Biomarker guided combinations for treating high-risk bladder cancer

生物标志物引导的组合治疗高危膀胱癌

基本信息

批准号：
10718874
负责人：
Vinata B Lokeshwar
金额：
$ 55.7万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-05 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10718874
关键词：
Ablation Address Adjuvant Adjuvant Chemotherapy Advanced Malignant Neoplasm Biological Markers Bladder Bladder Neoplasm CD44 gene Cancer Model Chemoresistance Chemotherapy-Oncologic Procedure Chondroitin Sulfate Proteoglycan Chondroitin Sulfates Chondroitinases Cisplatin Clinic Clinical Clip Combined Modality Therapy Cystectomy Cytidine Deaminase Development Dose Drug Kinetics Enzymes Evaluation Evidence based treatment Excision FDA approved Failure Goals Human Immunocompetent Immunotherapy Interstitial Cystitis Intravesical Instillation JAK2 gene Malignant neoplasm of urinary bladder Mediating Micrometastasis Modeling Molecular Morbidity - disease rate Multicenter Studies Mus Muscle Myelofibrosis Neoadjuvant Therapy Neoplasm Metastasis Operative Surgical Procedures Oral Outcome Pathway interactions Patients Pentosan Polysulfate Pharmaceutical Preparations Prediction of Response to Therapy Prognosis Radical Cystectomy Recurrence Recurrent Malignant Neoplasm Resistance STAT3 gene Serum Signal Pathway Signal Transduction Specificity Specimen Testing Tissues Toxic effect Transgenic Model Translating Treatment Failure Tumor Cell Invasion Up-Regulation Urologic Cancer Xenograft procedure cancer cell cancer recurrence chemotherapy clinical translation comparative efficacy design docetaxel drug repurposing evidence base gemcitabine high risk improved improved outcome inhibitor intravesical mortality mouse model muscle invasive bladder cancer mutant novel patient derived xenograft model pre-clinical predicting response prevent public health relevance response response biomarker standard care tumor tumor growth tumorigenesis

项目摘要

Bladder cancer (BC) is a common cancer of the urinary tract. While low-grade tumors have a good prognosis, two-thirds of patients with high-grade BC have tumors invading the bladder wall muscle and beyond (MIBC). Patients with MIBC are at high-risk for metastasis, significant morbidity, and mortality. Cystectomy (bladder removal) is the primary treatment for MIBC. Many patients with MIBC receive treatment before surgery (neoadjuvant) to downstage the tumor and to treat micrometastases. However, half of these patients develop metastasis within two years. Although immunotherapy is approved for treatment, the response rate is ~ 25%, leaving chemotherapy as the main treatment. Gemcitabine (Gem)-based combination treatments are used in the neoadjuvant, and adjuvant/salvage settings for better tolerability. Sequential Gem-based bladder instillations are increasingly being used to delay/prevent recurrence in patients with high-grade non-MIBC (NMIBC). However, Gem combinations are empirical, not without toxicity and few consider Gem-resistance. The goal of this study is to evaluate two evidence-based Gem combinations to improve outcome in patients with NMIBC and MIBC. Chase is the first of its kind in humans that cleaves chondroitin sulfate from proteoglycans. Chase was discovered to drive bladder tumorigenesis, tumor growth, metastasis, and Gem resistance. Chase and its molecular signaling pathway that induces Gem resistance are expressed in bladder tumor specimens. We found two well-characterized compounds with potential to overcome Chase-induced Gem resistance. While one compound inhibited the Chase activity, another inhibited its downstream signaling pathway. Combination of Gem with either compound re-sensitized Gem-resistant pre-clinical BC models to Gem. The project is designed to test the hypothesis that inhibition of Chase or its signaling abolishes Gem resistance. Furthermore, the development of Gem combinations with one or both compounds, together with the evaluation of Chase and Chase-signaling for predicting response to Gem-based treatments, will enable the clinical translation of these combinations for the treatment of advanced BC. In BC models, we will investigate the molecular mechanism of ablating Chase- induced Gem resistance by either of the two compounds (inhibitor of Chase or of Chase-signaling) (Aim 1). We will evaluate Chase-related molecules to predict treatment response, optimize the dose of the combinations and validate their favorable tolerability and target specificity (Aim 2). We will use advanced BC and patient-derived xenograft models to compare the efficacy of Gem combination with each compound and with the current Gem- based treatments (Aim 3). Impact: Few studies have evaluated Gem resistance, and how to overcome it. Evaluation of evidenced-based novel combinations that target Chase-induced Gem resistance, and of Chase-related molecules as predictors of response to Gem-based treatments, should reveal which combination is superior and who could receive it.

膀胱癌（BC）是一种常见的泌尿道癌症。虽然低级别肿瘤具有良好的预后，三分之二的高级别 BC 患者肿瘤侵犯膀胱壁肌肉及以上（MIBC）。 MIBC 患者具有高转移风险、显着的发病率和死亡率。膀胱切除术（膀胱切除）是 MIBC 的主要治疗方法。许多 MIBC 患者在手术前接受治疗（新辅助）使肿瘤降期并治疗微转移。然而，这些患者中有一半会出现两年内发生转移。尽管免疫疗法被批准用于治疗，但缓解率约为 25%，留下化疗作为主要治疗方法。基于吉西他滨 (Gem) 的联合治疗用于新辅助和辅助/挽救设置以获得更好的耐受性。基于宝石的顺序膀胱灌注是越来越多地用于延迟/预防高级别非 MIBC (NMIBC) 患者的复发。然而，宝石组合是经验性的，并非没有毒性，很少有人考虑宝石抗性。本研究的目标是评估两种基于证据的 Gem 组合以改善 NMIBC 和 MIBC 患者的预后。 Chase 是第一个在人类中从蛋白聚糖中裂解硫酸软骨素的公司。蔡斯是被发现可促进膀胱肿瘤发生、肿瘤生长、转移和 Gem 耐药性。大通及其诱导 Gem 抗性的分子信号通路在膀胱肿瘤标本中表达。我们发现两种特征良好的化合物有可能克服 Chase 引起的 Gem 耐药性。虽然一化合物抑制Chase活性，另一种化合物抑制其下游信号通路。宝石组合使用任一化合物使 Gem 抗性临床前 BC 模型对 Gem 重新敏感。该项目旨在测试抑制 Chase 或其信号传导可消除 Gem 抗性的假设。此外，发展与一种或两种化合物的宝石组合，以及 Chase 和 Chase 信号的评估用于预测对基于 Gem 的治疗的反应，将使这些组合的临床转化成为可能晚期 BC 的治疗。在BC模型中，我们将研究消融Chase-的分子机制。通过两种化合物（Chase 或 Chase 信号抑制剂）中的任何一种诱导 Gem 抗性（目标 1）。我们将评估 Chase 相关分子以预测治疗反应、优化组合剂量以及验证其良好的耐受性和目标特异性（目标 2）。我们将使用先进的 BC 和源自患者的异种移植模型，用于比较 Gem 组合与每种化合物以及当前 Gem-的功效基础治疗（目标 3）。影响：很少有研究评估宝石抵抗力以及如何克服它。循证评估针对 Chase 诱导的 Gem 抗性的新颖组合，以及作为预测因子的 Chase 相关分子对基于宝石的治疗的反应，应该揭示哪种组合更优越以及谁可以接受它。