Targeted Therapy in Neuroendocrine Cancer

神经内分泌癌的靶向治疗

• 批准号: 10702740
• 负责人: Samira Sadowski
• 金额: $ 130.21万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10702740
• 关键词: Affect; Affinity; Cancer Model; Candidate Disease Gene; Characteristics; Detection; Development; Diagnostic Imaging; Disseminated Malignant Neoplasm; Epigenetic Process; Excision; Goals; Growth; Learning; Ligand Binding; Malignant Neoplasms; Modeling; Molecular; Mus; Neoplasm Metastasis; Neuroendocrine Tumors; Operative Surgical Procedures; Organoids; Pancreas; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Positron-Emission Tomography; Radio; Radiolabeled; Regulation; Role; SSTR2 gene; Somatostatin Receptor; Surface; Testing; Tumor Cell Biology; Up-Regulation; Work; Xenograft procedure; analog; differential expression; epigenetic drug; gastrointestinal; imaging agent; inhibitor; interest; molecular targeted therapies; mouse model; neuroendocrine cancer; novel; receptor; somatostatin receptor 1; targeted treatment; treatment response; tumor; tumor growth

Our prior work at the NCI led to the FDA approval of a PET-imaging agent, Ga-68 DOTATATE, a high affinity ligand that binds somatostatin receptor (SSTR). These cancers are very rare and are unique in that they have characteristic surface receptor repertoire, the somatostatin receptors 1-5 (most prevalent SSTR2), that not only help identify them as neuroendocrine tumors, but also represent key pro-growth and pro-survival pathways. In aggressive or metastatic neuroendocrine tumors, that are not amenable to surgical resection, a novel radiolabeled SSTR2 analogs for the therapy of metastatic lesions (Lu177-DOTATATE) has been used. Unfortunately, with dedifferentiation, the tumors lose SSTR2 expression, and renders them invisible or not amenable for targeted therapy. SSTR2 expression is controlled by epigenetic mechanisms. Studies have shown that epigenetic drugs manage to modulate or even upregulate this receptor. Our studies will identify several candidate genes and mechanisms that are dysregulated in neuroendocrine cancers and have an important role in tumor cell biology. We will use molecular inhibitors or stimulators to test whether targeting these epigenetic mechanisms will affect tumor growth, metastasis and upregulation of targets, and ultimately the response to therapy. We will also evaluate molecular targets for therapy in a xenograft and metastatic mouse model for pancreatic and gastro-intestinal neuroendocrine cancers.

我们先前在NCI的工作导致了FDA的宠物成像剂Ga-68 dotatate，这是一种结合生体抑素受体（SSTR）的高亲和力配体。这些癌症非常罕见，并且独一无二，因为它们具有特征性的表面受体库，生长抑素受体1-5（最普遍的SSTR2），不仅有助于将它们鉴定为神经内分泌肿瘤，而且代表了关键的促促生长和促育育肥途径。在不适合手术切除的侵袭性或转移性神经内分泌肿瘤中，已使用了一种新型的放射性标记的SSTR2类似物，用于疗法治疗转移性病变（LU177-二酸）。不幸的是，通过去分化，肿瘤会失去SSTR2的表达，并使它们看不见或不适合靶向治疗。 SSTR2表达受到表观遗传机制的控制。研究表明，表观遗传药物设法调节甚至上调该受体。我们的研究将确定几种在神经内分泌癌症中失调的候选基因和机制，并在肿瘤细胞生物学中起重要作用。我们将使用分子抑制剂或刺激剂来测试靶向这些表观遗传机制是否会影响肿瘤的生长，转移和靶标的上调以及最终对治疗的反应。我们还将评估用于胰腺和胃肠道神经内分泌癌的异种移植和转移小鼠模型中治疗的分子靶标。