Lymphagiogenesis and Lymphatic Metastasis in Prostate Cancer

前列腺癌的淋巴管生成和淋巴管转移

• 批准号: 7679544
• 负责人: DAVID B AGUS
• 金额: $ 23.91万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-15 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7679544
• 关键词: Address; Adenovirus Vector; Animals; Antibodies; Area; BAY 54-9085; Biological Assay; Biological Markers; Blood; Blood Circulation; Blood Vessels; Cancer Patient; Clinic; Clinical Management; Clinical Research; Clinical Trials; Complex; Development; Diagnostic Imaging; Disease; Disease Progression; Distal; End Point; Evaluation; Extracapsular; Functional Imaging; Future; Gleason Grade for Prostate Cancer; Growth; Hand; Human; Image; Imaging technology; Immune system; Institution; Intervention; Invasive; Investigation; Life; Liver; Localized; Lung; Lymphangiogenesis; Lymphatic; Lymphatic Metastasis; Lymphatic vessel; Malignant neoplasm of prostate; Metastatic Prostate Cancer; Modality; Modeling; Molecular; Monitor; Mus; Neoadjuvant Therapy; Neoplasm Metastasis; Nodal; Organ; Palpable; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phosphotransferases; Positive Lymph Node; Positron-Emission Tomography; Pre-Clinical Model; Process; Prostate; Prostatectomy; Prostatic Neoplasms; Receptor Protein-Tyrosine Kinases; Recurrence; Recurrent disease; Reporter Genes; Reporting; Reproduction spores; Research Personnel; Risk; Route; Sampling; Seminal Vesicles; Sentinel Lymph Node; Signal Transduction; Site; Source; Staging; Surrogate Markers; System; Testing; Therapeutic Effect; Therapeutic Intervention; Time; Tissue Microarray; Tissue Sample; Tumor Angiogenesis; Universities; Use Effectiveness; Vascular Endothelial Growth Factor C; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factor Receptor-3; Vascular Endothelial Growth Factors; Washington; Work; Xenograft Model; angiogenesis; autocrine; base; clinically relevant; concept; density; improved; inhibitor/antagonist; interest; kinase inhibitor; lymph nodes; lymphatic circulation; macrophage; metastatic process; molecular imaging; mortality; neoplastic cell; novel; prognostic; programs; research study; tumor; tumor progression; vector

Metastasis is the main cause of prostate cancer mortality. The support of prostate cancer SPORE Developmental Program in the past two years has enabled us to investigate the contribution of lymphangiogenesis to prostate cancer metastasis. We discovered that elevated pro-lymphangiogenic factor (VEGF-C) in the prostate tumors induces the growth of lymphatic vessels, which in turn facilitates tumor cell dissemination to regional lymph nodes. Moreover, the lymphatic dissemination process also greatly impacts metastasis to distal organs, such as lung and liver. Hence, our current working hypothesis suggests that lymphatic circulation is a preferred route of dissemination and that regional lymph nodes provide a reservoir from which subsequent dissemination to distal sites occurs. This proposal will investigate this hypothesis further. In particular, we will examine in detail the connection between lymphangiogenic pathways and metastasis in prostate cancer patients, focusing our molecular and histological analyses on the patients with node positive and recurrent disease. Using many relevant preclinical models developed at our institution, our efforts will be directed towards addressing two areas of great need, i.e. therapeutic intervention and diagnostic imaging of nodal metastasis. We will investigate therapeutic effects of blockading the lymphangiogenic tyrosine kinase receptor by specific VEGFR3 antibody, and Sorafenib, a multi-kinase inhibitor known to target both VEGFR3. Molecular imaging technologies will be applied to monitor the impact of these interventions on the metastatic process. We will also evaluate the ability of a prostate-specific imaging adenoviral vector to specifically detect nodal metastases in preclinical models. In addition, we will develop and assess potential circulating surrogate markers for the lymphangiogenic pathways. The lack of such markers has halted progress in anti-metastatic treatment. The prostate cancer SPORE program at University of Washington is initiating a phase II neoadjuvant clinical trial of Sorafenib in patients with high- risk localized prostate cancer. In a collaborative effort with this study, we will obtain blood and tissue samples from the patients to analyze the molecular activity of Sorafenib against the VEGFR3 pathway and tumor lymphangiogenesis axis. The myriad of approaches taken in this proposal is directed towards improving the clinical management of metastasis stage of prostate cancer in the future.

转移是前列腺癌死亡率的主要原因。前列腺癌孢子的支持 在过去的两年中，发展计划使我们能够调查 前列腺癌转移的淋巴管生成。我们发现升高的促淋巴染因子升高 （VEGF-C）在前列腺肿瘤中诱导淋巴血管的生长，从而促进肿瘤细胞 传播到区域淋巴结。此外，淋巴传播过程也极大地影响 转移到远端器官，例如肺和肝脏。因此，我们目前的工作假设表明 淋巴循环是一种首选的传播途径，区域淋巴结提供了储层 随后的传播到远端。该提议将调查这一假设 更远。特别是，我们将详细研究淋巴管途径与 前列腺癌患者的转移，将我们的分子和组织学分析集中在患者上 节点阳性和复发性疾病。使用在我们机构开发的许多相关临床前模型， 我们的努力将致力于解决两个急需的领域，即治疗干预和 淋巴结转移的诊断成像。我们将调查阻塞的治疗作用 特定VEGFR3抗体和多激酶的淋巴管酪氨酸激酶受体受体 已知靶向两个VEGFR3的抑制剂。分子成像技术将用于监测影响 在转移过程中的这些干预措施中。我们还将评估前列腺特异性的能力 成像腺病毒载体在临床前模型中特异性检测淋巴结转移。此外，我们将 开发和评估淋巴管生成途径的潜在循环替代标记。缺乏 这种标记已停止了抗转移治疗的进展。前列腺癌孢子计划 华盛顿大学正在对索拉非尼的II期新辅助临床试验进行高位 风险局部前列腺癌。在与这项研究的合作努力中，我们将获得血液和组织 来自患者的样本分析索拉非尼对VEGFR3途径的分子活性和 肿瘤淋巴管生成轴。该提案中采取的无数方法是针对的 改善未来前列腺癌转移阶段的临床管理。