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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.

局限性膀胱癌进展机制及耐药机制的研究少年派：尤金·皮塔扎克，医学博士摘要我们的总体目标是开发有选择性地针对导致疾病进展的分子改变的治疗方法。从非侵袭性膀胱癌到通常致命的肌肉浸润性疾病。适用于患有非肌肉浸润性膀胱癌(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时，部分患者随后进展为肌肉浸润性膀胱癌(MIBC)。我们的初步结果表明，这种称为“继发性MIBC”的疾病状态对以顺铂为基础的药物具有耐药性。化疗。当前提案的目标是了解治疗耐药的基因组基础卡介苗，并找出替代的分子导向疗法，可以实现疾病治愈而不需要需要做根治性手术。建议的研究是基于初步数据表明细胞毒性膀胱癌的化疗敏感性受体细胞和生殖系基因组图谱的影响 DNA损伤反应(DDR)途径基因的特殊突变，最常见的是核苷酸内切除修复基因ERCC2。因为我们的初步数据表明，DDR途径基因的突变也可能关于卡介苗的敏感性，我们假设之前用卡介苗治疗会导致对随后的全身化疗。为了检验这一假设，我们将利用几个预期组装的膀胱癌队列，包括BCG前和进展到MIBC后收集的肿瘤对。这些将使用队列来验证DDR突变作为BCG和基于顺铂的化疗的预测因子并确定从NMIBC向继发性MIBC进展的机制。作为基因组异质性在膀胱癌中很常见，我们将用多区域来补充批量测序研究尿液中无细胞DNA测序和分析以确定肿瘤异质性对癌症的影响早期膀胱癌的预后。我国高危NMIBC与继发性MIBC的初步分析还发现ERBB2突变/扩增是肌肉侵袭性进展的潜在媒介疾病。将使用几个独特的患者队列来确定ERBB2突变/扩增的频率 HER2在高危NMIBC和继发性MIBC中高表达。前人对其作用的功能研究由于缺乏患者来源的ERBB2模型，HER2在膀胱癌发病机制中的作用受到阻碍突变和基因扩增。因此，我们将利用最近开发的患者来源的生物库含有ERBB2突变/扩增的有机模型研究ERBB2与突变状态/HER2表达、对HER2的致癌依赖性和对HER2的敏感性抗体药物结合疗法，转移性膀胱癌的一种有希望的突破性疗法。总而言之，我们的长期的翻译目标是使用综合的临床和实验室研究来开发更有效的对局限性膀胱癌患者的毒性较低的治疗，这是一种经常致命但研究不足的疾病。