Unravel the role of CD276 and determine efficacy of CD276-targeted therapy on Merkel cell carcinoma progression and metastasis

揭示 CD276 的作用并确定 CD276 靶向治疗对默克尔细胞癌进展和转移的疗效

• 批准号: 10584403
• 负责人: Ling Gao
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10584403
• 关键词: Acceleration; Affect; Antibodies; Antibody-drug conjugates; Biological; Biological Markers; Biology; Blocking Antibodies; CAR T cell therapy; CD276 gene; Cancer Model; Caucasians; Cause of Death; Cell Line; Certification; Clinical; Clinical Trials; Collaborations; Couples; DNA Binding Agent; Data; Diagnosis; Endowment; Evaluation; Fruit; Future; Health; Healthcare; Healthcare Systems; Human; Immune; Immune system; Immunotherapy; Improve Access; Inter-tumoral heterogeneity; Investigation; Malignant Neoplasms; Medical center; Merkel cell carcinoma; Modeling; Mus; National Cancer Institute; Neoplasm Metastasis; Outcome; Patients; Pharmaceutical Preparations; Positioning Attribute; Pre-Clinical Model; Prediction of Response to Therapy; Productivity; Reporting; Resistance; Resources; Role; Safety; Skin; Skin Cancer; Solid Neoplasm; Stromal Cells; Stromal Neoplasm; Survival Rate; Testing; Therapeutic; Treatment Efficacy; Tumor-Derived; Up-Regulation; Veterans; Visceral; Work; Xenograft Model; Xenograft procedure; advanced disease; anti-cancer; base; biomarker identification; cancer cell; cancer stem cell; cancer therapy; clinically relevant; cohort; comorbidity; confirmatory clinical trial; cost effective; cost effectiveness; cytotoxic; design; drug discovery; efficacy evaluation; established cell line; in vivo; insight; male; melanoma; mortality; mouse model; neuroendocrine cancer; novel; novel strategies; novel therapeutics; overexpression; patient derived xenograft model; pre-clinical; preclinical study; prevent; rare cancer; reconstitution; response; response biomarker; subcutaneous; success; targeted treatment; therapy resistant; treatment response; tumor; tumor microenvironment

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine cancer of the skin with a dismal five-year survival rate of less than 18% in advanced disease and a mortality rate 3-times higher than melanoma. MCC disproportionately and predominantly affects Caucasian males older than 65, who are well represented among Veterans, and more than 5000 new MCC cases have been diagnosed among Veterans. Hence, MCC has a growing impact on Veterans’ health and VA healthcare system. Notwithstanding the approval of immunotherapy, treating metastatic MCC remains a challenge. Thus, we are compelled to seek novel therapies to overcome resistance, or to serve as definitive treatments for MCC patients who are ineligible for immunotherapy due to comorbidities. In this proposal, we will collaborate with VA Medical Centers encountering most Veteran MCC patients to define the role of B7-H3 (encoded by CD276) in MCC patient survival in a large cohort of Veteran patients. Moreover, we will determine the efficacy of CD276-targeted therapy, as its overexpression has been associated with poor outcome in a myriad of advanced human cancer including MCC. Our collaborator, Dr. St. Croix at the National Cancer Institute, has developed a novel antibody-drug conjugate (ADC, m276-SL-PBD), which couples CD276 antibody with a cytotoxic DNA-binding agent PBD. Notably, m276-SL-PBD confers robust anti-tumor activities and long-term durability in a range of preclinical models, including our MCC cell line-derived xenograft (CDX) models (preliminary data leading to this proposal). Remarkably, m276-SL-PBD effectively prevents resistance by directly eradicating heterogenous cancer cells including cancer stem cells, tumor vasculatures and tumor stromal cells, where CD276 upregulation is endowed. Therefore, we postulate that m276-SL-PBD is a superior anti-MCC drug with sustainable response, underscoring a novel therapeutic advance in MCC. To overcome barriers, we have successfully established unique and robust models for MCC preclinical studies including multiple primary MCC cell lines, CDX, and patient tumor-derived xenograft (PDX) models with reconstituted human immune system. To simulate clinical scenario, we have first established human metastatic MCC cell lines with propensity for spontaneous visceral dissemination after subcutaneous inoculation in mice. Due to its finite resource, we will utilize single mouse testing (SMT)-base PDX trial strategies that are increasingly used to better capture inter-tumor heterogeneity and generate highly clinically relevant preclinical evidence. The cost-effectiveness of SMT-based studies allow to encompass a large cohort of patient tumors and evaluate heterogeneous drug effects across patients, which is of particular importance in rare cancer preclinical studies including MCC. Hence leveraging our singularly powerful patient MCC-derived models, we are ideally positioned to pursue proposed studies: 1) to determine safety, therapeutic efficacy, and direct drug effects of m276-SL-PBD and identify biomarkers for treatment response in MCC CDX models and metastatic models; 2) to determine therapeutic efficacy of m276-SL-PBD and its effects on MCC tumor microenvironment in a panel of PDX mouse models; 3) to define the impact of CD276 in MCC survival in Veteran patients. Findings will have near-term impact by setting the stage for an immediate confirmatory clinical trial inclusive of VA healthcare systems to ultimately improve access for Veterans suffering from this deadly skin cancer.

默克尔细胞癌（MCC）是皮肤的侵略性神经内分泌癌，五年 晚期疾病的存活率小于18％，死亡率比黑色素瘤高3倍。 MCC 不成比例和主要影响65岁以上的高加索男性，他们在 在退伍军人中，退伍军人和5000多个新的MCC案件已被诊断出。因此，MCC有一个 对退伍军人的健康和VA医疗保健系统的影响不断增长。尽管获得了免疫疗法的批准， 治疗转移性MCC仍然是一个挑战。那我们被迫寻求新的疗法来克服 抗药性，或者是由于不符合免疫疗法的MCC患者的确定治疗方法 合并症。 在此建议中，我们将与遇到大多数资深MCC患者的VA医疗中心合作 定义B7-H3（由CD276编码）在大量老将患者中的MCC患者存活中的作用。 此外，我们将确定CD276靶向疗法的效率，因为它的过表达与 在包括MCC在内的无数晚期人类癌症中的结果差。我们的合作者，圣克鲁瓦博士在 国家癌症研究所（National Cancer Institute CD276具有细胞毒性DNA结合剂PBD的抗体。值得注意的是，M276-SL-PBD赋予了强大的抗肿瘤 在一系列临床前模型中的活动和长期耐用性，包括我们的MCC细胞线衍生的异种移植物 （CDX）模型（导致该建议的初步数据）。值得注意的是，M276-SL-PBD有效防止 通过直接根除包括癌细胞，肿瘤血管的异质癌细胞的抗性 和肿瘤基质细胞，其中CD276上调被赋予。因此，我们假设M276-SL-PBD是 一种具有可持续反应的优质抗MCC药物，强调了MCC中新型的热促进。 为了克服障碍，我们成功地为MCC临床前建立了独特而健壮的模型 研究包括多个主要的MCC细胞系，CDX和患者肿瘤衍生的Xenographotic（PDX）模型 重构的人类免疫系统。为了模拟临床方案，我们首先建立了人类转移 MCC细胞系有望在小鼠皮下接种后发起内脏传播。 由于其有限资源，我们将使用单个鼠标测试（SMT） - 基本PDX试验策略 越来越多地用于更好地捕获肿瘤间异质性并产生高度临床相关的临床前 证据。基于SMT的研究的成本效益允许涵盖大量患者肿瘤 并评估患者的异质药物作用，这在稀有癌症中尤其重要 临床前研究，包括MCC。 因此，利用我们唯一功能强大的患者MCC衍生的模型，我们是理想的选择 拟议的研究：1）确定M276-SL-PBD和 识别MCC CDX模型和转移模型中治疗反应的生物标志物； 2）确定 M276-SL-PBD的治疗效率及其对PDX小鼠面板中MCC肿瘤微环境的影响 模型； 3）定义CD276在MCC存活中对退伍军人患者的影响。调查结果将有近期 通过为即时确认临床试验设置舞台，包括VA医疗保健系统的影响 最终改善了患有这种致命皮肤癌的退伍军人的进入。