Clot formation in the tumor stroma as a target for prostate cancer treatment

肿瘤基质中的凝块形成作为前列腺癌治疗的靶点

• 批准号: 7673465
• 负责人: Jan Pilch
• 金额: $ 31.44万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-12 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7673465
• 关键词: Ablation; Adverse effects; Affinity; American; Amino Acid Sequence; Androgens; Antibodies; Bacteriophages; Binding; Binding Proteins; Binding Sites; Blood Clot; Blood coagulation; Cells; Characteristics; Clinical; Coagulation Process; Connective Tissue; Databases; Disease; Distant; Drug Carriers; Drug Delivery Systems; Endothelial Cells; Fibrin; Fibronectins; Goals; Home environment; Homing; In Vitro; Infiltration; Injection of therapeutic agent; Knowledge; Lead; Libraries; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Metastatic Prostate Cancer; Mus; Necrosis; Neoplasm Metastasis; Organ; Outcome; Patients; Peptides; Pharmaceutical Preparations; Pharmacia brand of estropipate; Physiological; Plasma; Plasma Proteins; Proliferating; Property; Prostatic Neoplasms; Protein Fragment; Proteins; Radiation therapy; Research Project Grants; Role; Scheme; Screening procedure; Skin Cancer; Staging; Structure; Structure-Activity Relationship; Testing; Therapeutic; Tissues; Translating; Treatment Efficacy; Tumor Burden; Vascular Endothelial Growth Factors; Withdrawal; Xenograft Model; Xenograft procedure; antitumor drug; base; cancer therapy; cytotoxic; cytotoxicity; deprivation; hormone refractory prostate cancer; improved; in vivo; interstitial; lymph nodes; male; man; neoplastic cell; novel; public health relevance; targeted delivery; tumor; tumor specificity

DESCRIPTION (provided by applicant): Prostate cancer is, after skin cancer, the most common malignancy in man. There are a variety of treatment options for localized prostate cancer, but the disease becomes virtually incurable once the cancer has metastasized to the lymph nodes or distant organs. The long-term objective of this proposed research project is to elucidate the role of blood clot in the prostate tumor stroma and utilize this knowledge to treat metastatic prostate cancer. The presence of blood clot in the tumor stroma has been recognized for many years. Clotted plasma is a specific component of the tumor stroma and, therefore an excellent target for drug delivery. We recently identified two peptides CLT1 and CLT2, which upon injection into mice associate with clotted plasma proteins in the stroma of a variety of tumors including prostate cancer xenografts. However, the CLT peptides do not bind to healthy organs. CLT1 has an additional function as it is cytotoxic for proliferating endothelial and prostate tumor cells; CLT1 has no effect on confluent (non-proliferative) endothelial cells. Overall, these observations support the hypothesis that the CLT peptides bind to the prostate tumor stroma based on their affinity for a unique binding site in blood clot and that this affinity can be used to treat end stage prostate cancer. The specific aims are: (1) To isolate a protein or protein fragment from clotted plasma encompassing the CLT binding site in prostate tumor interstitial spaces. We will identify the tumor- specific clot protein (= CLT-binding protein or CLT-BP) that binds to the CLT peptides and develop an antibody to analyze the expression of the CLT-BP in clinical prostate cancer. We will also identify the minimal amino acid sequence within the CLT peptide (CLT-motif) that mediates binding to the CLT-BP. The identification of the CLT-motif will allow us to identify physiological binding partners of the CLT-BP by screening data bases for homologies. (2) To determine if CLT1 is effective in treating prostate cancer and prostate cancer metastases. We will determine whether the cytotoxicity of CLT1 translates into anti-tumor and anti-metastatic activity for prostate cancer in a mouse xenograft model in vivo and elucidate the cytotoxic function of CLT1 by analyzing its structure activity relationship in vitro. (3) To determine if androgen deprivation therapy increases homing of the D-K6L9-CLT1 fusion peptide to prostate tumors and metastases and if homing of D-K6L9-CLT1 improves the anti-tumor and anti-metastatic effect of the androgen deprivation therapy. We will determine if D-K6L9 becomes a more effective anti-tumor drug after conjugation to CLT1 which is expected to direct D-K6L9 to clot in prostate tumor necroses caused by androgen ablation. The results of this study will lead to novel information about the structure and function of the prostate tumor stroma. This knowledge will be immediately translated into new treatment options for metastatic prostate cancer. PUBLIC HEALTH RELEVANCE. Prostate cancer is, after skin cancer, the most common malignancy in male Americans and becomes virtually incurable once the cancer has spread to the lymph nodes or distant organs. This project will determine if treatment with the CLT peptides can provide a cure or at least a therapy that inhibits prostate cancer from further spreading without causing major side effects. Delineating the interaction of CLT1 and CLT2 with the prostate tumor is an important milestone for further developing the peptides into a useful drug or drug carrier.

描述（由申请人提供）：在皮肤癌后，前列腺癌是人中最常见的恶性肿瘤。局部前列腺癌有多种治疗选择，但是一旦癌症转移到淋巴结或远处器官，该疾病几乎无法治愈。该提出的研究项目的长期目标是阐明血块在前列腺肿瘤基质中的作用，并利用这种知识来治疗转移性前列腺癌。肿瘤基质中血凝块的存在已被识别多年。凝结的血浆是肿瘤基质的特定组成部分，因此是药物输送的绝佳靶标。我们最近确定了两种肽CLT1和CLT2，它们在注射到小鼠中与凝结的血浆蛋白相关后，在包括前列腺癌异种移植物在内的多种肿瘤的基质中。但是，CLT肽不与健康的器官结合。 CLT1具有附加功能，因为它具有细胞毒性，可用于增殖内皮和前列腺肿瘤细胞。 CLT1对汇合（非增殖）内皮细胞没有影响。总体而言，这些观察结果支持以下假设：CLT肽基于血凝块中独特的结合位点的亲和力与前列腺肿瘤基质结合，并且该亲和力可用于治疗终阶段前列腺癌。具体目的是：（1）将蛋白质或蛋白质片段分离从凝结的血浆中，其中包含前列腺肿瘤间质空间中的CLT结合位点。我们将确定与CLT肽结合并开发抗体以分析CLT-BP在临床前列腺癌中的表达的肿瘤特异性凝块蛋白（= CLT结合蛋白或CLT-BP）。我们还将确定介导与CLT-BP结合的CLT肽（CLT-MOTIF）内的最小氨基酸序列。 CLT-MOTIF的识别将使我们能够通过筛选数据库的同源物来识别CLT-BP的生理结合伙伴。 （2）确定CLT1是否有效治疗前列腺癌和前列腺癌转移。我们将确定在体内小鼠异种移植模型中，CLT1的细胞毒性是否转化为前列腺癌的抗肿瘤和抗转移活性，并通过在体外分析其结构活性关系来阐明CLT1的细胞毒性功能。 （3）确定雄激素剥夺治疗是否会增加D-K6L9-CLT1融合肽的归巢，以提高前列腺肿瘤和转移酶，以及D-K6L9-CLT1的归位会改善抗肿瘤和抗抑制作用的抗肿瘤和抗量子效应。我们将确定D-K6L9与CLT1结合后是否成为一种更有效的抗肿瘤药物，该药物有望将D-K6L9引导至由雄激素消融引起的前列腺肿瘤坏死。这项研究的结果将导致有关前列腺肿瘤基质的结构和功能的新信息。这些知识将立即转化为转移性前列腺癌的新治疗选择。 公共卫生相关性。在皮肤癌后，前列腺癌是男性美国人最常见的恶性肿瘤，一旦癌症扩散到淋巴结或远处器官，几乎无法治愈。该项目将确定用CLT肽的治疗是否可以提供治疗或至少抑制前列腺癌进一步扩散而不会引起重大副作用的疗法。描述CLT1和CLT2与前列腺肿瘤的相互作用是将肽进一步发展为有用的药物或药物载体的重要里程碑。