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

描述（由申请人提供）：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；但晚期疾病通常需要辅助治疗。大约55%的结直肠癌患者有转移性疾病，尽管伊立替康、奥沙利铂和靶向药物的引入逐渐改善了预后，但预后很差。后者包括抗体，西妥昔单抗和帕尼单抗，最初被FDA批准用于化疗失败的患者。选择这些抗体是因为它们能够通过阻断表皮生长因子受体（EGFR）杀死肿瘤。然而，尽管与化疗相比，抗egfr抗体承诺有效且毒性降低，但只有不到12%的结直肠癌患者对抗体作为单一药物有反应。耐药主要是由于激活KRAS癌基因的突变独立于EGFR信号驱动CRC生长。FDA已经限制西妥昔单抗和帕尼单抗用于治疗表达非突变KRAS的转移性结直肠癌。一种新的治疗方法可能是利用西妥昔单抗的另一种作用机制，即抗体依赖性细胞毒性（ADCC）。无论肿瘤是否有KRAS突变，西妥昔单抗都可以通过ADCC作用于先天杀伤细胞（K细胞）杀死肿瘤细胞。然而，当西妥昔单抗作为单一药物使用时，ADCC的临床益处似乎很少。改善ADCC影响的一种方法是将西妥昔单抗与一种可以提高K细胞杀伤肿瘤效率的药物联合使用。之所以选择ARI-4175，是因为初步结果表明，它可以刺激西妥昔单抗介导的ADCC在小鼠KRAS突变型CRC中产生肿瘤应答。特异性目的是证明ali -4175可以扩增西妥昔单抗介导的ADCC，在对西妥昔单抗耐药的人KRAS突变型CRC细胞系（HCT-116）攻击的裸鼠中产生显著的肿瘤应答。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评估K细胞对肿瘤的攻击，并在体外分析实验治疗对ADCC的影响。该方法将寻求证实初步证据，表明ARI-4175激活一种特定类型的K细胞-自然杀伤（NK）细胞-通过ADCC杀死肿瘤。为了使ARI-4175成为可行的候选药物，它必须与西妥昔单抗相互作用，在HCT-116模型中产生显著的肿瘤反应，并证明其具有免疫作用机制。如果STTR I期研究成功，将为STTR II期提出ind支持研究和ARI-4175的I期临床试验。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: In 2012, 103,170 cases of colon cancer, 40,290 cases of rectal cancer, and 51,690 deaths from colorectal cancer (CRC, accounting for 9% of all cancer deaths) are predicted to occur in the United States. The anti- epidermal growth factor (EGFR) antibodies, cetuximab and panitumumab, appeared promising, initially, for treatment of metastatic CRC (mCRC) that is not amenable to surgery and resistant to chemotherapy; but it has turned out that less than 12% of patients respond to the antibodies as single agents, largely due to KRAS mutations that drive tumor growth independently of the EGFR. This project will test the feasibility of ARI-4175 as an immunotherapeutic agent that can enable cetuximab to successfully treat mCRC by the alternative mecha- nism of antibody-dependent cellular cytotoxicity, which is not affected by KRAS mutations.