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）是尿路的常见癌症。低级肿瘤的良好 预后，三分之二的公元前患者有肿瘤侵入膀胱壁肌肉及以后 （MIBC）。 MIBC患者处于高危转移，明显的发病率和死亡率的高风险。膀胱切除术 （去除膀胱）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）以下降肿瘤并处理微转移。但是，其中一半的患者发展 转移两年内。尽管免疫疗法被批准用于治疗，但缓解率为约25％， 将化学疗法作为主要疗法。吉西他滨（GEM）基于基于GEM的组合治疗在 新辅助和辅助/打捞设置，可更好地耐受性。基于宝石的顺序膀胱灌输是 越来越多地用于延迟/预防高级非MIBC（NMIBC）患者的复发。然而， 宝石的组合是经验的，并非没有毒性，很少有人考虑耐宝石。这项研究的目的是 评估两种基于证据的GEM组合以改善NMIBC和MIBC患者的预后。 Chase是人类中第一个从蛋白聚糖中裂解硫酸软骨素的人。蔡斯是 被发现是为了驱动膀胱肿瘤发生，肿瘤生长，转移和宝石耐药性。追逐及其 诱导GEM耐药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，具有克服追逐诱导的宝石抗性的潜力。而一个 化合物抑制了追逐活性，另一种抑制其下游信号通路。宝石的组合 两种化合物重新敏感的宝石前临床前BC模型都可以将其添加到宝石上。该项目旨在测试 抑制追逐或其信号传导的假设消除了宝石的抗性。此外，发展 与一种或两种化合物的宝石组合以及追逐和追逐信号的评估 为了预测对基于宝石的疗法的反应，将使这些组合的临床翻译能够 卑诗省晚期的处理。在卑诗省模型中，我们将研究消融追逐的分子机制 两种化合物中的任何一种（Chase或Chase-Signaling的抑制剂）诱导的GEM抗性（AIM 1）。我们 将评估追逐相关的分子以预测治疗反应，优化组合剂量和 验证其有利的耐受性和目标特异性（AIM 2）。我们将使用高级卑诗省和患者来源 异种移植模型将GEM组合与每种化合物的功效以及当前的宝石进行比较 基于治疗方法（目标3）。 影响：很少有研究评估了GEM耐药性以及如何克服它。基于证据的评估 靶向追逐诱导的宝石抗性的新型组合以及与追逐相关的分子作为预测指标 对基于宝石的疗法的反应应揭示哪种组合优越并可以接受。