Linking tumor chemoresistance to TLR variants that mediate damage chain reaction

将肿瘤化疗耐药性与介导损伤链反应的 TLR 变异联系起来

• 批准号: 8385728
• 负责人: Nathalie Scholler
• 金额: $ 20.88万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-09 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8385728
• 关键词: Adjuvant Therapy; Agonist; Angiogenic Factor; Antigen Presentation; Antineoplastic Agents; Apoptosis; B-Lymphocytes; Binding; CD4 Positive T Lymphocytes; Cancer Patient; Carboplatin; Carcinogens; Cell Death; Cells; Chronic; Cisplatin; Clinic; Clinical; Clinical Data; Coculture Techniques; Data; Dendritic Cells; Development; Drug resistance; Drug usage; Endocytosis; Event; Exhibits; Genetic Polymorphism; Goals; Immune; Immune response; Immune system; Immunotherapy; In Vitro; In complete remission; Inflammation; Knockout Mice; Knowledge; Ligands; Link; Lymphocyte; Malignant Neoplasms; Malignant neoplasm of ovary; Malignant neoplasm of prostate; Measures; Mediating; Microtubules; Mission; Molecular; Outcome; Paclitaxel; Patients; Pattern; Pattern recognition receptor; Peripheral; Peripheral Blood Lymphocyte; Phagocytes; Pharmaceutical Preparations; Phenotype; Platinum Compounds; Play; Production; Public Health; Reaction; Regulatory T-Lymphocyte; Relapse; Reporting; Research; Resistance; Role; S100 Proteins; S100A8 gene; Screening for cancer; Screening procedure; Sequence Analysis; Serous; Signal Transduction; Single Nucleotide Polymorphism; Specimen; TLR3 gene; TLR4 gene; TLR7 gene; Testing; The Cancer Genome Atlas; Therapeutic; Tissues; Toll-like receptors; Translating; Variant; Work; anticancer treatment; base; cancer cell; cancer risk; cancer therapy; candidate marker; chemotherapy; cytokine; cytotoxicity; design; improved; innovation; macrophage; neoplastic; neoplastic cell; novel therapeutics; outcome forecast; ovarian neoplasm; pathogen; prevent; programs; response; standard care; success; therapeutic target; toll-like receptor 4; tumor; tumor growth; tumor immunology

DESCRIPTION (provided by applicant): Designing novel therapeutic strategies for ovarian cancer requires understanding chemoresistance molecular mechanisms. MyD88 plays a critical role in cancer. MyD88 knockout mice (MyD88-/-) are resistant to various carcinogen-induced cancers, and MyD88 expression correlates with negative survival of ovarian cancer patients. All Toll-like receptors (TLRs), but TLR3, signal through MyD88, which triggers the production of proinflammatory cytokines. TLRs are pattern recognition receptors (PRRs) that recognize both conserved pathogen-associated molecular patterns (PAMPs) and endogenous danger signals (DAMPs). TLR ligands have been used in clinics as immunostimulatory molecules in combination with anticancer treatments, but they can evoke either beneficial or deleterious effects. Reasons explaining these contradictory results include the binding of Paclitaxel, one of the main chemotherapeutic drugs used against ovarian cancer, to TLR4, and the existence of TLR4 variants linked with cancer risk. No link has been described as yet between TLR variants and ovarian cancer. Our long term goal is to develop personalized therapeutic strategies to prevent and/or overcome cancer chemoresistance. The objective of the studies herein is to identify TLR variants expressed by tumor-infiltrating immune cells that can mediate damage chain reaction after engagement by Paclitaxel and/or tumor-released DAMPs. Our central hypothesis is that chemotherapy can re-program tumor-infiltrating immune cells through the engagement of TLR variants by PAMPS and tumor-released DAMPs, leading to tumor rejection or chronic inflammation, damage chain reaction and chemoresistance, depending on the patients' TLR variants. The rationale is that the identification of TLR variants that promote tumor rejection or chronic inflammation in reaction to chemotherapy will permit to design personalized treatments and greatly improve patient prognosis. This hypothesis will be tested by pursuing two specific aims: 1) Identification of donors prone to damage chain reaction by screening peripheral blood lymphocytes for functional polymorphism in reaction to Paclitaxel and tumor-released DAMPs. Phenotype and functional changes of immune cells from 200 healthy donors will be characterized after co-culture with chemosensitive and chemoresistant ovarian tumor cells in presence of Paclitaxel; 2) [deletion of previous aim#2] Study of TLR snp association in serous ovarian cancer specimens that are linked to clinical data related to chemotherapy responses and clinical outcome. The approach is innovative because it proposes to examine ovarian cancer chemoresistance as a consequence of the specific engagement by Paclitaxel and tumor-released DAMPs to constitutive TLR variants on immune cells. This research is significant because, if successful, it will enable the design of personalized therapeutics targeted against DAMPs to block aberrant binding to TLR variants, thus chronic inflammation, therefore enabling patient responses to chemotherapeutic drugs. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because it proposes to identify constitutive molecular variants of toll-like receptors (TLR variants) that can be activated by tumor cell debris (DAMPs) generated by chemotherapeutic drugs, leading to chronic inflammation in the tumor microenvironment, tumor growth and chemoresistance. The project includes 1/ in vitro functional studies and TLR sequencing of immune cells from healthy donors to link TLR variants with DAMP-dependant functional polymorphisms, and 2/ [deletion of previous aim#2] identifications of TLR single-nucleotide polymorphisms linked to ovarian cancer chemoresistance using The Cancer Genome Atlas (NCI) bank. The proposed research is relevant to NIH's mission to developing fundamental knowledge that can translate into screening tests enabling cancer early detection and personalized anti-cancer therapy.

描述（由申请人提供）：设计卵巢癌的新型治疗策略需要了解化学抗性分子机制。 MyD88在癌症中起着至关重要的作用。 MyD88敲除小鼠（MYD88 - / - ）对各种致癌物癌的抗性，MyD88的表达与卵巢癌患者的阴性生存率相关。所有Toll样受体（TLR），但TLR3通过MyD88发出信号，这会触发促炎细胞因子的产生。 TLR是模式识别受体（PRR），它们既识别保守的病原体相关分子模式（PAMP）和内源性危险信号（湿度）。 TLR配体已在诊所中用作免疫刺激分子与抗癌治疗结合使用，但它们可以引起有益或有害作用。解释这些矛盾结果的原因包括紫杉醇是针对卵巢癌的主要化学治疗药物之一与TLR4的结合，以及与癌症风险相关的TLR4变体的存在。在TLR变体和卵巢癌之间尚未描述任何联系。我们的长期目标是制定个性化的治疗策略，以预防和/或克服癌症化学抗性。本文研究的目的是鉴定通过肿瘤浸润的免疫细胞表达的TLR变体，这些变体可以介导紫杉醇和/或肿瘤释放的潮湿后介导损伤链反应。我们的中心假设是，化学疗法可以通过PAMP和肿瘤释放的湿度参与TLR变体来重新编程肿瘤浸润的免疫细胞，从而导致肿瘤排斥或慢性炎症，损伤链链反应和化学抗性，取决于患者的TLR变体。理由是鉴定促进肿瘤的TLR变体 对化学疗法的反应反应或慢性炎症将允许设计个性化治疗方法并大大改善患者的预后。该假设将通过追求两个具体目的来检验：1）供体鉴定容易损害链反应的供体，通过筛选外周血淋巴细胞，以使功能性多态性对紫杉醇和肿瘤释放的潮湿的反应。在紫杉醇存在下与化学敏感和化学敏感性的卵巢肿瘤细胞共培养后，将对来自200个健康供体的免疫细胞的表型和功能变化进行表征。 2）[删除先前的目标＃2] TLR SNP关联的浆液卵巢癌标本研究研究与与化学疗法反应和临床结果有关的临床数据相关。该方法具有创新性，因为它建议由于紫杉醇和肿瘤释放的潮湿对免疫细胞的组成型TLR变体的特定参与而检查卵巢癌化学抗性。这项研究很重要，因为如果成功，它将能够设计针对湿的个性化治疗剂，以阻止与TLR变体的异常结合，从而慢性炎症，从而使患者对化学治疗药物的反应。 公共卫生相关性：拟议的研究与公共卫生有关，因为它建议识别可以构成类似收费的受体（TLR变体）的分子变体 被化学治疗药物产生的肿瘤细胞碎屑（湿）激活，导致肿瘤微环境，肿瘤生长和化学抗性的慢性炎症。该项目包括1/体外功能研究和来自健康供体的免疫细胞的TLR测序，将TLR变体与抑制依赖性功能多态性联系起来，以及使用卵巢癌化学量cantlas（NCI）（NCI）（NCI）链接的TLR单核苷酸多态性的TLR单核苷酸多态性的鉴定。拟议的研究与NIH的使命是发展基本知识的使命，这些知识可以转化为筛查测试，从而使癌症早期发现和个性化的抗癌治疗。