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) 是一种侵袭性皮肤神经内分泌癌，五年发病率令人沮丧 晚期疾病的存活率低于 18%，死亡率比黑色素瘤高 3 倍。 不成比例且主要影响 65 岁以上的白人男性，他们在 退伍军人，退伍军人中诊断出超过 5000 例新的 MCC 病例，因此，MCC 有一个。 尽管免疫疗法获得批准，但对退伍军人的健康和退伍军人管理局医疗保健系统的影响越来越大。 治疗转移性 MCC 仍然是一个挑战，因此，我们不得不寻找新的疗法来克服。 耐药性，或作为因以下原因不适合免疫治疗的 MCC 患者的最终治疗方法 合并症。 在此提案中，我们将与 VA 医疗中心合作，帮助大多数退伍军人 MCC 患者 在一大群退伍军人患者中，定义了 B7-H3（由 CD276 编码）在 MCC 患者生存中的作用。 此外，我们将确定 CD276 靶向治疗的功效，因为它的过度表达与 我们的合作者 St. Croix 博士在治疗多种晚期人类癌症（包括 MCC）时效果不佳。 美国国家癌症研究所开发了一种新型抗体药物偶联物（ADC，m276-SL-PBD），它将 CD276 抗体与细胞毒性 DNA 结合剂 PBD 值得注意的是，m276-SL-PBD 具有强大的抗肿瘤作用。 在一系列临床前模型（包括我们的 MCC 细胞系来源的异种移植模型）中具有活性和长期耐久性 (CDX) 模型（得出该建议的初步数据） 值得注意的是，m276-SL-PBD 有效地防止了这种情况。 通过直接根除异质癌细胞（包括癌症干细胞、肿瘤血管系统）来产生耐药性 和肿瘤基质细胞，其中 CD276 上调，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，突显了 MCC 治疗的新进展。 为了克服障碍，我们成功建立了独特且稳健的 MCC 临床前模型 研究包括多种原代 MCC 细胞系、CDX 和患者肿瘤衍生异种移植 (PDX) 模型 为了模拟临床场景，我们首先建立了人体转移瘤。 MCC 细胞系在小鼠皮下接种后具有自发内脏传播的倾向。 由于资源有限，我们将利用基于单鼠测试 (SMT) 的 PDX 试验策略，这些策略是 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 基于 SMT 的研究的成本效益允许涵盖大量肿瘤患者。 并评估不同患者的异质药物效应，这对于罕见癌症尤为重要 临床前研究，包括 MCC。 因此，利用我们极其强大的患者 MCC 衍生模型，我们处于理想的位置，可以追求 拟议的研究：1) 确定 m276-SL-PBD 和 m276-SL-PBD 的安全性、治疗效果和直接药物作用 确定 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 的治疗效果及其对 PDX 小鼠 MCC 肿瘤微环境的影响 模型；3) 确定 CD276 对退伍军人 MCC 生存的影响 近期研究结果将产生。 通过为包括 VA 医疗保健系统在内的立即验证性临床试验奠定基础来产生影响 最终改善患有这种致命皮肤癌的退伍军人的治疗机会。