MUC1 enhances Neuropilin-1 signaling in pancreatic ductal adenocarcinoma

MUC1 增强胰腺导管腺癌中的 Neuropilin-1 信号传导

• 批准号: 8434641
• 负责人: Pinku Mukherjee
• 金额: $ 43.4万
• 依托单位: UNIVERSITY OF NORTH CAROLINA CHARLOTTE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-05 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8434641
• 关键词: Adenocarcinoma; Adenocarcinoma Cell; Adverse effects; Allergic Reaction; American Cancer Society; Angiogenesis Inhibitors; Antibodies; Area; Automobile Driving; Award; Binding; Biology; Breast Carcinoma; Cell physiology; Cells; Clinical Data; Desmoplastic; Detection; Development; Disease; Disease Progression; Dose; Drug Delivery Systems; Drug Targeting; Endothelial Cells; Environment; Event; Funding; Glioma; Glycoproteins; Goals; Grant; Growth Factor Interaction; Human; Hypertension; In Vitro; Injection of therapeutic agent; Institution; Lead; Legal patent; Lesion; Malignant Neoplasms; Malignant neoplasm of pancreas; Metastatic Lesion; Methods; Molecular; Monoclonal Antibodies; Mucins; Mus; Nature; Neoplasm Metastasis; Neuropilin-1; Non-Small-Cell Lung Carcinoma; Pancreas; Pancreatic Ductal Adenocarcinoma; Pancreatic Intraepithelial Neoplasia; Peptides; Pharmaceutical Preparations; Phenotype; Protein Isoforms; Radiation therapy; Receptor Signaling; Research; Resistance; Role; Science; Signal Transduction; Site; Students; Tandem Repeat Sequences; Testing; Therapeutic; Up-Regulation; VEGF165; VEGFA gene; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factors; Work; angiogenesis; antibody conjugate; clinically significant; effective therapy; glycosylation; human disease; improved; in vivo; mouse model; new therapeutic target; novel; outcome forecast; pancreatic cancer cells; pancreatic neoplasm; public health relevance; receptor; response; small molecule; targeted delivery; tumor; tumor growth; tumor microenvironment

DESCRIPTION (provided by applicant): Pancreatic cancer (PC) is a highly metastatic disease with few effective treatment options. MUC1 is a glycoprotein that is over-expressed and aberrantly glycosylated in over 60% of PC and 100% of PC metastases. Tumor-associated MUC1 is a marker of an aggressive phenotype, as its expression is correlated with high metastases and poor prognosis. We have recently found that pancreatic cancer cells and tumors expressing high MUC1 have increased levels of neuropilin-1 (NRP-1), a co-receptor of VEGFA as compared to PDA with no or low MUC1. NRP-1 potentiates VEGF receptor signaling and pro-angiogenic activities. This may be indicative of enhanced intra-tumoral angiogenesis and disease progression. However, many drugs targeting angiogenesis have produced serious side effects, including hypertension, thrombotic events, and allergic reactions. Additionally, it i well accepted that drug delivery into the pancreas is difficult, as PC is highly desmoplastic with dense stroma. Thus, we hypothesize that MUC1 induces a pro-angiogenic tumor microenvironment by increasing levels of NRP-1 and subsequent VEGFA signaling. This may be the leading cause for the highly metastatic and aggressive tumor phenotype associated with MUC1. Second, we hypothesize that blocking the interaction between VEGF165 and NRP-1 within the tumor microenvironment will lead to therapeutic benefit. We will therefore first aim to study the effects of MUC1+ PDA cells on endothelial cell function in an NRP-1-dependent fashion in vitro. Second, we will determine if MUC1 creates a pro-angiogenic niche in vivo by up-regulating NRP-1 and VEGF signaling. Finally, we will deliver a VEGF165-NRP-1 inhibitory peptide directly to the MUC1-expressing pancreatic tumor microenvironment using a novel MUC1 antibody to deliver the peptide blocker. We propose to use appropriate PDA mouse models to study in vivo angiogenesis and drug delivery. In these mice, pancreatic tumors occur within the pancreas and recapitulate the human disease, progressing through the full spectrum of pancreatic intraepithelial neoplasia (PanINs) lesions to invasive adenocarcinoma with metastases. These mice either express human MUC1 (KCM) or are null for Muc1 (KCKO). By using these mouse models, we will be able to evaluate angiogenesis switch in an appropriate setting which will include the dense stromal component of the pancreas. Further, the use of the KCM mice will render our results highly translatable, as we are able to test our therapy targeting human MUC1. We recognize that such targeted delivery using a MUC1 antibody has never been attempted but if this works, it will revolutionize the way small molecules and peptides are delivered to the pancreas without unwanted side effects. If funded, this AREA grant will guarantee a strong research environment in the PI's lab, and will enhance the overall research environment that will help draw in the highest quality students, which is critical to successful development of a major research institution.

描述(申请人提供)：胰腺癌(PC)是一种高度转移性疾病，几乎没有有效的治疗选择。MUC1是一种糖蛋白，在超过60%的PC和100%的PC转移瘤中过度表达和异常糖基化。肿瘤相关的MUC1是侵袭性表型的标志，因为它的表达与高转移和不良预后相关。我们最近发现，与不表达或不表达MUC1的PDA相比，高表达MUC1的胰腺癌细胞和肿瘤中VEGFA的共同受体--神经粘连蛋白-1(NRP-1)的水平升高。NRP-1增强血管内皮生长因子受体信号转导和促血管生成活性。这可能预示着肿瘤内血管生成增强和疾病进展。然而，许多针对血管生成的药物都产生了严重的副作用，包括高血压、血栓事件和过敏反应。此外，我很好地接受了这样一个事实，即药物很难进入胰腺，因为PC是高度促结缔组织生长的，间质致密。因此，我们假设MUC1通过增加NRP-1和随后的VEGFA信号水平来诱导促血管生成的肿瘤微环境。这可能是与MUC1相关的高度转移和侵袭性肿瘤表型的主要原因。其次，我们假设在肿瘤微环境中阻断VEGF165和NRP-1之间的相互作用将带来治疗益处。因此，我们将首先以NRP-1依赖的方式在体外研究MUC1+PDA细胞对内皮细胞功能的影响。其次，我们将确定MUC1是否通过上调NRP-1和VEGF信号在体内创造了一个促进血管生成的生态位。最后，我们将使用一种新型的MUC1抗体来递送VEGF165-NRP-1抑制肽到表达MUC1的胰腺肿瘤微环境中。我们建议使用合适的PDA小鼠模型来研究体内血管生成和药物输送。在这些小鼠中，胰腺肿瘤发生在胰腺内，并概括了人类的疾病，通过胰腺上皮内瘤变(Panins)的全谱病变发展到侵袭性腺癌并转移。这些小鼠要么表达人MUC1(KCM)，要么不表达MUC1(KCKO)。通过使用这些小鼠模型，我们将能够在适当的环境中评估血管生成开关，其中将包括胰腺致密的间质成分。此外，KCM小鼠的使用将使我们的结果具有高度的可译性，因为我们能够测试我们针对人类MUC1的治疗。我们认识到，使用MUC1抗体的这种靶向传递从未被尝试过，但如果这种方法奏效，它将彻底改变小分子和多肽被传递到胰腺的方式，而不会产生不想要的副作用。如果获得资金，这一领域的拨款将保证在PI的实验室中有一个强大的研究环境，并将改善整体研究环境，这将有助于吸引最高质量的学生，这对一个主要研究机构的成功发展至关重要。