Ligand-Directed Targeting in Prostate Cancer Metastasis

前列腺癌转移中的配体定向靶向

• 批准号: 7743204
• 负责人: RENATA PASQUALINI
• 金额: $ 24.73万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7743204
• 关键词: Accounting; Address; Affect; Affinity; Androgen Receptor; Androgens; Angiogenic Factor; Antibodies; Apoptosis; Apoptotic; Binding; Biological Assay; Biology; Biopsy; Blood Vessels; Bone Marrow; Cancer Center; Cancer Patient; Castration; Cell Proliferation; Cells; Cessation of life; Chemicals; Clinic; Clinical; Clinical Protocols; Clinical Research; Clinical Trials; Complement; Cytokine Receptors; Data; Detection; Development; Disease; Disease Progression; Dose; Drug Kinetics; Endothelial Cells; Evaluation; Exclusion Criteria; Fibroblast Growth Factor 2; Financial Support; Foundations; Funding; Future; Goals; Growth; Homing; Human; Human Biology; Image; Immunohistochemistry; In Situ Nick-End Labeling; In Vitro; Induction of Apoptosis; Injection of therapeutic agent; Instruction; Interleukin-1; Interleukin-11; Laboratories; Lead; Learning; Libraries; Ligands; Link; Macaca fascicularis; Malignant Neoplasms; Malignant neoplasm of prostate; Maps; Measurement; Measures; Mediating; Medicine; Metastatic Neoplasm to the Bone; Metastatic Prostate Cancer; Methodology; Mitochondria; Modeling; Molecular; Monitor; Mus; Nature; Neoplasm Metastasis; Neoplasms in Vascular Tissue; Organ; Outcome; PC3 cell line; Pathology; Pathway interactions; Patient Selection; Patients; Peptide Library; Peptides; Pericytes; Phage Display; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phase I Clinical Trials; Phenotype; Pre-Clinical Model; Principal Investigator; Production; Prostate; Proteins; Protocols documentation; Rattus; Reproduction spores; Research Ethics Committees; Research Personnel; Resistance; Sampling; Screening procedure; Seminal; Signal Transduction; Site; Solid; Sorting - Cell Movement; Specificity; Staging; Stat3 protein; Stimulus; Stromal Cells; Structure; System; Techniques; Testing; Therapeutic; Therapeutic Agents; Time; Tissue Sample; Tissues; Toxic effect; Toxicology; Translational Research; United States; Up-Regulation; Validation; Vascular Endothelial Growth Factors; Vascular Endothelium; Work; Xenograft Model; Xenograft procedure; angiogenesis; base; bone; cell killing; cell type; clinical application; combinatorial; density; design; disease natural history; disease phenotype; effective therapy; good laboratory practice; human IL11RA protein; human data; human tissue; in vivo; inclusion criteria; injured; insight; interleukin 11 receptor, alpha chain 2 protein, mouse; interleukin-11 receptor; liquid chromatography mass spectrometry; neoplastic cell; novel; novel strategies; patient population; pre-clinical; programs; receptor; research study; therapeutic target; tumor; tumor growth; tumor progression

Our laboratory has used in vivo phage display (1) to demonstrate how the vascular endothelium of organs is modified in a tissue-specific manner, and (2) to prove that the development of cancer is accompanied by specific abnormalities in the cells that form tumor-associated blood vessels. From previous work in an IRB- approved protocol involving phage-display screening with a random library injected intravenously into an irreversibly injured patient, a homing peptide was isolated from post-injection prostate biopsies. The selected sequence mimicked a motif of interleukin 11 (IL-11), and it in fact was bound to IL-11 receptor alpha (IL- 11 R). Subsequent studies, including an extensive immunohistochemical analysis of primary and metastatic prostate cancer samples, showed increased expression of IL-1 IR during disease progression, particularly in bone metastases. The seminal observation that the vasculature of human prostate cancer selectively binds a small peptide motif via IL-11R raises many potential directions for both basic and translational research. In particular, it engenders the novel hypothesis that IL-11R-mediated signaling is biologically important in the progression of prostate cancer to a lethal phenotype; and, that understanding how this expression is regulated-particularty in relation to progression to a castrate-resistant state-will provide novel and relevant insights into the biology of human prostate cancer. The discovery of this prostate-homing peptide also suggests the use of novel imaging and therapeutic agents based on the selective binding. We have chosen to pursue aggressively a therapeutic application: we have produced an agent, BMTP-11 (Bone Metastasis Targeting Peptide-11), in which the selected peptide motif is combined with the mitochondrial disrupting, and therefore apoptosis-inducing moiety. The most important translational research issues in this context are: 1) Does BMTP-11 selectively distribute to prostate cancer in human patients, 2) How is IL-11R expression regulated, because this information is important for the selection of patients and the modulation of effective BMTP-11 treatment, and 3) What are the toxicities of this agent, and how can they be mechanistically understood and thereby mitigated. The following Specific Aimis state our priorities relevant to these questions. We will (i) Study the induction and activity of IL-11 and the IL-11Ra within the tumor microenvironment during prostate cancer progression; (ii) Determine the stimuli mediating up-regulation and activation ofthe IL-11Ra. Potential interplay linking IL-11, IL-11R and castrate-resistant tumor growth will be investigated; and (iii) Develop pre-clinical and clinical assays to evaluate BMTP-11 activity in patients. RELEVANCE (See instructions): Metastatic, castration-resistant prostate cancer continues to be a lethal disease phenotype, with median survival time of about 18 months and accounting for over 28,000 deaths annually in the United States. There is a pressing need for new approaches. Targeting the bone compartment can alter the natural history of the disease. BMTP-11 is especially attractive because it may be capable of selectively delivering an apoptosis- inducing agent by means of ligand-directed targeting of bone metastases.

我们实验室利用体内噬菌体展示（1）来演示器官的血管内皮是如何 以组织特异性方式进行修饰，以及（2）证明癌症的发展伴随着 形成肿瘤相关血管的细胞的特定异常。根据之前在 IRB 的工作 - 批准的方案涉及噬菌体展示筛选，随机文库静脉注射到 对于不可逆损伤的患者，从注射后前列腺活检中分离出归巢肽。所选择的 该序列模仿了白细胞介素 11 (IL-11) 的基序，事实上它与 IL-11 受体 α (IL-11) 结合。 11R）。随后的研究，包括对原发性和转移性的广泛免疫组织化学分析 前列腺癌样本显示，在疾病进展过程中，IL-1 IR 的表达增加，特别是在 骨转移。人类前列腺癌的脉管系统选择性结合a的开创性观察 通过 IL-11R 的小肽基序为基础和转化研究提出了许多潜在的方向。在 特别是，它产生了一个新的假设，即 IL-11R 介导的信号传导在 前列腺癌进展为致命表型；并且，了解这个表达是如何表达的 与进展到去势抵抗状态相关的监管特殊性将提供新颖且相关的 对人类前列腺癌生物学的见解。这种前列腺归巢肽的发现也 建议使用基于选择性结合的新型成像和治疗剂。我们选择了 积极追求治疗应用：我们生产了一种药物 BMTP-11（骨转移 靶向肽-11)，其中选定的肽基序与线粒体破坏相结合，以及 因此是细胞凋亡诱导部分。在这方面最重要的转化研究问题是：1） BMTP-11 是否选择性分布到人类患者的前列腺癌中，2) IL-11R 表达如何 受到监管，因为这些信息对于患者的选择和有效治疗的调节很重要 BMTP-11 治疗，以及 3) 该药物的毒性是什么，其机制如何 理解并从而减轻。以下具体目标阐述了我们与这些目标相关的优先事项 问题。我们将 (i) 研究肿瘤内 IL-11 和 IL-11Ra 的诱导和活性 前列腺癌进展过程中的微环境； (ii) 确定介导上调的刺激物 IL-11Ra 的激活。 IL-11、IL-11R 和去势抵抗性肿瘤生长之间的潜在相互作用将是 调查； (iii) 开发临床前和临床检测来评估患者的 BMTP-11 活性。 相关性（参见说明）： 转移性去势抵抗性前列腺癌仍然是一种致命的疾病表型，中位 其生存时间约为 18 个月，在美国每年导致 28,000 多人死亡。那里 迫切需要新的方法。靶向骨室可以改变骨的自然历史 疾病。 BMTP-11 特别有吸引力，因为它可能能够选择性地传递细胞凋亡- 通过配体定向靶向骨转移的诱导剂。