Somatostatin receptor 2 (SSTR2) antibody-drug conjugate for pancreatic neuroendocrine tumor (PanNET) therapy

用于胰腺神经内分泌肿瘤 (PanNET) 治疗的生长抑素受体 2 (SSTR2) 抗体-药物偶联物

• 批准号: 9895383
• 负责人: Renata Jaskula-Sztul
• 金额: $ 19.95万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9895383
• 关键词: Antibodies; Antibody Specificity; Antibody-drug conjugates; Antitumor Response; Apoptosis; Binding; Biodistribution; Biological Assay; Cell Culture Techniques; Cell Cycle; Cell Proliferation; Cell Survival; Cell membrane; Clinical; Clinical Trials; Complex; Cytotoxic agent; Development; Diagnosis; Disease; Dose; Excision; Flow Cytometry; Future; Genetic; Growth; Health; Hormone secretion; Human; In Vitro; Incidence; Investigation; Investigational Therapies; Islet Cell Tumor; Malignant neoplasm of pancreas; Maximum Tolerated Dose; Metastatic Neoplasm to the Liver; Modeling; Molecular; Monoclonal Antibodies; Mus; Neoplasm Metastasis; Neurosecretory Systems; Operative Surgical Procedures; Outcome; Pancreas; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Pharmacology; Phenotype; Porifera; Pre-Clinical Model; Property; Protein Isoforms; Proteomics; Quantitative Reverse Transcriptase PCR; SDZ RAD; Signal Transduction; Somatostatin Receptor; Specificity; Surface; Survival Rate; Testing; Therapeutic; Therapeutic Agents; Time; Treatment Efficacy; Tumor Burden; Tumor Cell Line; Tumor Markers; Tumor-Derived; Western Blotting; Xenograft Model; advanced disease; anti-cancer; antitumor effect; base; cancer cell; cell growth; comparative; cytotoxicity; design; drug candidate; experimental study; high throughput screening; improved; in vitro Model; in vivo; inhibitor/antagonist; mTOR Inhibitor; malignant phenotype; mouse model; neoplastic cell; neuroendocrine cancer; neuroendocrine phenotype; notch protein; novel therapeutics; overexpression; pharmacokinetics and pharmacodynamics; pre-clinical; preclinical development; promoter; receptor binding; response; side effect; small molecule; somatostatin analog; somatostatin receptor 2; systemic toxicity; targeted treatment; tumor; tumor growth; tumor progression

Pancreatic neuroendocrine tumors (PanNETs) are increasing in incidence, and 40-95% of them are metastatic at the time of initial diagnosis. Despite various complex management strategies for neuroendocrine liver metastases, surgery is the only treatment that offers potential for cure. There is a critical need to develop new therapeutic options to reduce PanNETs progression. We have discovered that PanNETs are deficient in Notch signaling, and reinstitution of this pathway alters the malignant phenotype. Therefore, there is a need for an effective Notch activator as a therapeutic agent against PanNETs. We hypothesize that the induction of Notch signaling with small molecule compounds will provide an effective strategy to treat patients with PanNETs. High- throughput screening for Notch pathway activators identified a natural compound originating from marine sponges (DHN-III-14) capable of inhibiting PanNETs proliferation and altering the neuroendocrine (NE) cancer phenotype. To improve therapeutic efficacy, we propose to conjugate the drug candidate with an antibody that specifically binds to somatostatin receptor (SSTR2) which is overexpressed on the surfaces of PanNETs cells. Such antibody-drug conjugate (ADC) can selectively deliver a lethal agent to tumor cells and minimize side effects to patients. To delineate the antitumor efficacy of the ADC, we will use the in vitro PanNET cell cultures and the in vivo preclinical mouse model of liver metastases. If the anticancer efficacy will be confirmed in the preclinical models, this will be the first ADC toward targeted therapy for PanNETS.

胰腺神经内分泌肿瘤(PanNETs)的发病率呈上升趋势，其中40-95% 在最初诊断时是转移性的。尽管有各种复杂的管理策略， 对于神经内分泌肝转移，手术是唯一有可能治愈的治疗方法。那里 迫切需要开发新的治疗方案来减少PanNETs的进展。我们有 发现PanNETs在Notch信号转导方面存在缺陷，而这一途径的重新建立会改变 恶性表型。因此，需要一种有效的凹槽激活剂作为 抗PanNETs的治疗剂。我们假设Notch信号的诱导与 小分子化合物将为治疗PanNETs患者提供一种有效的策略。高- Notch途径激活剂的吞吐量筛选鉴定一种来源于 海洋海绵(DHN-III-14)能够抑制PanNETs的增殖并改变 神经内分泌(NE)癌表型。为提高治疗效果，我们建议 将候选药物与特异性结合生长抑素受体的抗体偶联 (SSTR2)，它在PanNETs细胞表面过表达。这种抗体药物 偶联物(ADC)可以选择性地将致死剂输送到肿瘤细胞，并将副作用降至最低 病人。为了阐明ADC的抗肿瘤效果，我们将使用体外的Pannet细胞 培养和体内临床前小鼠肝转移模型。如果抗癌功效将 在临床前模型中得到证实，这将是第一个靶向治疗的ADC PanNETS。