Ligand-Directed Targeting in Prostate Cancer Metastasis

前列腺癌转移中的配体定向靶向

基本信息

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
项目类别：
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

项目摘要

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.

我们的实验室使用体内噬菌体显示（1）来证明器官的血管内皮是如何以组织特异性修饰，（2）证明癌症的发展伴随着形成肿瘤相关血管的细胞中的特定异常。从以前的IRB- 批准的协议涉及用随机库静脉注射到一个随机库中的噬菌体显示筛选从注射后的前列腺活检中分离出不可逆转的损伤患者，归因肽。选定的序列模拟了白介素11（IL-11）的基序，实际上它与IL-11受体α（IL- 11 R）。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有选择地结合A的开创性观察通过IL-11R的小肽基序为基础研究和转化研究提供了许多潜在的方向。在特别是，它引起了新的假设，即IL-11R介导的信号在生物学上在生物学上很重要前列腺癌的进展为致命表型；而且，理解这种表达方式与castrate抗性的州有关的规范合法性的参与者将提供新颖的和相关的对人前列腺癌的生物学的见解。也发现了这种前列腺毒的肽建议基于选择性结合的新成像和治疗剂。我们选择了积极地进行治疗应用：我们产生了一种药物BMTP-11（骨转移靶向肽-11），其中所选肽基序与线粒体破坏相结合，并且因此诱导细胞凋亡的部分。在这种情况下，最重要的翻译研究问题是：1） BMTP-11是否在人类患者中有选择地分布到前列腺癌，2）IL-11R表达如何受监管，因为此信息对于选择患者和有效的调节很重要 BMTP-11治疗和3）该药物的毒性是什么，它们如何机械上理解并因此缓解。以下特定的目标指出我们与这些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和 IL-11RA的激活。连接IL-11，IL-11R和耐Castrate肿瘤生长的潜在相互作用将是调查；（iii）开发临床前和临床测定法，以评估患者的BMTP-11活性。相关性（请参阅说明）：转移性，耐castration的前列腺癌仍然是一种致命的疾病表型，中位数在美国，生存时间约为18个月，每年占28,000多次死亡。那里是对新方法的迫切需求。靶向骨室可以改变疾病。 BMTP-11特别有吸引力，因为它可能能够选择性地提供凋亡 - 通过配体定向的骨转移靶向诱导剂。