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: 10563188
• 负责人: DONALD W. KUFE
• 金额: $ 20.47万
• 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/10563188
• 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; Penetration; Peptides; Play; Principal Investigator; Proteins; Role; Signal Pathway; Signal Transduction; Therapeutic; Toxin; Tumorigenicity; Work; Writing; anticancer research; 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; new therapeutic target; patient derived xenograft model; pluripotency; programs; repaired; response; self-renewal; small cell lung carcinoma; 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。 用免疫检查点抑制剂治疗SCLC的反应率为10-14%， 与化疗联合使用可以提高生存率。尽管有这些进展， 小细胞肺癌的中位总生存期约为1年，强调了鉴别可药物治疗的迫切需要。 有助于SCLC进展的目标。 致癌MUC 1-C蛋白出现在哺乳动物中，以保护肺和其他类型的肿瘤。 上皮细胞因暴露于外部环境而失去稳态。MUC1-C 激活炎症、增殖和重塑信号通路，促进伤口愈合 反应重要的是，在具有重复的损伤和修复周期的慢性炎症环境中， 延长的MUC 1-C激活促进癌症进展。 MUC 1-C在SCLC中没有已知的参与。我们提出的工作解决了以前 MUC 1-C在促进SCLC进展中起主要作用，并且是一个未探索的假设， SCLC治疗的药物靶点。这一假设部分基于初步观察， MUC 1-C促进SCLC细胞染色质结构的重编程，这是多能性所必需的 和谱系可塑性，并且靶向MUC 1-C消除了染色质可及性的那些改变。 MUC 1-C激活SCLC细胞中MYC信号传导的发现进一步支持了我们的假设 并诱导NOTCH 2的表达，NOTCH 2是肺神经内分泌（NE）干细胞的标志物， 损伤后修复，是SCLC起源的建议细胞。沿着这些思路，靶向MUC 1-C抑制了 MYC和NOTCH 2表达的抑制，因此代表了一种有吸引力的治疗策略，用于抑制MYC和NOTCH 2的表达。 SCLC细胞自我更新能力和致瘤性。 MUC 1-C被CAR-T细胞、抗体-药物缀合物和MUC 1-C的直接抑制剂靶向 正在临床开发中的功能。我们的研究将评估靶向MUC 1-C的作用， 在体外生长的人SCLC细胞系和作为肿瘤异种移植物以及SCLC PDX肿瘤上进行 模型这些研究将结合靶向MUC 1-C对SCLC细胞染色质的影响 重塑和基因表达模式与抑制谱系可塑性， 和致瘤性。 这项工作的总体目标是通过以下方法来提高我们对小细胞肺癌发病机制的认识 这表明MUC 1-C代表了一种以前未被认识到的效应物，它在肿瘤发生中起着重要作用。 这种高度侵袭性恶性肿瘤的进展。MUC 1-C是一个可药物化的靶点，根据我们的发现， 可以为推进SCLC治疗提供新的机会。