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。