Biomarker guided combinations for treating high-risk bladder cancer

膀胱癌(BC)是一种常见的尿道癌。而低级别肿瘤有很好的 预后：三分之二的高级别BC患者的肿瘤侵犯膀胱壁肌肉或更远 (MIBC)。MIBC患者有很高的转移风险、显著的发病率和死亡率。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 (新辅助剂)以降低肿瘤的阶段和治疗微转移。然而，这些患者中有一半发展为 两年内转移。虽然免疫疗法被批准用于治疗，但应答率为~25%， 化疗仍是主要治疗手段。以吉西他滨(Gem)为基础的联合治疗用于 新佐剂，以及更好的耐受性的佐剂/补救设置。基于宝石的顺序膀胱灌注术是 越来越多地被用于延迟/预防高级别非MIBC(NMIBC)患者的复发。然而， 创业板组合是经验性的，并非没有毒性，很少有人考虑创业板的抗性。这项研究的目标是 评估两种基于证据的Gem组合改善NMIBC和MIBC患者的预后。 Chase是人类第一个从蛋白多糖中分离出硫酸软骨素的药物。蔡斯是 已发现可促进膀胱肿瘤的发生、肿瘤的生长、转移和对GEM的耐药性。大通银行及其相关业务 诱导GEM耐药的分子信号通路在膀胱癌标本中表达。我们发现 两个具有良好特征的化合物具有克服Chase诱导的宝石抗性的潜力。而另一个 化合物抑制Chase活性，另一种化合物抑制其下游信号通路。宝石的组合 任何一种化合物都会使Gem耐药的临床前BC模型对Gem重新敏化。该项目旨在测试 一种假说，认为抑制Chase或其信号可以消除对Gem的抗性。此外，该发展 宝石与一种或两种化合物的组合以及Chase和Chase信号转导的评价 用于预测对基于Gem的治疗的反应，将使这些组合的临床翻译成为可能 晚期BC的治疗。在BC模型中，我们将研究消融Chase-的分子机制。 这两种化合物(Chase或Chase信号的抑制剂)中的任何一种都能诱导Gem抗性(目标1)。我们 将评估Chase相关分子以预测治疗反应，优化组合的剂量和 验证其良好的耐受性和靶向性(目标2)。我们将使用高级BC和患者派生的 建立异种移植模型，比较Gem与每种化合物结合的效果，以及与现有的Gem-Gem-Gem的结合效果。 以治疗为基础(目标3)。 影响：很少有研究评估GEM耐药性，以及如何克服它。基于证据的评价 靶向Chase诱导的宝石抗性的新组合，以及Chase相关分子作为预测因子 对基于宝石的治疗的反应，应该表明哪种组合更好，谁可以接受它。

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.