Targeted therapeutics for ovarian cancer and its microenvironment - treatment and theoretical modeling

卵巢癌及其微环境的靶向治疗——治疗和理论模型

• 批准号: 9260671
• 负责人: Gabriel Lopez-Berestein
• 金额: $ 51.52万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9260671
• 关键词: Address; Affinity; Amendment; Apoptosis; Biological; Biological Response Modifier Therapy; CC chemokine receptor 2; Cancer Model; Cancer Patient; Cells; Cisplatin; Clinical; Cytotoxic Chemotherapy; Data; Development; Disease; Drug Kinetics; Drug Targeting; Drug resistance; Gene Silencing; Growth; Hybrids; Inflammation; Ligands; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Mediator of activation protein; Modeling; Molecular; Molecular Target; Monocyte Chemoattractant Proteins; Neoplasm Metastasis; Oncogenic; Operative Surgical Procedures; Outcome; Ovarian; Paclitaxel; Particle Size; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phenotype; Physiological; Play; Pre-Clinical Model; Recruitment Activity; Regimen; Regulation; Resistance; Role; Serous; Serum; Shapes; Signal Transduction; Small Interfering RNA; Survival Rate; System; Testing; Theoretical model; Therapeutic; Tissues; Toxic effect; Treatment Efficacy; Tumor Tissue; Work; Zoledronic Acid; angiogenesis; aptamer; axl receptor tyrosine kinase; base; biophysical properties; chemokine; chemotherapy; density; design; improved; in vivo; inhibitor/antagonist; innovation; macrophage; mathematical methods; mathematical model; monocyte; multi-scale modeling; nanoparticle; neoplastic cell; new therapeutic target; novel; ovarian neoplasm; overexpression; receptor; receptor binding; targeted agent; targeted delivery; targeted treatment; therapeutic target; traditional therapy; treatment strategy; tumor; tumor growth; tumor microenvironment; tumor progression; uptake

Project Summary With the traditional therapies for ovarian cancer (OC) that include surgery followed by cytotoxic chemotherapy patient survival is still extremely poor and 5-year survival rate is less than 30%. Therefore, new treatment strategies are needed to cure or improve dismal patient survival. Recent clinical and experimental evidence including ours indicate that the monocyte-macrophage axis (MMA) and tumor-associated macrophages (TAMs) play a significant role in tumor growth and progression by contributing to angiogenesis, invasion/metastasis, and drug resistance. We found OC patients with increased numbers of circulating monocytes and intratumoral TAMs have poor clinical outcomes and significantly shorter patient survival. Our studies also indicate that the tumor microenvironment and TAMs are attractive therapeutic targets in ovarian and other cancers and reduction of TAMs inhibits angiogenesis, invasion and metastasis, and drug resistance in ovarian cancer models. Overall data indicate that in contrast to the conventional drugs that target only tumor cells, targeting tumor microenvironment is required to achieve maximal anti-tumor efficacy. Also, lack of critical molecular targets for this purpose and together with a lack of effective delivery systems, biological barriers for drugs, including poor tissue-specific delivery, toxicity, and the inability to deliver high concentrations of therapeutics into tumor microenvironment, therapeutic strategies fail to cure OC. The use of siRNA bearing- nanoparticles targeted to the tumor and the microenvironment is a particularly attractive approach for targeting molecular targets, reprogramming the tumor microenvironment and development of the most effective therapeutic strategies for OC. To directly address these unmet needs we recently developed various nanoparticle (NP) platforms including, (1) long-acting, slow-release dual assembly NPs (DANPs); (2) serum resistant AXL-receptor binding-aptamers for development of targeted therapies in OC and validated each NP- based approach in multiple OC tumor models with robust and sustained target silencing and significant antitumor efficacy. In this study we will test the hypothesis that the blockade of the tumor and tumor microenvironment interactions by highly versatile NPs that encase therapeutic cargos will provide significant antitumor activity and enhance the efficacy of current regimens in OC. Thus we will determine mechanism of TAM regulation and determine the biological and therapeutic efficacy of targeting MMA/TAMs using highly targeted dual effect NPs in OC models as well as by applying mathematical models.

项目概要 卵巢癌 (OC) 的传统疗法包括手术后进行细胞毒性化疗 患者的生存率仍然极低，5年生存率不足30%。因此，新的治疗 需要采取策略来治愈或改善惨淡的患者生存率。最近的临床和实验证据 包括我们的在内表明单核细胞-巨噬细胞轴（MMA）和肿瘤相关巨噬细胞 （TAM）通过促进血管生成在肿瘤生长和进展中发挥重要作用， 侵袭/转移和耐药性。我们发现 OC 患者的循环次数增加 单核细胞和瘤内 TAM 的临床结果较差，患者生存期显着缩短。我们的 研究还表明肿瘤微环境和 TAM 是卵巢癌有吸引力的治疗靶点 和其他癌症，TAM 的减少会抑制血管生成、侵袭和转移以及耐药性 在卵巢癌模型中。总体数据表明，与仅针对肿瘤的传统药物相比 细胞，需要针对肿瘤微环境来实现最大的抗肿瘤功效。另外，缺乏批判性 用于此目的的分子靶点以及缺乏有效的递送系统、生物屏障 药物，包括组织特异性递送不良、毒性以及无法递送高浓度的药物 治疗进入肿瘤微环境，治疗策略无法治愈 OC。 siRNA轴承的使用- 针对肿瘤和微环境的纳米颗粒是一种特别有吸引力的靶向方法 分子靶点，重新编程肿瘤微环境并开发最有效的 OC 的治疗策略。为了直接解决这些未满足的需求，我们最近开发了各种 纳米颗粒（NP）平台包括：（1）长效、缓释双组装纳米颗粒（DANP）； (2)血清 抗性 AXL 受体结合适体用于 OC 靶向治疗的开发并验证了每个 NP- 基于多种 OC 肿瘤模型的方法，具有强大且持续的靶标沉默和显着的效果 抗肿瘤功效。在这项研究中，我们将检验以下假设：肿瘤和肿瘤的阻断 包裹治疗性货物的高度通用的纳米粒子与微环境的相互作用将提供重要的 抗肿瘤活性并增强当前 OC 治疗方案的疗效。因此我们将确定机制 TAM 调节并确定靶向 MMA/TAM 的生物学和治疗功效 在 OC 模型中以及通过应用数学模型来靶向双效 NP。