BCG therapy of bladder cancer: the role of BCG uptake by bladder cancer cells

BCG 治疗膀胱癌：膀胱癌细胞摄取 BCG 的作用

• 批准号: 9128679
• 负责人: Gil Redelman-Sidi
• 金额: $ 17.77万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-16 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9128679
• 关键词: Advisory Committees; Bacteria; Biological Assay; Biological Response Modifier Therapy; Bladder; Bladder Neoplasm; Cancer Biology; Cancer Model; Cell Cycle Regulation; Cell Line; Cells; Characteristics; Clinical; Clinical Research; Clinical Trials; Cultured Cells; Development; Excision; Genes; Genetic; Goals; Immune system; Immunology; Implant; Individual; Infection; Intravesical Instillation; Invaded; Laboratories; Lead; Life; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Memorial Sloan-Kettering Cancer Center; Methods; Mus; Muscle; Mutation; Oncogenic; PTEN gene; Pathway interactions; Patients; Physicians; Protein-Serine-Threonine Kinases; Recombinants; Recurrence; Research Personnel; Residual Tumors; Resistance; Risk; Role; Safety; Scientist; Series; Signal Transduction; Specificity; Staging; Technical Expertise; Testing; Training; Training Programs; Translating; Treatment Efficacy; Tuberculosis; Vaccines; arm; assay development; base; cancer cell; career; improved; in vivo Model; interest; intravesical; knowledge base; meetings; microbial; mouse model; mutant; mycobacterial; overexpression; personalized care; practical application; public health relevance; response; symposium; transposon site hybridization; treatment response; tumor; tumor progression; uptake; whole genome

 DESCRIPTION (provided by applicant): The candidate, Gil Redelman-Sidi, a physician-scientist in Memorial Sloan Kettering Cancer Center with a clinical and research interest in the interface between infection and cancer, seeks to achieve a career as a researcher in the field of the treatment of bladder cancer with microbial biotherapies. This proposal describes a 5-year training program that will provide the candidate with the knowledge base and technical skills necessary to achieve this goal. In addition to intensive laboratory-based experimental training, the training program will include regular meetings with an advisory committee of experts in the relevant fields, active involvement in conferences and meetings, and formal didactics that will include a full course in cell signaling and development, cell cycle control, immunology and cancer biology. At the end of the period of support, the candidate will be poised to undertake a career as an independent physician-scientist. This revised proposal focuses on the mechanisms of action of BCG for the treatment of bladder cancer, one of the most common cancers worldwide. The standard therapy for patients with early-stage bladder cancer (not invading the muscular layer of the bladder wall) is tumor resection followed by bladder instillation therapy with BCG, a live bacterium originally developed as a vaccine against tuberculosis. BCG effectively eradicates residual tumor and lowers risk of recurrence. Nevertheless, bladder cancer recurs or progresses in over a third of BCG-treated patients. Despite being in use for nearly four decades, the mechanism by which BCG acts remains poorly understood, and there is no way to reliably predict clinical response. Bladder cancer cells can internalize BCG, but until recently the pathway of uptake was not known. The candidate has shown that this pathway is macropinocytosis. Furthermore, the candidate has shown that the ability of bladder cancer cells to internalize BCG depends on the presence of certain oncogenic (tumor- causing) mutations. Recently, the candidate, through a series of whole-genome screens, has identified numerous additional genes, in bladder cancer cells and in BCG, that determine the internalization or survival of BCG in bladder cancer cells. In this project, the candidate will extend these prior findings to an in vivo model of bladder cancer progression and BCG response. The specific aims are as follows: (1) Establish the relationship between BCG internalization by bladder cancer cells and clinical response to BCG therapy in murine models of bladder cancer by testing clinical response to BCG therapy in mice implanted with tumors in which pathways implicated in macropinocytotic BCG uptake, including the Wnt pathway (identified in our whole-genome screens as stimulating BCG uptake and involved in macropinocytosis), have been manipulated through genetic or pharmacologic means. (2) Test, in cultured cells and in the murine bladder cancer model, response to recombinant BCG strains lacking or overexpressing the serine/threonine protein kinases pknG and pknL, both of which we have identified as determinants of BCG uptake and/or survival within bladder cancer cells. If successful, this project could lead to clinical trials in patients receiving BCG for bladder cancer Potential clinical benefits of these studies include: (1) development of assays to predict a patient's response to BCG therapy based on phenotypic or genotypic characteristics of his/her tumor; testing methods to improve BCG efficacy, including (2) through co-administration of BCG with pharmacologic agents that increase its uptake by bladder cancer cells and (3) by constructing recombinant BCG strains with improved therapeutic efficacy and improved safety.

 申请者描述：候选人Gil Redelman-Sidi是纪念斯隆-凯特琳癌症中心的内科科学家，对感染和癌症之间的接口具有临床和研究兴趣，希望成为一名使用微生物生物疗法治疗膀胱癌领域的研究人员。这份建议书描述了一个为期5年的培训计划，该计划将为应聘者提供实现这一目标所需的知识基础和技术技能。除了密集的实验室实验培训外，培训计划还将包括与相关领域专家咨询委员会的定期会议，积极参与各种会议，以及正式的教学，其中将包括细胞信号与发育、细胞周期控制、免疫学和癌症生物学的完整课程。在支持期结束时，候选人将作为一名独立的内科科学家从事职业生涯。这项修订后的提案侧重于卡介苗治疗膀胱癌的作用机制，膀胱癌是世界上最常见的癌症之一。对早期膀胱癌(不侵犯膀胱壁肌肉层)患者的标准治疗方法是肿瘤切除，然后用卡介苗进行膀胱灌注治疗，卡介苗是一种活细菌，最初是作为结核病疫苗开发的。卡介苗可有效根除残留肿瘤，降低复发风险。然而，在接受卡介苗治疗的患者中，超过三分之一的患者膀胱癌复发或进展。尽管已经使用了近40年，但卡介苗的作用机制仍然知之甚少，也没有办法可靠地预测临床反应。膀胱癌细胞可以内化卡介苗，但直到最近，摄取的途径还不清楚。候选人已经证明，这一途径是巨噬细胞吞噬作用。此外，候选人还表明，膀胱癌细胞内化卡介苗的能力取决于某些致癌(致癌)突变的存在。最近，这位候选人通过一系列全基因组筛选，在膀胱癌细胞和卡介苗中发现了许多其他基因，这些基因决定了卡介苗在膀胱癌细胞中的内化或存活。在这个项目中，候选人将把这些先前的发现扩展到膀胱癌进展和卡介苗反应的体内模型。具体目的如下：(1)在小鼠膀胱癌模型中，通过测试卡介苗对移植瘤小鼠的临床疗效，建立卡介苗被膀胱癌细胞内化与临床疗效之间的关系。在这些肿瘤中，参与大吞噬卡介苗摄取的通路，包括Wnt通路(在我们的全基因组筛选中被确定为刺激卡介苗摄取，参与巨饮细胞吞噬)已通过遗传学或药理学手段进行操纵。(2)在培养细胞和小鼠膀胱癌模型中，检测重组卡介苗缺乏或过度表达丝氨酸/苏氨酸蛋白激酶pKNG和pKNL的反应，我们已经确定这两个基因都是BCG摄取和/或在膀胱癌细胞内存活的决定因素。如果成功，该项目可能会导致对接受卡介苗治疗膀胱癌的患者进行临床试验这些研究的潜在临床好处包括：(1)开发根据患者肿瘤的表型或基因特征预测其对卡介苗治疗反应的分析方法；(2)通过与增加膀胱癌细胞摄取卡介苗的药理物质联用来提高卡介苗的疗效的测试方法；(3)通过构建具有更高疗效和更高安全性的重组卡介苗菌株。