Neutralizing Stromal NetrinG1 to Intercept Pancreatic Cancer

中和基质 NetrinG1 以阻止胰腺癌

• 批准号: 10505615
• 负责人: Edna Cukierman
• 金额: $ 41.8万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10505615
• 关键词: 3-Dimensional; Address; Adult; Affinity; Antibody Therapy; BRCA2 Mutation; BRCA2 gene; Benign; Binding; Biological Assay; Biological Availability; Biology; Blood Vessels; Body Weight; Cell model; Cells; Clinical; Coculture Techniques; Collagen; Data; Data Analyses; Desmoplastic; Development; Diabetes Mellitus; Diagnosis; Ductal Epithelial Cell; Early Diagnosis; Engineering; Environment; Epithelial Cells; Epitopes; Evolution; Exposure to; Extracellular Matrix; Familial pancreatic cancer; Family history of; Fibroblasts; Fox Chase Cancer Center; Genes; Genetic Predisposition to Disease; Germ-Line Mutation; Goals; Growth; Human; Immunologic Surveillance; In Vitro; Individual; Inherited; Intercept; Interruption; Intervention; Lead; Lesion; Malignant Neoplasms; Malignant neoplasm of pancreas; Measures; Molecular Target; Monoclonal Antibodies; Mus; Mutagens; Nutrient; Nutritional Support; Organ; PALB2 gene; Pancreas; Pancreatic Intraepithelial Neoplasia; Pancreatic duct; Pancreatitis; Patients; Penetration; Phenocopy; Phenotype; Population; Premalignant Cell; Preventive; Primary Neoplasm; Property; Proprotein Convertase 2; Risk Factors; Safety; Series; Signal Transduction; Smoker; Stress; Syndrome; System; Testing; Tissues; Toxic effect; Tumor Suppressor Proteins; Work; base; cancer prevention; cancer risk; cell growth; cellular engineering; chemokine; clinical candidate; effectiveness evaluation; efficacy testing; experimental study; genetic variant; high risk; improved; in vivo; inhibiting antibody; lead candidate; lifetime risk; liver function; loss of function; molecular marker; netrin-G1; neutralizing antibody; neutralizing monoclonal antibodies; novel; novel strategies; pancreatic cancer cells; pancreatic cancer model; pancreatic cancer patients; premalignant; programs; screening; targeted agent; tumor; tumor progression; tumor-immune system interactions; tumorigenesis; tumorigenic

PROJECT SUMMARY - PROJECT 2 Most patients with pancreatic cancer (PC) do not survive one year and less than 10% survive five years. This is unfortunate, given the slow rate of growth of PC over many years, and the large window of opportunity for potential intervention prior to diagnosis. Patients with hereditary familial PC (~10% of PC cases), as well as those exposed to mutagens and presenting with predisposing clinical conditions like pancreatitis and new onset of diabetes, are at high risk for PC and would benefit greatly from improved early detection, cancer prevention, and/or interception strategies. The proposed project addresses this unmet need by joining the FCCC Cancer Prevention-Interception Targeted Agent Discovery Program (CAP-IT) at the “Agent Identification and Screening” stage. The proposal is the first, to our knowledge, to employ a stroma-targeting strategy to intercept progression of precancerous tissue to overt PC. This proposal exploits our work in studying desmoplasia – a unique microenvironment enriched in stromal fibroblasts and dense extracellular matrix (ECM) that characterizes PC. We have defined distinct subsets of tumor-promoting and tumor-suppressing fibroblasts (TPFs and TSFs), which can reversibly interconvert in phenotype. We have shown that TPFs arise in early precancerous tissue, and are characterized by expression of Netrin G1 (NetG1). NetG1-dependent signaling is essential for premalignant cells to thrive as tumors. Mechanistically, we have shown that NetG1+ TPFs provide nutritional support to premalignant initiated epithelial cells (IECs) and tumors, allowing them to survive in the nutrient-poor desmoplastic environment and escape immunosurveillance by inducing an immunosuppressive microenvironment. While some support is delivered via TPF secretion of nutrients and chemokines; additional support is provided by the TPF-generated ECM. Critically, we have shown that a commercial monoclonal antibody (mAb) that inhibits NetG1 reverts all of these tumor-promoting properties and intercepts the formation of PC. Although the commercial mAb is sufficient for proof-of-concept experiments, it is not sufficiently potent as a clinical candidate. A large panel of mAbs targeting diverse NetG1 epitopes, with higher binding affinities than the one above-mentioned, has been generated. In Aim 1, we will determine which of the new mAbs functionally reverts TPFs to TSFs, based on the expression of molecular markers that distinguish between the two classes. In Aim 2, co-culture experiments will be used to identify mAbs that reduce the ability of TPFs to provide nutritional support to IECs, and assess whether the same mAbs decrease the ability of the ECM, produced by TPFs, to enhance IEC growth. New IEC models will be engineered that parallel the loss of function genetic variants seen in populations at high risk for PC. In Aim 3, the lead candidate mAbs that can intercept the transition from precancer to cancer in vitro will be evaluated for their toxicity profiles and ability to inhibit formation of PanINs, the precursor of PC, in KC mice, a model of PC. These studies are expected to yield novel agents that target the stroma for PC prevention and/or interception.

项目摘要--项目2 大多数胰腺癌(PC)患者无法存活一年，只有不到10%的患者存活五年。这是 不幸的是，考虑到PC多年来的缓慢增长速度，以及 诊断前的潜在干预措施。遗传性家族性PC患者(约占PC病例的10%) 暴露于诱变剂，并出现易发临床症状，如胰腺炎和新发的 糖尿病是PC的高风险人群，如果能改进早期发现、癌症预防、 和/或拦截策略。拟议的项目通过加入fccc癌症基金会来解决这一未得到满足的需求。 “代理识别和筛选”中的预防-拦截目标代理发现计划(CAP-IT) 舞台。据我们所知，这项提议是第一次使用基质靶向策略来拦截进程 癌前组织转移到公开的个人计算机。这项建议利用了我们在研究促结缔组织增生症方面的工作--一种独特的 微环境丰富的间质成纤维细胞和致密的细胞外基质(ECM)是PC的特征。 我们已经定义了不同的肿瘤促进和肿瘤抑制成纤维细胞亚群(TPF和TSFs)，它们 可以在表型上可逆地相互转换。我们已经证明，TPF出现在早期的癌前组织中，并且 以Netrin G1(NetG1)的表达为特征。NetG1依赖的信号转导对癌前细胞至关重要 像肿瘤一样茁壮成长。从机制上讲，我们已经证明了NetG1+TPF为 癌前启动的上皮细胞(IECS)和肿瘤，使它们能够在营养贫乏的环境中生存 促结缔组织生长环境与通过诱导免疫抑制逃避免疫监视 微环境。虽然一些支持是通过TPF分泌营养物质和趋化因子来提供的；另外 支持由TPF生成的ECM提供。关键的是，我们已经证明了一种商业化的单克隆 抑制NetG1的抗体(MAb)逆转了所有这些促进肿瘤的特性，并阻止了这种形成 PC的性能。尽管商用单抗足以进行概念验证实验，但它的效力还不够。 临床候选人。针对不同NetG1表位的大量mAb板，结合亲和力高于 上面提到的那个，已经产生了。在目标1中，我们将从功能上确定哪些新单抗 基于区分这两个类别的分子标记的表达，将TPF恢复为TSFs。 在目标2中，将使用共培养实验来鉴定降低TPF提供营养的能力的单抗 对IECS的支持，并评估相同的单抗是否会降低TPF产生的ECM的能力 促进IEC增长。新的IEC模型将被设计成与功能遗传变异的丧失平行 在PC高危人群中。在目标3中，领先的候选单抗可以拦截来自 将评估它们的毒性分布和抑制Panins形成的能力。 PC的前体，在KC小鼠中，是PC的模型。这些研究有望产生针对 用于PC预防和/或拦截的基质。