PHSCN Therapies to Prevent Prostate Cancer Progression

预防前列腺癌进展的 PHSCN 疗法

• 批准号: 7275436
• 负责人: DONNA Lucy LIVANT
• 金额: $ 26.13万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-14 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7275436
• 关键词: Address; African American; American; Antimetastatic Agent; Apoptosis; Appendix; Basement membrane; Binding; Blood; Cancer Etiology; Cancer Patient; Cell Survival; Cell physiology; Cells; Cessation of life; Crosslinker; Cysteine; DNA Sequence Rearrangement; Development; Disease; Disease Progression; Embryo; Epitopes; Extravasation; Generations; Goals; Growth; In Vitro; Incidence; Induction of Apoptosis; Inhibition of Apoptosis; Integrin alpha Chains; Integrin alpha5beta1; Integrins; Ions; Lesion; Liver; Location; Lung; Lysine; Malignant neoplasm of prostate; Mediating; Metastatic Neoplasm to the Liver; Metastatic Prostate Cancer; Micrometastasis; Modeling; Monoclonal Antibodies; N-terminal; Neoplasm Metastasis; Newly Diagnosed; Nucleic Acid Regulatory Sequences; Nude Mice; Numbers; Organ; PC3 cell line; Palliative Care; Pathway interactions; Patients; Pattern; Peptides; Personal Satisfaction; Phase I Clinical Trials; Play; Polylysine; Pre-Clinical Model; Primary Neoplasm; Prostate; Proteins; Public Health; Publishing; Recurrence; Reducing Agents; Research; Research Personnel; Resistance; Role; Sea Urchins; Second Primary Neoplasms; Serum; Side; Signal Pathway; Site; Specificity; Specimen; Stable Disease; Standards of Weights and Measures; Structure of parenchyma of lung; Systemic Therapy; Techniques; Testing; Therapeutic Agents; Time; Tissues; Toxic effect; Tumor Cell Invasion; acetyl-prolyl-histidyl-seryl-cysteinyl-asparaginamide; cancer cell; cell killing; chemotherapy; compare effectiveness; crosslink; design; disulfide bond; in vivo; inhibitor/antagonist; men; monomer; neoplastic cell; prevent; programs; receptor; research study; tandem mass spectrometry; therapeutic target; tumor; tumor growth; tumor progression

DESCRIPTION (provided by applicant): Unlike organ-confined disease, metastatic prostate cancer is incurable. Chemotherapy can be toxic; while palliative therapies do not prevent disease progression. The alpha5beta1 integrin receptor is an attractive therapeutic target. While it is widely expressed, inactive alpha5beta1 does not mediate invasion. However, activated alpha5beta1 is found specifically on prostate cancer cells, and functions in invasion and metastasis, as well as in survival. Since activation causes significant structural rearrangements, like changes in disulfide bonding patterns in both the alpha5 and the beta1 subunits, agents may be designed to interact only with activated alpha5beta1 receptors. Because of their specificity, we hypothesize that these agents will be potent inhibitors of prostate cancer metastasis, while having minimal toxic effects on healthy tissues. Our published and preliminary results suggest that the PHSCN peptide binds activated alpha5beta1 specifically, thereby blocking invasion and inducing apoptosis in vitro, and preventing growth, metastasis and tumor recurrence in preclinical models of prostate cancer. Moreover in a recent Phase I clinical trial, systemic PHSCN monotherapy was well tolerated, and metastatic disease failed to progress for 4-14 months in 38% of patients receiving it. Here, we propose to enhance the development of PHSCN as a therapeutic agent by defining its target on alpha5beta1 integrin. We have recently developed a more potent derivative of PHSCN: the PHSCN-polylysine dendrimer. Thus, we also propose to compare the PHSCN peptide and the PHSCN-dendrimer as inhibitors of invasion and survival in metastatic human prostate cancer cell lines. Finally, we propose to quantitate invasion and metastasis inhibition, and apoptosis induction in primary tumors and in lung and liver metastases of human prostate cancer in nude mice. The proposed research may have a major impact on public health because prostate cancer is the most common noncutaneous neoplasm, and the second leading cause of cancer death in American men; moreover, its incidence is increasing. Furthermore, it is especially prevalent in African American men. Also, 50% to 90% of newly diagnosed prostate cancer patients already have locally advanced or metastatic disease. Thus, an effective, well-tolerated, nontoxic therapy that prevents prostate cancer progression for long periods of time could be very beneficial to many patients.

描述（由申请人提供）：与器官疾病不同，前列腺癌是无法治愈的。化学疗法可能有毒；虽然姑息治疗并不能阻止疾病进展。 Alpha5beta1整联蛋白受体是一个有吸引力的治疗靶点。虽然被广泛表达，但无活动的alpha5beta1不能介导侵袭。然而，活化的α5Beta1专门在前列腺癌细胞上发现，在侵袭和转移以及生存中起作用。由于激活会引起明显的结构重排，就像α5和beta1亚基中二硫键模式的变化一样，可以设计代理仅与活化的alpha5beta1受体相互作用。由于其特异性，我们假设这些药物将是前列腺癌转移的有效抑制剂，同时对健康组织的毒性影响很小。我们发表的初步结果表明，PHSCN肽特别结合了激活的α5BETA1，从而在前列腺癌的临床前模型中阻止了体外侵袭并诱导体外凋亡，并预防生长，转移和肿瘤复发。此外，在最近的I期临床试验中，全身性PHSCN单一疗法的耐受性很好，转移性疾病在38％的患者中未能进展4-14个月。在这里，我们建议通过定义其对α5Beta1整合素的靶标，以增强PHSCN作为治疗剂的发展。我们最近开发了PHSCN的更有效的衍生物：PHSCN-溶解树状聚合物。因此，我们还建议将PHSCN肽和PHSCN树枝状大分子作为浸润和生存的抑制剂进行比较。最后，我们建议定量侵袭和转移抑制作用，以及原发性肿瘤以及裸鼠人类前列腺癌的肺和肝转移中的凋亡诱导。拟议的研究可能会对公共卫生产生重大影响，因为前列腺癌是最常见的肿瘤，也是美国男性癌症死亡的第二大主要原因。而且，其发病率正在增加。此外，在非裔美国人中尤其普遍。此外，有50％至90％的新诊断的前列腺癌患者已经患有局部晚期或转移性疾病。因此，一种有效，耐受性良好的无毒疗法可防止长期前列腺癌的进展，对许多患者可能非常有益。