A Small Molecule to Activate Cetuximab to Kill K-RAS Mutant Colorectal Tumors

激活西妥昔单抗杀死 K-RAS 突变结直肠肿瘤的小分子

• 批准号: 8647920
• 负责人: WILLIAM W BACHOVCHIN
• 金额: $ 14.7万
• 依托单位: ARISAPH PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-24 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8647920
• 关键词: Accounting; Activated Natural Killer Cell; Adjuvant Therapy; Affect; Antibodies; Antigen Targeting; Binding; Biological Assay; Cancer Etiology; Cancer Patient; Cancer cell line; Cells; Cessation of life; Cetuximab; Chronic Lymphocytic Leukemia; Clinical; Colon Carcinoma; Colorectal Cancer; Colorectal Neoplasms; Disease; Dose; Early treatment; Effector Cell; Enhancing Antibodies; Epidermal Growth Factor; Epidermal Growth Factor Receptor; Extracellular Domain; FDA approved; Family; Fc Receptor; Growth; Histology; Human; IgG1; Immune; Immunoglobulin G; Immunotherapeutic agent; Infiltration; Investigational Therapies; KRAS2 gene; Killer Cells; Lead; Malignant Neoplasms; Measures; Mediating; Modeling; Mus; Mutation; Natural Killer Cells; Non-Hodgkin' s Lymphoma; Nude Mice; Oncogenes; Operative Surgical Procedures; Patients; Peptide Hydrolases; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Production; Receptor Signaling; Rectal Cancer; Reporting; Resistance; Safety; Signal Transduction; Small Business Technology Transfer Research; Staging; Testing; Toxic effect; Trastuzumab; Tumor Antibodies; United States; Up-Regulation; Xenograft procedure; advanced disease; analog; antibody-dependent cell cytotoxicity; anticancer activity; arm; base; chemokine; chemotherapy; chimeric antibody; cytokine; drug candidate; improved; in vivo; inhibitor/antagonist; irinotecan; killings; metastatic colorectal; mortality; mouse model; mutant; neoplastic cell; novel therapeutic intervention; outcome forecast; oxaliplatin; panitumumab; phase 1 study; phase 2 study; response; rituximab; small molecule; tumor; tumor growth; tumor microenvironment

In the United States colorectal cancer (CRC) is the third leading cause of cancer mortality. Surgery is the primary treatment for early stage CRC; but adjuvant therapy is usually needed in advanced disease. Approximately 55% of CRC patients have metastatic disease for which the prognosis is poor despite incremental improvements due to introduction of irinotecan, oxaliplatin and targeted agents. The latter include the antibodies, cetuximab and panitumumab, initially approved by the FDA for patients who fail chemotherapy. The antibodies were selected for their ability to kill tumors by blockade of the epidermal growth factor receptor (EGFR). How- ever, although the anti-EGFR antibodies promised efficacy with reduced toxicity compared to chemotherapy, less than 12% of CRC patients respond to the antibodies as single agents. Resistance is largely due to mutations that activate the KRAS oncogene to drive CRC growth independently of EGFR signaling. The FDA has restricted cetuximab and panitumumab to treatment of metastatic CRC that expresses non-mutated KRAS. A new therapeutic approach in CRC might be to exploit an alternative mechanism of action for cetuximab called antibody-dependent cellular cytotoxicity (ADCC). Cetuximab can potentially engage innate killer cells (K cells) to kill tumor cells by ADCC, regardless of whether or not the tumor has the KRAS mutation. However, when cetuximab is used as a single agent, little clinical benefit appears to come from ADCC. One way to improve the impact of ADCC would be to combine cetuximab with an agent that can enhance the efficiency of tumor killing by K cells. ARI-4175 has been selected for this purpose because preliminary results suggest it can stimulate cetuximab-mediated ADCC to produce tumor responses in KRAS mutant CRC in mice. The Specific Aim is to demonstrate that ARI-4175 can amplify cetuximab-mediated ADCC to produce significant tumor responses in nude mice challenged with a human KRAS mutant CRC cell line (HCT-116) that is resistant to cetuximab as a single agent. Tumor responses to treatment will be measured, tumor attack by K cells will be assessed by histology and immunostaining of responsive tumors, and the effect of experimental therapy on ADCC will be assayed ex vivo. The approach will seek to substantiate preliminary evidence suggesting that ARI-4175 activates a particular type of K cell-the natural killer (NK) cell-to kill tumors by ADCC. For ARI-4175 to be a viable drug candidate it must interact with cetuximab to produce significant tumor responses in the HCT-116 model with evidence of an immune mechanism of action. If the STTR Phase I study is successful, IND-enabling studies and the initiation of a phase 1 clinical trial of ARI-4175 will be proposed for STTR Phase II.

在美国，结直肠癌(CRC)是癌症死亡的第三大原因。手术是早期结直肠癌的主要治疗方法，但对于晚期结直肠癌通常需要辅助治疗。大约55%的结直肠癌患者有转移性疾病，尽管由于伊立替康、奥沙利铂和靶向药物的引入而逐渐改善，但预后很差。后者包括抗体西妥昔单抗和帕尼图单抗，最初由FDA批准用于化疗失败的患者。这些抗体的选择是因为它们能够通过阻断表皮生长因子受体(EGFR)来杀死肿瘤。然而，尽管与化疗相比，抗EGFR抗体保证了疗效和降低的毒性，但只有不到12%的CRC患者作为单一药物对抗体有反应。耐药性在很大程度上是由于突变激活了KRAS癌基因，从而独立于EGFR信号驱动结直肠癌生长。FDA限制西妥昔单抗和帕尼妥单抗用于治疗表达非突变KRAS的转移性结直肠癌。 一种新的治疗结直肠癌的方法可能是开发西妥昔单抗的另一种作用机制，称为抗体依赖性细胞毒性(ADCC)。无论肿瘤是否存在KRAS突变，西妥昔单抗都有可能通过ADCC激活先天杀伤细胞(K细胞)来杀死肿瘤细胞。然而，当西妥昔单抗作为单一药物使用时，ADCC似乎没有多少临床益处。改善ADCC效果的一种方法是将西妥昔单抗与一种可以提高K细胞杀瘤效率的药物相结合。ARI-4175被选择用于这一目的，因为初步结果表明，它可以刺激西妥昔单抗介导的ADCC在KRAS突变的小鼠结直肠癌中产生肿瘤反应。具体目的是证明ARI-4175能够扩增西妥昔单抗介导的ADCC，在裸鼠体内产生显著的肿瘤反应，攻击对西妥昔单抗耐药的人KRAS突变CRC细胞系(HCT-116)。将测量肿瘤对治疗的反应，通过组织学和反应性肿瘤的免疫染色来评估K细胞对肿瘤的攻击，并将在体外检测实验性治疗对ADCC的影响。该方法将寻求证实初步证据表明，ARI-4175激活了一种特定类型的K细胞--自然杀伤(NK)细胞--通过ADCC杀死肿瘤。要使ARI-4175成为可行的候选药物，它必须与西妥昔单抗相互作用，才能在HCT-116模型中产生显着的肿瘤反应，并证明其具有免疫作用机制。如果STTR第一阶段研究成功，第二阶段将建议进行IND使能研究和启动ARI-4175的第一阶段临床试验。