule inhibition of ARF likewise reduces tumor formation and growth These results suggest that ARF inhibition may be an effective method for treating both primary and metastatic uveal melanoma In this Phase I study we will test our hypothesis by pursuing two aims In Aim we will determine whether novel ARF inhibitors can inhibit proliferation anchorage independent colony growth and invasion of uveal melanoma cells In Aim we will test the efficacy of our inhibitors in our orthotopic xenograft model of human uveal melanoma As noted above G proteins play important roles in many cancers Therefore results from this Phase I study may have much broader implications for the treatment of multiple cancers Success will place us in an ideal position to proceed to a Phase II study in which we will continue to examine the efficacy of these compounds in other animal models of uveal melanoma to show general applicability while also performing pharmacokinetic and detailed toxicity studies These Phase II studies will be necessary to obtain IND approval and allow for future clinical trials PUBLIC HEALTH RELEVANCE Uveal melanoma is the most common adult primary tumor of the eyeball and often has a propensity to spread to other parts of the body especially the liver where it establishes secondary tumors that are invariably fatal We have identified a protein that plays an important role in the molecular signaling pathways that control the establishment and growth of uveal melanomas and have synthesized small molecule compounds that can inhibit the activity of this required protein In this Phase I study we will determine whether these small molecule inhibitors are appropriate for further drug development by testing whether they can inhibit the establishment and growth of tumors in an animal model of human uveal melanoma