Defining Mechanisms of Progression and Treatment Resistance in Localized Bladder Cancer

局限性膀胱癌进展和治疗耐药的定义机制

基本信息

批准号：
10567452
负责人：
Eugene Pietzak
金额：
$ 51.42万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-12-01 至 2027-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10567452
关键词：
Acute Adjuvant Chemotherapy Antibody-drug conjugates BCG Live Bacillus Calmette-Guerin Therapy Bladder Bladder Neoplasm Cancer Patient Cell Separation Chemoresistance Cisplatin Clinical Clinical Research Clinical Trials Cystectomy Cytotoxic Chemotherapy DNA Damage Data Dependence Diagnosis Disease Disease Progression ERBB2 gene ERCC2 gene Frequencies Funding Gene Amplification Gene Mutation Genes Genetic Genomics Goals Heterogeneity Immunotherapy Laboratory Study Malignant Neoplasms Malignant neoplasm of urinary bladder Mediator Modality Modeling Molecular Molecular Profiling Molecular Target Multi-Institutional Clinical Trial Muscle Mutation Neoadjuvant Therapy Nucleotide Excision Repair Oncogenic Oncology Operative Surgical Procedures Organoids Outcome Pathogenesis Pathway interactions Patients Platinum Protein Overexpression Radical Cystectomy Recurrence Recurrent disease Research Resistance Risk Reduction Role Sampling Secondary to Somatic Mutation Testing Urine Xenograft Model biobank cancer cell cell free DNA chemotherapy cohort curative treatments exome sequencing genomic profiles high risk intravesical muscle invasive bladder cancer mutational status new therapeutic target non-muscle invasive bladder cancer novel overexpression patient subsets pre-clinical predicting response prevent progression risk prospective response therapy development therapy resistant translational goal treatment response treatment strategy tumor tumor heterogeneity

项目摘要

Defining Mechanisms of Progression and Treatment Resistance in Localized Bladder Cancer PI: Eugene Pietzak, MD SUMMARY Our overall goal is to develop therapies that selectively target molecular alterations responsible for progression of bladder cancers from non-invasive to the often-lethal muscle-invasive disease state. For patients with non- muscle invasive bladder cancer (NMIBC), the current standard is bacillus Calmette-Guérin (BCG), a nonspecific immunotherapy instilled directly into the bladder lumen. While BCG can reduce the risk of disease recurrence, a proportion of patients subsequently progress to muscle-invasive bladder cancer (MIBC). Our preliminary results indicate that this disease state, termed “secondary MIBC”, is resistant to cisplatin-based chemotherapy. The goals in the current proposal are to understand the genomic basis for treatment resistance to BCG and to identify alternative molecularly directed treatments that can achieve disease cure without the need for radical surgery. The studies proposed are based on preliminary data indicating that cytotoxic chemotherapy sensitivity in bladder cancer is influenced by somatic and germline genomic profiles, in particular mutations in DNA damage response (DDR) pathway genes, most commonly within the nucleotide excision repair gene ERCC2. As our preliminary data suggest that mutations in DDR pathway genes may also confer sensitivity to BCG, we hypothesize that prior treatment with BCG results in cross-resistance to subsequent systemic chemotherapy. To test this hypothesis, we will leverage several prospectively assembled bladder cancer cohorts, including tumor pairs collected pre-BCG and following progression to MIBC. These cohorts will be used to validate DDR mutations as predictors of BCG and cisplatin-based chemotherapy sensitivity and to identify mechanisms of progression from NMIBC to secondary MIBC. As genomic heterogeneity is common in bladder cancer, we will supplement bulk sequencing studies with multi-regional sequencing and analysis of cell-free DNA from urine to define the influence of tumor heterogeneity on cancer outcomes in early-stage bladder cancer. Our preliminary analyses of high-risk NMIBC and secondary MIBC have also identified ERBB2 mutations/amplifications as potential mediators of progression to muscle-invasive disease. Several unique patient cohorts will be used to define the frequency of ERBB2 mutation/ amplification and HER2 overexpression in high-risk NMIBC and secondary MIBC. Prior functional studies of the role of HER2 in bladder cancer pathogenesis have been impeded by a lack of patient-derived models with ERBB2 mutations and gene amplification. We will thus leverage a recently developed biobank of patient-derived organoid models containing ERBB2 mutation/amplification to study the associations between ERBB2 mutational status/HER2 expression, oncogenic dependence on HER2, and sensitivity to HER2-directed antibody drug conjugate therapy, a promising breakthrough therapy for metastatic bladder cancer. In sum, our long-term translational goals are to use integrated clinical and laboratory studies to develop more effective and less toxic treatments for patients with localized bladder cancer, a frequently fatal yet understudied disease.

局限性膀胱癌进展和治疗耐药的定义机制 PI：Eugene Pietzak，医学博士概括我们的总体目标是开发选择性靶向导致进展的分子改变的疗法膀胱癌从非侵袭性到常常致命的肌肉侵袭性疾病状态。肌层浸润性膀胱癌（NMIBC），目前的标准是卡介苗（BCG），一种非特异性免疫疗法直接注入膀胱腔，而卡介苗可以降低患病风险。复发后，一部分患者随后进展为肌层浸润性膀胱癌（MIBC）。初步结果表明，这种称为“继发性 MIBC”的疾病状态对基于顺铂的药物具有耐药性当前提案的目标是了解治疗耐药性的基因组基础。 BCG 并确定替代的分子定向治疗方法，无需使用 BCG 即可实现疾病治愈拟议的研究基于表明细胞毒性的初步数据。膀胱癌的化疗敏感性受到体细胞和种系基因组图谱的影响， DNA 损伤反应 (DDR) 途径基因中的特定突变，最常见于核苷酸内我们的初步数据表明，DDR 通路基因的突变也可能是切除修复基因 ERCC2。赋予对 BCG 的敏感性，我们勇敢地承认先前使用 BCG 治疗会导致交叉耐药性为了检验这一假设，我们将利用几种前瞻性组合。膀胱癌队列，包括 BCG 前和进展为 MIBC 后收集的肿瘤对。队列将用于验证 DDR 突变作为 BCG 和顺铂化疗的预测因子敏感性并确定从 NMIBC 进展为继发性 MIBC 的机制。异质性在膀胱癌中很常见，我们将通过多区域的批量测序研究来补充对尿液中的游离 DNA 进行测序和分析，以确定肿瘤异质性对癌症的影响我们对高风险 NMIBC 和继发性 MIBC 的初步分析。还发现 ERBB2 突变/扩增是进展为肌肉侵袭性的潜在介质几个独特的患者队列将用于定义 ERBB2 突变/扩增的频率。以及 HER2 过度表达在高危 NMIBC 和继发性 MIBC 中的作用的先前功能研究。由于缺乏源自患者的 ERBB2 模型，HER2 在膀胱癌发病机制中的作用受到阻碍因此，我们将利用最近开发的源自患者的生物库。含有 ERBB2 突变/扩增的类器官模型，用于研究 ERBB2 之间的关联突变状态/HER2 表达、对 HER2 的致癌依赖性以及对 HER2 导向的敏感性抗体药物结合疗法是转移性膀胱癌的一种有希望的突破性疗法。长期转化目标是利用综合临床和实验室研究来开发更有效的对局部膀胱癌患者进行毒性较小的治疗，这是一种经常致命但尚未得到充分研究的疾病。