Targeting Tumor Microenvironment-Induced Therapy Resistance in Prostate Cancer Bone Metastasis

针对前列腺癌骨转移中肿瘤微环境诱导的治疗耐药性

• 批准号: 8999529
• 负责人: SUE-HWA LIN
• 金额: $ 29.92万
• 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: 2009-09-02 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8999529
• 关键词: Ablation; Accounting; Bone Marrow; Bone Matrix; Bone neoplasms; Cancer Center; Cancer Patient; Cell Survival; Cells; Cessation of life; Clinical; Clinical Trials; Clinical/Radiologic; Combined Modality Therapy; Conditioned Culture Media; Disease Progression; Employee Strikes; Generations; Genes; Goals; Hormones; Immature Bone; In Vitro; Integrins; KDR gene; Lead; Ligands; Malignant neoplasm of prostate; Mediating; Mediator of activation protein; Metastatic Neoplasm to the Bone; Metastatic Prostate Cancer; Molecular Profiling; Morbidity - disease rate; Mutation; Neoplasm Metastasis; Oral; Osteoblasts; Osteogenesis; PTK2 gene; Pathway interactions; Patients; Pharmacodynamics; Phenotype; Phosphorylation; Play; Progression-Free Survivals; Proteins; Radiation; Recurrence; Refractory; Resistance; Resolution; Role; Serum; Signal Transduction; Structure; Study models; Symptoms; Testing; Therapeutic; Therapeutic Agents; Tissues; Toxic effect; Treatment Efficacy; Xenograft Model; Xenograft procedure; antiangiogenesis therapy; bone; bone imaging; bone lead; chemotherapy; disorder control; docetaxel; improved; in vivo; inhibitor/antagonist; kinase inhibitor; men; mortality; mouse model; neoplastic cell; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; osteogenic; paracrine; patient population; predictive marker; prostate cancer cell; release factor; resistance mechanism; response; serum PSA; standard of care; targeted treatment; theories; therapeutic angiogenesis; therapeutic target; therapy resistant; tumor; tumor growth; tumor microenvironment

PROJECT SUMMARY (Project 2) Metastatic castrate resistant prostate cancer (mCRPC) in bone is almost universally fatal. While new targeted therapeutics have improved patient survival, resistance invariably develops. Treatment refractory bone metastases lead to morbidity and mortality in patients with mCRPC. Long-term goals of this proposal are to understand mechanisms of therapy resistance and strategies to overcome them. Studies of this proposal focus on resistance mediated from the bone microenvironment. Specifically, using an osteogenic prostate cancer xenograft, MDA-PCa-118, we found that treatment with cabozantinib, an oral multi-kinase inhibitor with potent activity against p-MET and p-VEGFR-2, demonstrated striking initial responses. However, resistance rapidly occurs, as first evidenced by viable cells tumor cells found in proximity to newly formed bone matrix. Because prostate cancer bone metastasis presents with a unique bone-forming phenotype, we hypothesize that factors released from tumor-induced bone lead to pre-existing resistance, in which the microenvironment has already contributed factors that mediate resistance prior to application of therapy. To study the mechanisms of this form of resistance, a secretome analysis was performed on conditioned medium from prostate cancer-induced bone, which identified 121 bone-secreted proteins. Many of these bone-secreted proteins activate integrins through paracrine effects, increasing tumor cell survival. We term these osteoblast-secreted paracrine factors “osteocrines”. Consistent with the involvement of integrins in therapy resistance, we found that FAK, the downstream effector of integrin signaling, is highly activated in therapy-resistant tumor cells. Thus, we hypothesize that osteocrines released from prostate cancer-induced bone form a pre-existing resistance niche that mediates therapy resistance of prostate cancer cells through activation of FAK. We will test this hypothesis by: (1) Examining the ability of selected osteocrines to confer therapy resistance through activation of FAK; (2) Examining the effects of second-generation FAK inhibitors (VS-6063 or VS- 4718) on overcoming osteocrine-induced therapy resistance in xenograft mouse models; and (3) Conducting a clinical trial to examine the toxicity and efficacy of a FAK inhibitor (VS-6063 or VS-4718) in men with treatment- refractory bone-metastatic castrate-resistant prostate cancer. The studies would be paradigm shifting by demonstrating that the tumor microenvironment can provide a niche of “pre-existing resistance”, a mechanism of resistance in addition to tumor adaptation to therapy, which is likely applicable to multiple therapies in mCRPC. The studies would also demonstrate the potential efficacy of FAK inhibitors for treatment of bone-metastatic CRPC. In addition, delineating mechanisms of this “pre-existing resistance” will provide new predictive markers to guide therapeutic strategies to overcome resistance.

项目总结(项目2) 骨转移性去势耐药前列腺癌(MCRPC)几乎是一种常见的致命性疾病。虽然新的目标是 治疗方法提高了患者的存活率，但不可避免地会产生耐药性。治疗难治性骨 转移导致mCRPC患者的发病率和死亡率。这项提议的长期目标是 了解治疗抵抗的机制和克服它们的策略。对这一建议的研究重点 论骨微环境介导的阻力。具体地说，使用成骨性前列腺癌 异种移植，MDA-PCA-118，我们发现用卡波赞替尼治疗，一种口服多激酶抑制剂，有效 对p-Met和p-VEGFR-2的活性表现出显著的初步反应。然而，抗药性迅速 发生，最早的证据是在新形成的骨基质附近发现的活细胞肿瘤细胞。因为 前列腺癌骨转移呈现一种独特的骨形成表型，我们假设 从肿瘤诱导的骨骼中释放导致预先存在的抵抗，其中的微环境已经 在应用治疗之前，促成了调解耐药性的因素。为了研究这一现象的机制 耐药的形式，对前列腺癌诱导的条件培养液进行分泌组分析 鉴定出121种骨骼分泌蛋白。许多这些骨分泌蛋白激活整合素。 通过旁分泌作用，提高肿瘤细胞存活率。我们将这些成骨细胞分泌的旁分泌因子称为 “骨分泌”。与整合素参与治疗耐药一致，我们发现FAK， 整合素信号的下游效应器，在耐药肿瘤细胞中高度激活。因此，我们 假设前列腺癌诱导骨释放的骨分泌形成预先存在的 通过激活FAK来调节前列腺癌细胞治疗耐药性的耐药生态位。 我们将通过以下方式验证这一假设：(1)检验选定的骨分泌细胞产生治疗抵抗的能力。 通过激活FAK；(2)检测第二代FAK抑制剂(VS-6063或VS-6063)的作用。 4718)在异种移植小鼠模型中克服骨分泌诱导的治疗抵抗；以及(3)进行 临床试验检查FAK抑制剂(VS-6063或VS-4718)对患有以下疾病的男性的毒性和疗效 难治性骨转移性去势抵抗前列腺癌。 这些研究将通过证明肿瘤微环境可以提供一个利基环境来实现范式转变 除了肿瘤对治疗的适应之外，还有一种抵抗机制，即 可能适用于mCRPC的多种疗法。这些研究还将证明， FAK抑制剂用于治疗骨转移的CRPC。此外，勾勒出这一“预先存在”的机制 耐药性“将提供新的预测标记物来指导克服耐药性的治疗策略。