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

• 批准号: 8521751
• 负责人: WILLIAM W BACHOVCHIN
• 金额: $ 23.29万
• 依托单位: ARISAPH PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 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/8521751
• 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; 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

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年约有76,250例新型黑色素瘤和9,180例与黑色素瘤相关的死亡。目前可用的治疗选择，转移性黑色素瘤患者面临着最佳的前景，10个月的生存和10年生存的机会。手术和放射疗法是治疗的主要手段。 30年后，基于Dacarbazine的化学疗法仍然是主要的全身疗法。由于目前使用，免疫疗法几乎没有改善。高剂量IL-2（proleukin）和ipilimumab（Yervoy）可以增加存活率，但只有少数患者，并且有严重毒性的风险。突变 BRAF癌基因发生在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。新的靶向剂Vemurafenib（PLX4032）抑制了黑色素瘤中85％BRAF突变中的V600E突变激活的B-RAF。高反应率，良性和可控制的毒性以及对BRAFV600E突变的伴侣诊断的可用性提高了转移性黑色素瘤治愈的前景。仅在响应PLX4032时，耐药性的发展和恶性疾病的复发就挫败了这种希望。 PLX4032产生的缓解周期为免疫治疗方法提供了机会窗口，该方法可能会激活肿瘤免疫力以抑制PLX4032耐药性黑色素瘤的复发。 ARISAPH已经确定了prolyl肽酶家族的小分子抑制剂ARI-4175，该抑制剂可以通过诱导免疫调节细胞因子和趋化因子和趋化因子来激活肿瘤免疫以杀死肿瘤。与相关化合物PT-100（Talabostat）相比，ARISAPH选择了ARI-417作为具有更大活性和毒性更高的第二代药物候选药物（Talabostat）。 ARI-4175在产生小鼠的肿瘤免疫排斥反应方面非常有效。因此，如果在PLX4032产生的缓解期间给出，ARI-4175可能会激活可以抑制疾病重新出现的免疫反应。该假设将进行检验，以证明ARI-4175在BRAFV600E阳性黑色素瘤模型中，ARI-4175可以抑制肿瘤的进展，该模型由Philip Hinds博士（Tufts Medical Center）建立。为了成为可行的候选药物，ARI-4175必须通过PLX4032治疗在BRAFV600E阳性黑色素瘤中的PLX4032治疗后仅激活PLX4032的抗肿瘤效应。如果ARI-4175符合STTR I期的可行性测试，则将提出针对II阶段的研究和临床试验进行研究的研究和临床试验。