Characterizing ALCAM as an oncoprotein and immunotherapeutic target in neuroblastoma

将 ALCAM 描述为神经母细胞瘤的癌蛋白和免疫治疗靶点

• 批准号: 10452634
• 负责人: Jarrett Lindsay
• 金额: $ 3.42万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10452634
• 关键词: ALCAM gene; Adult; Antibodies; Antibody-drug conjugates; Antigens; Binding; Bioinformatics; Biological Assay; CRISPR interference; Cell Adhesion; Cell Adhesion Molecules; Cell Line; Cell Surface Proteins; Cell Survival; Cell surface; ChIP-seq; Child; Childhood; Clinical; Clinical Trials; Colorectal Cancer; Credentialing; DNA sequencing; Data; Data Set; Defect; Development; Diagnosis; Disease; Dopamine-beta-monooxygenase; Down-Regulation; Effectiveness; Face; Ganglioside GD2; Genes; Genetic Transcription; Growth; Immunotherapeutic agent; Immunotherapy; In Vitro; Intervention; Lesion; MAP Kinase Gene; Malignant Childhood Neoplasm; Malignant Neoplasms; Malignant neoplasm of prostate; Masks; Mediating; Metalloproteases; Migration Assay; Modeling; Molecular Biology; Monoclonal Antibodies; Monoclonal Antibody Therapy; Mutation; Neoplasm Metastasis; Neural Crest; Neurites; Neuroblastoma; Neurosecretory Systems; Nociceptors; Oncogenic; Oncoproteins; Ontology; Operative Surgical Procedures; Pathway interactions; Patients; Peptide Hydrolases; Peptides; Pharmaceutical Preparations; Phase I/II Clinical Trial; Phenotype; Primary Neoplasm; Process; Prognostic Marker; Prostate; Public Health; Radiation; Refractory; Regulation; Relapse; Research; Retinal Ganglion Cells; Role; Sampling; Scientist; Solid; Survival Rate; Sympathetic Nervous System; Therapeutic; Tissues; Toxic effect; Translational Research; Tumor Antigens; Tyrosine 3-Monooxygenase; Unresectable; Xenograft procedure; bone; cancer stem cell; cell growth; cell motility; chemotherapy; chromatin modification; defined contribution; differential expression; genomic locus; high risk; improved; in vivo; knock-down; lung small cell carcinoma; mortality risk; neuroblastoma cell; neurotransmission; noradrenergic; novel; novel therapeutic intervention; novel therapeutics; overexpression; preclinical development; progenitor; protein expression; research clinical testing; resistance mechanism; skills; small hairpin RNA; stem cell biomarkers; targeted treatment; therapeutic development; transcription factor; transcriptome sequencing; tumor; tumor growth; tumorigenesis

Project Summary Neuroblastoma is a pediatric extracranial solid malignancy that arises from the developing sympathetic nervous system. Patients with high risk neuroblastoma face five-year survival rates of only 50%, despite intensive intervention with chemotherapy, surgery, radiation, and immunotherapy. Development of new therapies for neuroblastoma has been challenging due to the paucity of targetable oncogenic mutations. However, recent approval of monoclonal antibody therapy targeting GD2 has credentialed immunotherapy as a new avenue of therapeutic development in neuroblastoma. Conversely anti-GD2 therapy causes significant on-target, off-tumor toxicity due to the presence of GD2 on nociceptive neurons, and relapse due to loss of GD2 expression remains common. To subvert antigen downregulation as a mechanism of resistance, our lab focuses on development of immunotherapy targets that are both differentially expressed and necessary for tumor survival. We recently identified the cell adhesion molecule ALCAM as a potential target for immunotherapy development. ALCAM is a cellular adhesion molecule involved in retinal ganglion development, and high ALCAM expression is a negative prognostic marker in a variety of cancers. Our RNA-sequencing data shows ALCAM is highly expressed in most patient neuroblastomas. Furthermore, an ALCAM-targeted antibody-drug conjugate, CX-2009, is currently in clinical trials for advanced metastatic or locally unresectable adult cancers. This project aims to discover the mechanism of ALCAM overexpression in neuroblastoma, as well as define the contribution of ALCAM overexpression to tumor growth and metastasis. Preliminary data suggests shRNA-mediated ALCAM knockdown induces neurite formation in vitro, a phenotype associated with differentiation. Additionally, ChIP- sequencing data from two neuroblastoma cell lines shows expression ALCAM may be regulated by a network of transcription factors termed the core regulatory circuit (CRC). The CRC is a feed-forward transcriptional regulatory circuit in which each transcription factor regulates the expression of itself and the others, together defining a noradrenergic phenotype characterized by expression of proteins such as tyrosine hydroxylase and dopamine beta hydroxylase. By integrating bioinformatics and molecular biology approaches, we will uncover the mechanism of ALCAM overexpression in neuroblastoma. More broadly, this project will credential ALCAM as a viable target of immunotherapy, as well as an oncoprotein necessary for tumor survival.

项目摘要 神经母细胞瘤是一种儿童颅外实体恶性肿瘤，起源于发育中的交感神经。 系统。高危神经母细胞瘤患者面临的五年存活率只有50%，尽管进行了密集治疗 通过化疗、手术、放射治疗和免疫治疗进行干预。新的治疗方法的开发 由于缺乏有针对性的致癌基因突变，神经母细胞瘤一直具有挑战性。然而，最近 针对GD2的单抗疗法的批准使免疫疗法成为一种新的治疗方法 神经母细胞瘤的治疗进展。相反，抗GD2治疗导致显著的靶向上、肿瘤外 GD2对伤害性神经元的毒性，以及GD2表达缺失导致的复发 很普通。为了颠覆抗原下调作为一种耐药机制，我们的实验室专注于开发 免疫治疗靶点既有差异表达，也是肿瘤生存所必需的。我们最近 确定细胞黏附分子alcam为免疫治疗发展的潜在靶点。Alcam是一种 细胞黏附分子参与视网膜神经节的发育，而alcam的高表达是阴性的 多种癌症的预后标记物。我们的rna测序数据显示alcam在大多数 病人神经母细胞瘤。此外，一种针对alcam的抗体-药物结合物cx-2009目前正在 晚期转移性或局部无法切除的成人癌症的临床试验。该项目旨在发现 神经母细胞瘤中alcam过表达的机制及其作用机制 过度表达对肿瘤的生长和转移有促进作用。初步数据表明shRNA介导的alcam 基因敲除可在体外诱导神经突起的形成，这是一种与分化相关的表型。此外，芯片- 来自两个神经母细胞瘤细胞系的测序数据显示，alcam的表达可能受 转录因子被称为核心调节回路(CRC)。CRC是一种前馈转录 每个转录因子共同调节自身和其他转录因子的表达的调节回路。 定义一种去甲肾上腺素的表型，其特征是表达酪氨酸羟化酶和 多巴胺β羟基酶。通过整合生物信息学和分子生物学方法，我们将揭示 神经母细胞瘤中alcam过度表达的机制。更广泛地说，该项目将为alcam提供凭据 作为免疫治疗的有效靶点，以及肿瘤生存所必需的癌蛋白。

项目成果

The B7-H3-Targeting Antibody-Drug Conjugate m276-SL-PBD Is Potently Effective Against Pediatric Cancer Preclinical Solid Tumor Models.

• DOI: 10.1158/1078-0432.ccr-20-4221
• 发表时间: 2021-05-15
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Kendsersky NM;Lindsay J;Kolb EA;Smith MA;Teicher BA;Erickson SW;Earley EJ;Mosse YP;Martinez D;Pogoriler J;Krytska K;Patel K;Groff D;Tsang M;Ghilu S;Wang Y;Seaman S;Feng Y;Croix BS;Gorlick R;Kurmasheva R;Houghton PJ;Maris JM
• 通讯作者: Maris JM