Control of lethal prostate cancer with a bispecific av and a5b1 integrin antibody

使用双特异性 av 和 a5b1 整合素抗体控制致命性前列腺癌

基本信息

批准号：
10413148
负责人：
Paul Mathew
金额：
$ 46.74万
依托单位：
TUFTS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10413148
关键词：
Adhesives Affect African Androgen Receptor Animal Model Anoikis Antibodies Antibody Therapy Autopsy Behavior Benign Biological Markers Bispecific Antibodies Bone Marrow Breast Castration Caucasians Cell Communication Cessation of life Characteristics Chemotaxis Clinical Clinical Trials Data Dimensions Disease Disease Progression Down-Regulation Elements Endothelium Epithelial Experimental Models Fibronectins Functional disorder Generations Genetic Goals Growth Homing Human ITGA5 gene Image Immunodeficient Mouse In Vitro Integrin Binding Integrin alpha5beta1 Integrin alphaV Integrins Kidney Knowledge Laboratory Study Life Link Lung Malignant Neoplasms Malignant neoplasm of prostate Matrix Metalloproteinases Measures Mediating Mesenchymal Metastatic Neoplasm to the Bone Metastatic Prostate Cancer Mission Molecular Molecular Mechanisms of Action Neoplasm Metastasis Noninfiltrating Intraductal Carcinoma Organ Organ Specificity Outcome Pathway interactions Patients Pattern Phenotype Prostate Adenocarcinoma Prostatic Neoplasms Public Health Quality of life Research Resistance Role Signal Transduction Skeleton Solid Neoplasm Specificity Stromal Cells Testing Therapeutic Therapeutic antibodies Treatment Efficacy Tumor Burden United States National Institutes of Health Up-Regulation Visceral advanced disease base biobank bone clinical research site crosslink improved in vivo in vivo Model innovation lymph nodes malignant breast neoplasm men mesenchymal stromal cell migration neoplastic cell novel novel therapeutic intervention patient derived xenograft model pharmacodynamic biomarker premature prostate cancer cell prostate cancer metastasis prostate cancer progression receptor response survival outcome tissue resource tumor

Adhesives Affect African Androgen Receptor Animal Model Anoikis Antibodies Antibody Therapy Autopsy Behavior Benign Biological Markers Bispecific Antibodies Bone Marrow Breast Castration Caucasians Cell Communication Cessation of life Characteristics Chemotaxis Clinical Clinical Trials Data Dimensions Disease Disease Progression Down-Regulation Elements Endothelium Epithelial Experimental Models Fibronectins Functional disorder Generations Genetic Goals Growth Homing Human ITGA5 gene Image Immunodeficient Mouse In Vitro Integrin Binding Integrin alpha5beta1 Integrin alphaV Integrins Kidney Knowledge Laboratory Study Life Link Lung Malignant Neoplasms Malignant neoplasm of prostate Matrix Metalloproteinases Measures Mediating Mesenchymal Metastatic Neoplasm to the Bone Metastatic Prostate Cancer Mission Molecular Molecular Mechanisms of Action Neoplasm Metastasis Noninfiltrating Intraductal Carcinoma Organ Organ Specificity Outcome Pathway interactions Patients Pattern Phenotype Prostate Adenocarcinoma Prostatic Neoplasms Public Health Quality of life Research Resistance Role Signal Transduction Skeleton Solid Neoplasm Specificity Stromal Cells Testing Therapeutic Therapeutic antibodies Treatment Efficacy Tumor Burden United States National Institutes of Health Up-Regulation Visceral advanced disease base biobank bone clinical research site crosslink improved in vivo in vivo Model innovation lymph nodes malignant breast neoplasm men mesenchymal stromal cell migration neoplastic cell novel novel therapeutic intervention patient derived xenograft model pharmacodynamic biomarker premature prostate cancer cell prostate cancer metastasis prostate cancer progression receptor response survival outcome tissue resource tumor

展开

项目摘要

ABSTRACT The majority of the 300,000 annual deaths worldwide from prostate cancer are strongly attributed to bone metastasis because the skeleton is the exclusive site of clinical disease in the majority of men with advanced illness. There is a fundamental gap in our knowledge of the mechanisms that underpin the efficient and life- threatening colonization of the bone microenvironment by prostate cancer cells. Our long-term goal is to develop novel therapeutic strategies based on a molecular understanding of the pathophysiology of bone metastases in order to significantly improve survival and quality of life outcomes in prostate cancer. Our laboratory studies implicate two different but functionally related integrins expressed by prostate cancer cells in their homing, survival and lethal spread within the bone microenvironment. The rationale of this study is that a bispecific antibody that simultaneously targets these 2 integrins would optimally neutralize their function via its cross-linking mechanism of action and deliver an efficacious therapeutic strategy. Accordingly, a first-in-class bispecific antibody targeting these integrins demonstrated superior antitumor activity compared to monospecific antibodies alone or in combination. A distinct molecular mechanism of action for the bispecific antibody was defined. Following treatment with either or both monospecific integrin antibodies, adaptive upregulation of the integrins was seen whereas by contrast, downregulation of integrins followed bispecific antibody treatment via induction of internalization and lysosomal degradation of integrins. Our hypothesis is that the bispecific integrin antibody will halt the life-threatening progression of prostate cancer in the bone microenvironment. We plan to evaluate this hypothesis with three specific aims. First, we plan to assess the efficacy of the bispecific antibody compared to monospecific antibodies in distinct animal models of bone metastases that replicate key dimensions of the clinical disease: seeding of the bone marrow, interaction with human bone-derived stromal cells, accelerated growth and secondary dissemination from bone, and finally, generation of an osteoblastic phenotype. Secondly, we will further define the mechanism of action of the bispecific integrin antibody by assessing its impact on epithelial-mesenchymal transition, anoikis and clonogenic survival. Finally, we will determine the organ-specificity of the expression of the two integrins by comparing the expression of these integrins in bone metastases from prostate cancer and other solid tumors to metastases found in lymph nodes and visceral organs. Our innovative therapeutic strategy to disable the molecular mechanisms of colonization of the bone microenvironment by prostate cancer is significant because it has the potential to significantly prolong survival and improve quality of life of patients with prostate cancer. Solid tumors that colonize bone such as breast cancer may leverage the same molecular pathways, expanding the potential significance and impact of the bispecific antibody strategy in biomarker-supported clinical trials to follow.

抽象的全球300,000人死亡的前列腺癌死亡中的大多数归因于骨骼转移，因为骨骼是大多数患有晚期男性的临床疾病的独家部位疾病。我们对基于有效和寿命的机制的了解存在根本的差距威胁前列腺癌细胞对骨微环境定植。我们的长期目标是基于对骨骼病理生理学的分子理解，开发新的治疗策略转移为了显着改善前列腺癌的生存和生活质量。我们的实验室研究暗示了前列腺癌细胞表达的两个不同但功能相关的整合素他们的归巢，生存和致命散布在骨微环境中。这项研究的理由是双特异性抗体同时靶向这2个整合素将通过其功能最佳地中和它们的功能交联作用机理并提供有效的治疗策略。因此，是一流的靶向这些整联蛋白的双特异性抗体与单独或组合单独的抗体。双特异性的独特的分子作用机理定义了抗体。用一种或两种单特异性整合素抗体进行治疗后，自适应观察到整联蛋白的上调，而相比之下，整联蛋白的下调遵循双特异性通过诱导整合素的内在化和溶酶体降解，抗体处理。我们的假设是双特异性整联蛋白抗体将停止骨骼中前列腺癌的生命进展微环境。我们计划以三个特定目标评估这一假设。首先，我们计划评估与单特异性抗体相比，双特异性抗体的功效在不同的骨骼动物模型中复制临床疾病关键维度的转移酶：骨髓的播种，与人骨衍生的基质细胞，加速生长和从骨骼中传播的次要传播，最后成骨细胞表型的产生。其次，我们将进一步定义双特异性整联蛋白抗体通过评估其对上皮 - 间质转变，Anoikis和克隆生存。最后，我们将通过比较这些整合素在前列腺癌和其他实体瘤的骨转移酶中的表达在淋巴结和内脏器官中发现的转移酶。我们禁用的创新治疗策略前列腺癌骨微环境定植的分子机制很重要，因为它有可能显着延长生存率并改善前列腺癌患者的生活质量。实质性肿瘤殖民乳腺癌等骨骼可能会利用相同的分子途径，扩大双特异性抗体策略在生物标志物支持的临床试验中的潜在意义和影响跟随。