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

描述(申请人提供)：在美国，预计2012年约有76,250例新的黑色素瘤病例和9,180例与黑色素瘤相关的死亡病例。在目前可用的治疗方案下，转移性黑色素瘤患者面临着最多10个月存活的黯淡前景，以及十分之一的存活10年的机会。手术和放射治疗是治疗的主要手段。30年后，以达卡巴津为基础的化疗仍然是主要的全身治疗方法，因为没有更好的方法。就目前的使用情况而言，免疫疗法几乎没有什么改善。大剂量的IL-2(前列环素)和ipilimumab(伊尔韦)可以提高存活率，但只在少数患者中使用，而且有严重毒性的风险。基因突变 BRAF癌基因出现在80%的黑色素瘤中，并激活B-Raf丝氨酸/苏氨酸激酶来驱动不受控制的细胞生长。这种新的靶向药物维莫拉非尼(PLX4032)可以抑制由V600E突变激活的B-Raf，这种突变发生在85%的黑色素瘤BRAF突变中。高应答率、良性和可控的毒性，以及BRAFV600E突变的伴随诊断的可用性增加了治愈转移性黑色素瘤的前景。这一希望因耐药的发展和恶性疾病的复发而受挫，在PLX4032治疗后仅几个月就出现了回归。PLX4032产生的缓解期为免疫治疗方法提供了机会之窗，这些方法可能激活肿瘤免疫以抑制PLX4032耐药黑色素瘤的复发。Arisaph已经发现了一种脯氨酸肽酶家族的小分子抑制剂ARI-4175，它可以激活肿瘤免疫，通过诱导免疫调节细胞因子和趋化因子来杀死肿瘤。Arisaph已经选择ARI-417作为第二代候选药物，比相关化合物PT-100(塔拉博斯特)具有更强的活性和更低的毒性。ARI-4175对小鼠肿瘤产生免疫排斥反应效果显著。因此，如果在PLX4032产生的缓解期给予ARI-4175，可能会激活一种免疫反应，从而抑制疾病的复发。为了证明ARI-4175在PLX4032对BRAFV600E阳性黑色素瘤模型产生初步反应后，可以抑制肿瘤的进展，将测试这一假说。为了成为可行的候选药物，ARI-4175必须在PLX4032治疗BRAFV600E阳性黑色素瘤后，通过激活肿瘤免疫而产生比单独PLX4032明显更强的抗肿瘤作用。如果ARI-4175符合STTR第一阶段的可行性测试，第二阶段将建议进行IND使能研究和启动临床试验，以调查安全性和有效性。

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.