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

• 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
• 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

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。虽然低级别肿瘤有良好的 预后方面，三分之二的高级别BC患者的肿瘤侵犯膀胱壁肌肉及其他部位 （MIBC）。患有MIBC的患者具有高转移风险、显著的发病率和死亡率。膀胱切除 （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）以降低肿瘤的分期并治疗微转移。然而，这些患者中有一半会发展为 两年内转移。虽然免疫疗法被批准用于治疗，但应答率约为25%， 剩下化疗作为主要治疗手段。基于吉西他滨（Gem）的联合治疗用于治疗 新辅助治疗和辅助/挽救治疗以获得更好的耐受性。基于GEM的连续膀胱灌注是 越来越多地用于延迟/预防高级别非MIBC（NMIBC）患者的复发。然而，在这方面， 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。本研究的目的是 评价两种循证Gem联合治疗改善NMIBC和MIBC患者的结局。 Chase是人类中第一种将硫酸软骨素从蛋白聚糖中切割出来的药物。蔡斯是 发现其驱动膀胱肿瘤发生、肿瘤生长、转移和Gem抗性。Chase及其 诱导Gem抗性的分子信号传导途径在膀胱肿瘤标本中表达。我们发现 两个充分表征的化合物具有克服Chase诱导的Gem抗性的潜力。而一个 化合物抑制Chase活性，另一种抑制其下游信号通路。宝石组合 用任一化合物使GEM抗性临床前BC模型对GEM再致敏。该项目旨在测试 抑制Chase或其信号传导消除Gem抗性的假设。此外，发展 与一种或两种化合物的Gem组合，以及Chase和Chase信号传导的评估 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， 通过两种化合物中的任一种（Chase或Chase信号传导的抑制剂）诱导Gem抗性（目的1）。我们 将评估Chase相关分子以预测治疗反应，优化组合的剂量， 验证其良好的耐受性和靶点特异性（目标2）。我们将使用先进的BC和患者衍生的 异种移植模型，以比较Gem与每种化合物的组合以及与当前Gem的组合的功效。 基础治疗（目标3）。 影响：很少有研究评估Gem耐药性，以及如何克服它。 靶向Chase诱导的Gem抗性的新组合，以及Chase相关分子作为 对基于宝石的治疗的反应，应该揭示哪种组合更上级以及谁可以接受它。