A Small Molecule to Activate Tumor Immunity after PLX403 in V600E BRAF Melanoma

描述（由申请人提供）：在美国，预计2012年约有76,250例黑色素瘤新病例和9,180例黑色素瘤相关死亡。根据目前可用的治疗方案，转移性黑色素瘤患者面临的前景黯淡，最多只能存活10个月，而存活10年的几率只有十分之一。手术和放射治疗是主要的治疗方法。由于缺乏更好的治疗方法，以达卡巴嗪为基础的化疗在30年后仍然是主要的全身治疗方法。目前使用的免疫疗法几乎没有改善。高剂量IL-2 （Proleukin）和伊匹单抗（Yervoy）可以提高生存率，但仅适用于少数患者，并且存在严重毒性的风险。突变

DESCRIPTION (provided by applicant): In the United States, around 76,250 new cases of melanoma and 9,180 melanoma-related deaths are predicted for 2012. With the therapeutic options currently available, metastatic melanoma patients face the bleak prospect of at best, 10 month's survival and a one-in-ten chance of surviving for 10 years. Surgery and radiation therapy are the mainstay of treatment. Dacarbazine-based chemotherapy remains after 30 years, for want of anything better, to be the main systemic therapy. As currently used, immunotherapy affords little improvement. High dose IL-2 (Proleukin) and ipilimumab (Yervoy) can increase survival, but only in a few patients, and at the risk of severe toxicity. Mutations in the BRAF oncogene occur in 80% of melanomas and activate the B-Raf serine/threonine kinase to drive uncontrolled cell growth. The new, targeted agent, vemurafenib (PLX4032), inhibits B-Raf activated by the V600E mutation occurring in 85% of BRAF mutations in melanoma. High response rates, benign and manageable toxicities, and the availability of a companion diagnostic for the BRAFV600E mutation raised the prospect of a cure in metastatic melanoma. This hope has been thwarted by the development of drug resistance and the recurrence of malignant disease only months after regression in response to PLX4032. The period of remission produced by PLX4032 provides a window of opportunity for immunotherapeutic approaches that might activate tumor immunity to suppress the recurrence of PLX4032-resistant melanoma. Arisaph has identified a small molecule inhibitor of the prolyl peptidase family, ARI-4175, that can activate tumor immunity to kill tumors via the induction of immunoregulatory cytokines and chemokines. Arisaph has selected ARI-417 as a second-generation drug candidate with greater activity and less toxicity than the related compound, PT-100 (talabostat). ARI-4175 is remarkably effective in producing immune rejection of tumors in mice. Therefore, if given during the period of remission produced by PLX4032, ARI-4175 might activate an immune response that can suppress reemergence of disease. This hypothesis will be tested with the Specific Aim of demonstrating that ARI-4175 can inhibit progression of tumors after the initial response to PLX4032 in a model of BRAFV600E-positive melanoma established by Dr. Philip Hinds (Tufts Medical Center). In order to be a viable drug candidate, ARI-4175 must produce a significantly greater antitumor effect than PLX4032 alone by the activation of tumor immunity after PLX4032 treatment in BRAFV600E-positive melanoma in mice. If ARI-4175 meets the test of feasibility in STTR Phase I, IND-enabling studies and initiation of clinical trials to investigae safety and efficacy will be proposed for Phase II.