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

默克尔细胞癌(MCC)是一种侵袭性的皮肤神经内分泌癌，经历了令人沮丧的五年。 晚期疾病的存活率不到18%，死亡率比黑色素瘤高3倍。MCC 主要影响65岁以上的高加索男性，他们在 在退伍军人中，已确诊5000多例新的MCC病例。因此，MCC有一个 对退伍军人的健康和退伍军人医疗保健系统的影响越来越大。尽管免疫疗法得到了批准， 治疗转移性MCC仍然是一个挑战。因此，我们被迫寻找新的治疗方法来克服 耐药性，或作为MCC患者的最终治疗方法，这些患者因以下原因而不符合免疫治疗条件 合并症。 在这份提案中，我们将与退伍军人医学中心合作，遇到大多数资深MCC患者，以 确定B7-H3(由CD276编码)在一大群退伍军人患者中对MCC患者生存的作用。 此外，我们将确定CD276靶向治疗的疗效，因为它的过度表达与 在包括MCC在内的无数晚期人类癌症中预后不佳。我们的合作者，圣克罗伊博士 美国国家癌症研究所开发了一种新型抗体-药物结合物(ADC，m276-SL-PBD)，它可以将 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 一系列临床前模型的活性和长期耐受性，包括我们的MCC细胞来源的异种移植 (CDX)模型(导致这一提议的初步数据)。值得注意的是，M276-SL-PBD有效地防止了 通过直接根除包括肿瘤干细胞、肿瘤血管在内的异种癌细胞而产生的耐药性 和肿瘤基质细胞，CD276在其中上调。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，我们成功地为MCC临床前建立了独特和健壮的模型 研究包括多个原代MCC细胞系、CDX和患者肿瘤衍生异种移植(PDX)模型 重组的人体免疫系统。为了模拟临床情景，我们首先建立了人类转移瘤 小鼠皮下接种后有自发内脏扩散倾向的MCC细胞系。 由于其资源有限，我们将利用基于单鼠测试(SMT)的PDX试验策略，这些策略包括 越来越多地用于更好地捕捉肿瘤间的异质性，并产生高度临床相关性的临床前 证据。基于SMT的研究的成本效益允许包含大量的患者肿瘤 评估不同药物对患者的影响，这在罕见癌症中尤为重要 包括MCC在内的临床前研究。 因此，利用我们异常强大的患者MCC派生模型，我们处于理想的位置来追求 建议的研究：1)确定m276-SL-PBD的安全性、治疗效果和直接药物效应 确定MCC CDX模型和转移模型治疗反应的生物标志物；2)确定 M276-SL-PBD的疗效及其对PDX小鼠MCC肿瘤微环境的影响 3)明确CD276在退伍军人MCC生存中的作用。调查结果将在近期内 通过为立即进行验证性临床试验奠定基础，包括退伍军人医疗保健系统，以 最终改善患有这种致命皮肤癌的退伍军人的机会。

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.