Targeting MUC1-C for the Treatment of Small Cell Lung Cancer Progression

靶向 MUC1-C 治疗小细胞肺癌进展

• 批准号: 10354347
• 负责人: DONALD W. KUFE
• 金额: $ 23.23万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-04 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10354347
• 关键词: ATAC-seq; Address; Antibody-drug conjugates; Architecture; Cancer Patient; Cancer cell line; Cell Lineage; Cells; ChIP-seq; Chromatin; Chronic; Clinic; Cytoplasmic Tail; Development; Diagnosis; Environment; Epithelial Cells; Exposure to; Extracellular Domain; Funding; Gene Expression Profile; Homeostasis; Human; Immune checkpoint inhibitor; In Vitro; Inflammation; Inflammatory; Injury; Link; Lung; Malignant Neoplasms; Mammals; Modeling; Monoclonal Antibodies; Mucin 1 protein; Neurosecretory Systems; Oncogenic; Pathogenesis; Pathway interactions; Patients; Peptides; Play; Principal Investigator; Proteins; Role; Signal Pathway; Signal Transduction; Therapeutic; Toxin; Tumorigenicity; Work; anticancer research; base; cancer therapy; carcinogenesis; cell injury; chemotherapy; chimeric antigen receptor T cells; chromatin remodeling; cigarette smoke; citrate carrier; clinical development; druggable target; in vivo; inhibitor; lung cancer cell; lung injury; lung small cell carcinoma; new therapeutic target; patient derived xenograft model; pluripotency; programs; repaired; response; self-renewal; stem cells; stemness; targeted agent; transcriptome sequencing; tumor; tumor progression; tumor xenograft; tumorigenesis; wound healing

Small cell lung cancer (SCLC) is a highly aggressive malignancy that has limited therapeutic options. Treatment of SCLC with immune checkpoint inhibitors has been associated with response rates of 10-14% and increases in survival when combined with chemotherapy. Despite these advances, patients diagnosed with SCLC have a median overall survival of ~1 year, emphasizing the critical need for identifying druggable targets that contribute to SCLC progression. The oncogenic MUC1-C protein appeared in mammals to protect pulmonary and other types of epithelial cells from loss of homeostasis associated with exposure to the external environment. MUC1-C activates inflammatory, proliferative and remodeling signaling pathways that contribute to the wound healing response. Importantly, in settings of chronic inflammation with repetitive cycles of damage and repair, prolonged MUC1-C activation promotes cancer progression. There is no known involvement of MUC1-C in SCLC. Our proposed work addresses the previously unexplored hypothesis that MUC1-C plays a master role in promoting SCLC progression and is a druggable target for SCLC treatment. This hypothesis is based in part on preliminary observations that MUC1-C promotes reprogramming of SCLC cell chromatin architecture, which is necessary for pluripotency and lineage plasticity, and that targeting MUC1-C abrogates those alterations in chromatin accessibility. Our hypothesis is further supported by findings that MUC1-C activates MYC signaling in SCLC cells and induces the expression of NOTCH2, a marker of pulmonary neuroendocrine (NE) stem cells that initiate repair after injury and are the proposed cell of SCLC origin. Along these lines, targeting MUC1-C suppresses MYC and NOTCH2 expression and therefore represents an attractive therapeutic strategy for the inhibition of SCLC cell self-renewal capacity and tumorigenicity. MUC1-C is being targeted with CAR-T cells, antibody-drug conjugates and a direct inhibitor of MUC1-C function that are under clinical development. Our studies to assess the effects of targeting MUC1-C will be performed on human SCLC cell lines growing in vitro and as tumor xenografts and on SCLC PDX tumor models. The studies will be integrated with the impact of targeting MUC1-C on SCLC cell chromatin remodeling and gene expression patterns in association with the suppression of lineage plasticity, stemness and tumorigencity. The overall objective of the proposed work is to advance our understanding of SCLC pathogenesis by demonstrating that MUC1-C represents a previously unrecognized effector which plays an important role in the progression of this highly aggressive malignancy. MUC1-C is a druggable target that, based on our findings, could provide new opportunities for advancing SCLC treatment.

小细胞肺癌(SCLC)是一种高度侵袭性的恶性肿瘤，治疗选择有限。 使用免疫检查点抑制剂治疗小细胞肺癌的应答率为10%-14%， 与化疗相结合可提高存活率。尽管取得了这些进展，但被诊断为 小细胞肺癌的总体生存期中位数为~1年，强调了识别可用药的迫切需要 有助于SCLC进展的目标。 致癌的MUC1-C蛋白出现在哺乳动物中，以保护肺部和其他类型的 上皮细胞因暴露于外部环境而失去动态平衡。MUC1-C 激活有助于伤口愈合的炎症、增殖和重塑信号通路 回应。重要的是，在慢性炎症的环境中，损伤和修复重复循环， 长时间的MUC1-C激活会促进癌症的进展。 目前尚不清楚MUC1-C参与小细胞肺癌的发生。我们提出的工作解决了以前的 未探索的假说：MUC1-C在促进小细胞肺癌进展中发挥主要作用，是一种 治疗小细胞肺癌的药物靶点。这一假设部分建立在初步观察的基础上 MUC1-C促进小细胞肺癌细胞染色质结构的重新编程，这是多能性所必需的 和谱系可塑性，靶向MUC1-C的基因可以消除染色质可及性的这些变化。 我们的假设进一步得到以下发现的支持：MUC1-C激活了SCLC细胞中的MYC信号 并诱导NOTCH2的表达，NOTCH2是肺神经内分泌(NE)干细胞的标志， 损伤后修复，被认为是小细胞肺癌起源的细胞。沿着这些思路，靶向MUC1-C抑制了 MYC和NOTCH2的表达，因此是一种有吸引力的抑制卵巢癌的治疗策略 小细胞肺癌细胞的自我更新能力和致瘤性。 MUC1-C是CAR-T细胞、抗体-药物结合物和MUC1-C的直接抑制剂的靶点 正在临床开发中的功能。我们评估靶向MUC1-C的效果的研究将是 对体外生长的人小细胞肺癌细胞系、肿瘤移植瘤和小细胞肺癌PDX瘤进行了研究 模特们。这些研究将与靶向MUC1-C对小细胞肺癌细胞染色质的影响相结合 重塑和基因表达模式与谱系可塑性、干性抑制相关 和致瘤性。 拟议工作的总体目标是通过以下方式促进我们对小细胞肺癌发病机制的理解 证明MUC1-C代表一种以前未被识别的效应器，它在 这种高度侵袭性的恶性肿瘤的进展。根据我们的发现，MUC1-C是一个可下药的靶点， 可能为推进小细胞肺癌的治疗提供新的机遇。