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: 10706699
• 负责人: SUE-HWA LIN
• 金额: $ 11.3万
• 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 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10706699
• 关键词: Ablation; Administrative Supplement; Bone Marrow; Bone Matrix; Bone neoplasms; Cancer Center; Cancer Patient; Cell Survival; Cessation of life; Clinical; Clinical Trials; Clinical/Radiologic; Combined Modality Therapy; Conditioned Culture Media; Disease Progression; 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; castration resistant prostate cancer; chemotherapy; disorder control; docetaxel; improved; in vivo; inhibitor; men; mortality; mouse model; neoplastic cell; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; osteogenic; paracrine; patient derived xenograft model; patient population; predictive marker; prostate cancer cell; release factor; resistance mechanism; response; serum PSA; standard of care; targeted treatment; theories; 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.

项目概要（项目2） 骨转移性去势抵抗性前列腺癌（mCRPC）几乎普遍具有致死性。虽然新目标 虽然治疗方法提高了患者的存活率，但耐药性总是会发展。治疗难治性骨 转移导致mCRPC患者发病和死亡。该提案的长期目标是 了解治疗耐药性的机制以及克服这些机制的策略。本提案的研究重点 骨微环境介导的抵抗力。具体来说，使用成骨前列腺癌 在异种移植物MDA-PCa-118中，我们发现用卡博替尼（一种口服多激酶抑制剂，具有强效的 针对p-MET和p-VEGFR-2的活性，显示出惊人的初始应答。然而，抵抗迅速 发生，首先通过在新形成的骨基质附近发现的活细胞肿瘤细胞证明。因为 前列腺癌骨转移呈现出独特的骨形成表型，我们假设， 从肿瘤诱导的骨释放导致预先存在的阻力，其中微环境已经 在应用治疗之前介导耐药性的促成因素。为了研究这一机制， 为了评估前列腺癌的耐药形式，对来自前列腺癌诱导的细胞的条件培养基进行了分泌组分析。 bone，鉴定了121种骨分泌蛋白。这些骨分泌蛋白中的许多激活整合素 通过旁分泌效应，增加肿瘤细胞的存活率。我们称这些成骨细胞分泌的旁分泌因子 “骨分泌物”。与整合素参与治疗抵抗一致，我们发现FAK， 作为整合素信号传导的下游效应物，在治疗抗性肿瘤细胞中高度活化。因此我们 假设从前列腺癌诱导的骨中释放的骨分泌物形成预先存在的 耐药小生境通过激活FAK介导前列腺癌细胞的治疗耐药性。 我们将通过以下方式检验这一假设：（1）检查选定的骨分泌物赋予治疗抗性的能力 （2）检测第二代FAK抑制剂（VS-6063或VS-6064）对FAK的抑制作用。 4718）在异种移植小鼠模型中克服骨分泌诱导的治疗抗性;和（3）进行 在接受治疗的男性中检查FAK抑制剂（VS-6063或VS-4718）的毒性和疗效的临床试验- 难治性骨转移性去势抵抗性前列腺癌 这些研究将通过证明肿瘤微环境可以提供一个利基来改变范式 “预先存在的抗性”，除了肿瘤适应治疗之外的抗性机制， 可能适用于mCRPC的多种治疗。这些研究还将证明 用于治疗骨转移性CRPC的FAK抑制剂。此外，划定这种“预先存在的”机制， “耐药性”将提供新的预测标记，以指导克服耐药性的治疗策略。