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: 8928080
• 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/8928080
• 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; Genome; 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; Modeling; 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; Testing; Therapeutic; 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; mutant; mycobacterial; overexpression; personalized care; practical application; public health relevance; response; skills; symposium; transposon site hybridization; tumor; tumor progression; uptake

 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.

 描述（由申请人提供）：候选人Gil Redelman-Sidi是Memorial Sloan Kettering癌症中心的医生兼科学家，对感染和癌症之间的界面有临床和研究兴趣，旨在实现作为微生物生物疗法治疗膀胱癌领域的研究人员的职业生涯。本建议书描述了一个为期5年的培训计划，该计划将为候选人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的专家咨询委员会定期举行会议，积极参与会议和正式教学，包括细胞信号传导和发育，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，候选人将准备作为一名独立的医生科学家从事职业生涯。 该修订提案的重点是BCG治疗膀胱癌（全球最常见的癌症之一）的作用机制。早期膀胱癌（不侵犯膀胱壁的肌肉层）患者的标准治疗是肿瘤切除术，然后用BCG膀胱灌注治疗，BCG是一种最初作为结核疫苗开发的活细菌。BCG可有效根除残留肿瘤，降低复发风险。然而，超过三分之一的BCG治疗患者的膀胱癌复发或进展。尽管使用了近40年，BCG的作用机制仍然知之甚少，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，但直到最近才知道其摄入途径。候选人已经表明，这一途径是巨胞饮。此外，候选人已经表明，膀胱癌细胞内化BCG的能力取决于某些致癌（肿瘤引起）突变的存在。最近，通过一系列全基因组筛选，候选人已经在膀胱癌细胞和BCG中确定了许多其他基因，这些基因决定了BCG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BCG反应的体内模型。具体目标如下：（1）在膀胱癌的鼠模型中，通过在植入肿瘤的小鼠中测试对BCG疗法的临床应答，建立BCG被膀胱癌细胞内化与对BCG疗法的临床应答之间的关系，其中所述肿瘤中涉及巨胞饮BCG摄取的途径，包括Wnt途径（在我们的全基因组筛选中鉴定为刺激BCG摄取并参与巨胞饮作用），已经通过遗传或药理学手段进行了操作。(2)在培养的细胞和鼠膀胱癌模型中，测试对缺乏或过表达丝氨酸/苏氨酸蛋白激酶pknG和pknL的重组BCG菌株的反应，我们已经确定这两种激酶是膀胱癌细胞内BCG摄取和/或存活的决定因素。 这些研究的潜在临床益处包括：（1）开发基于患者肿瘤的表型或基因型特征预测患者对BCG治疗的反应的测定;测试方法以提高卡介苗的功效，包括（2）通过BCG与增加其被膀胱癌细胞摄取的药理学试剂的共同施用，和（3）通过构建具有改善的治疗功效和改善的安全性的重组BCG菌株。