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

V600E BRAF 黑色素瘤中 PLX403 后激活肿瘤免疫的小分子

基本信息

批准号：
8835639
负责人：
WILLIAM W BACHOVCHIN
金额：
$ 16.07万
依托单位：
ARISAPH PHARMACEUTICALS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-02 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8835639
关键词：
Achievement Aftercare Aldesleukin Antibodies BRAF gene Benign C57BL/6 Mouse CTLA4 gene Cessation of life Clinical Clinical Trials Companions Dacarbazine Development Diagnostic Diagnostic Neoplasm Staging Disease Disease remission Dose Drug resistance Dura Mater Effectiveness FDA approved Face Failure Family Generations Immune Immune response Immunotherapeutic agent Immunotherapy Implant Interleukin-2 Laboratories Lesion Lymphoid Tissue MAPK Signaling Pathway Pathway MEKs Malignant - descriptor Measures Mediating Medical Medical center Metastatic Melanoma Modeling Mus Mutation Non-Small-Cell Lung Carcinoma Oncogenes Operative Surgical Procedures Palpable Patients Peptide Hydrolases Phase Phase I Clinical Trials Phase II Clinical Trials Phase III Clinical Trials Phosphotransferases Placebos Protein-Serine-Threonine Kinases Proteins Proto-Oncogene Proteins B-raf Radiation therapy Raf Kinase Inhibitor Recurrence Residual state Resistance Risk Safety Serine Skin Cancer Small Business Technology Transfer Research Staging Systemic Therapy T-Lymphocyte Testing Therapeutic Toxic effect Tumor Immunity Tumor Tissue Tumor stage United States Variant Work advanced disease analog base cell growth chemokine chemotherapy cytokine drug candidate immune function in vivo inhibitor/antagonist killings meetings melanoma member mouse model novel therapeutic intervention pre-clinical prevent public health relevance response small molecule tumor tumor progression uncontrolled cell growth

项目摘要

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.

描述（由申请人提供）：在美国，预计 2012 年将出现约 76,250 例黑色素瘤新病例和 9,180 例与黑色素瘤相关的死亡。根据目前可用的治疗方案，转移性黑色素瘤患者最多只能存活 10 个月。以及十分之一的机会存活 10 年。手术和放射治疗是主要的治疗方法。 30 年后，由于没有更好的办法，以达卡巴嗪为基础的化疗仍然是主要的全身治疗。目前使用的免疫疗法几乎没有改善。高剂量IL-2（Proleukin）和ipilimumab（Yervoy）可以提高生存率，但仅限于少数患者，并且存在严重毒性的风险。突变在 BRAF 癌基因存在于 80% 的黑色素瘤中，并激活 B-Raf 丝氨酸/苏氨酸激酶以驱动不受控制的细胞生长。新的靶向药物维莫非尼 (PLX4032) 可抑制由 V600E 突变激活的 B-Raf，该突变发生在黑色素瘤 85% 的 BRAF 突变中。高缓解率、良性且可控的毒性以及 BRAFV600E 突变伴随诊断的可用性提高了治愈转移性黑色素瘤的前景。这一希望因 PLX4032 治疗后仅几个月就出现耐药性和恶性疾病复发而落空。 PLX4032 产生的缓解期为免疫治疗方法提供了一个机会之窗，这些方法可能会激活肿瘤免疫以抑制 PLX4032 耐药性黑色素瘤的复发。 Arisaph 发现了一种脯氨酰肽酶家族的小分子抑制剂 ARI-4175，它可以通过诱导免疫调节细胞因子和趋化因子来激活肿瘤免疫来杀死肿瘤。 Arisaph 选择 ARI-417 作为第二代候选药物，其活性比相关化合物 PT-100（talabostat）更高，毒性更低。 ARI-4175 在小鼠体内产生肿瘤免疫排斥反应非常有效。因此，如果在 PLX4032 产生的缓解期间给予 ARI-4175 可能会激活免疫反应，从而抑制疾病的复发。这一假设将得到检验，具体目的是证明 ARI-4175 在 Philip Hinds 博士（塔夫茨医学中心）建立的 BRAFV600E 阳性黑色素瘤模型中对 PLX4032 产生初步反应后可以抑制肿瘤的进展。为了成为可行的候选药物，ARI-4175 必须在对 BRAFV600E 阳性黑色素瘤小鼠进行 PLX4032 治疗后激活肿瘤免疫，从而产生比单独使用 PLX4032 显着更强的抗肿瘤效果。如果 ARI-4175 通过了 STTR 第一阶段的可行性测试，将建议第二阶段进行 IND 启用研究并启动临床试验以研究安全性和有效性。