PREVENT CANCER PRECLINICAL DRUG DEVELOPMENT PROGRAM: PRECLINICAL EFFICACY AND ENDPOINT BIOMARKERS. TASK ORDER TITLE: URINARY BLADDER CANCER PREVENTIO

预防癌症临床前药物开发计划：临床前疗效和终点生物标志物。

• 批准号: 10269136
• 负责人: Chinthalapally V. Rao
• 金额: $ 78.52万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-21 至 2022-09-20
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10269136
• 关键词: Adverse effects; American Cancer Society; Anti-Inflammatory Agents; Biological Markers; Bladder; Bladder Neoplasm; Cancer Model; Carcinogens; Carcinoma in Situ; Chemopreventive Agent; Clinical; Development; Disease; Dose; FDA approved; FRAP1 gene; Generations; Genetic Transcription; Goals; Inflammation; Intercept; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Modeling; Muscle; Mutation; Naproxen; Neoplasm Metastasis; New Agents; Non-Steroidal Anti-Inflammatory Agents; Normal tissue morphology; Organ; PI3K/AKT; Pathway interactions; Phase; Play; Preclinical Drug Development; Prevention; Preventive; Program Development; Rattus; Regimen; Research; Resistance; Risk; Role; SDZ RAD; Sampling; Schedule; Testing; Therapeutic; Time; Toxic effect; Travel; United States; United States Food and Drug Administration; advanced breast cancer; bladder cancer prevention; cancer cell; cancer therapy; clinical development; clinical translation; clinically relevant; drug development; efficacy study; high risk; mTOR Inhibitor; novel; pharmacodynamic biomarker; pre-clinical; preclinical development; preclinical efficacy; predictive marker; prevent; prevention clinical trial; side effect; treatment strategy; tumor; tumor progression; tumorigenesis

The American Cancer Society's estimate for new bladder cancer cases in the United States for 2020 is 80,400. Despite the latest advances in treatment strategies, most bladder tumors recur within 2-5 years and many progress to muscle-invasive disease, which poses a high risk for metastasis. Evidently, there is a clear need for the clinical development of new agents with novel mechanisms of action that exert higher efficacy with minimal toxicity for the prevention of progression of early stage bladder cancers. Like many other cancers, bladder cancer also takes significant time (~20 years) from the time of initiation to transform into malignant cells. About half of all bladder cancers are first found while the cancer is still confined to the inner layer of the bladder wall (non-invasive or in situ cancers) thereby significantly increasing the chance for successful chemopreventive interception. Genetic alterations such as mutations, copy number alterations or RNA expression changes in the PI3K/AKT/mTOR pathway are found in more than 40% of urinary bladder cancers, suggesting that mTOR inhibitors may prevent bladder cancer progression. Everolimus (RAD001), an mTOR inhibitor, is a second generation rapalog approved by the U.S. Food and Drug Administration to be used in combination with other agents to treat advanced-stage breast cancer. Inflammation also plays a significant and important role in bladder cancer development. Anti-inflammatory NSAID naproxen is highly effective in the prevention of urinary bladder cancer in a rat model of bladder tumorigenesis. However, higher doses of NSAIDs are associated with unwanted side-effects. To avoid or reduce such untoward adverse effects, alternative dosing regimens may be explored. For example, intermittent/short-term frequent dosing with naproxen has been shown to be as effective as daily dosing for the prevention of bladder cancer. Use of clinically ready agents will significantly shorten the time required from the preclinical development phase to the start of prevention clinical trials. Targeting complementary pathways will likely achieve better efficacy than a single agent standard therapeutic-dose strategy that could increase the risk of side effects or allow for the development of tumor resistance. Both everolimus and naproxen are FDA approved, and can be repurposed to prevent bladder cancer. Such “clinical-ready” agents, already in clinical use for treatment of cancer and other diseases, offer prevention options that may be primed for clinical translation within a much shorter timeframe, if favorable toxicity profiles can be established in the prevention setting. Alternative modes of administration of these clinical-ready agents - including lower, potentially less toxic doses, represent a viable approach to drug development for prevention of bladder cancer. The overarching goal of this task order is to preclinically evaluate the chemopreventive efficacy of an mTOR inhibitor, everolimus, given in combination with an NSAID, naproxen, through continuous vs. intermittent dosing schedules using a carcinogen-induced rat bladder cancer model.

美国癌症协会估计，2020年美国新发膀胱癌病例为80，400例。尽管治疗策略取得了最新进展，但大多数膀胱肿瘤在2-5年内复发，许多进展为肌肉浸润性疾病，这对转移构成了高风险。显然，临床上明显需要开发具有新作用机制的新药剂，其发挥更高的功效和最小的毒性，用于预防早期膀胱癌的进展。与许多其他癌症一样，膀胱癌从开始到转化为恶性细胞也需要相当长的时间（约20年）。大约一半的膀胱癌是在癌症仍然局限于膀胱壁的内层（非侵入性或原位癌）时首次发现的，从而显着增加了成功化学预防拦截的机会。在超过40%的膀胱癌中发现了PI 3 K/AKT/mTOR通路中的基因改变，如突变，拷贝数改变或RNA表达变化，这表明mTOR抑制剂可以预防膀胱癌进展。依维莫司（RAD 001）是一种mTOR抑制剂，是美国食品和药物管理局批准的第二代雷帕霉素，可与其他药物联合治疗晚期乳腺癌。 炎症在膀胱癌的发展中也起着重要的作用。在膀胱肿瘤发生的大鼠模型中，抗炎性NSAID萘普生在预防膀胱癌方面非常有效。然而，较高剂量的NSAID与不必要的副作用有关。为了避免或减少这种不利的副作用，可以探索替代的给药方案。例如，间歇/短期频繁给药萘普生已被证明与每日给药一样有效，可预防膀胱癌。 使用临床上现成的药物将大大缩短从临床前开发阶段到开始预防临床试验所需的时间。靶向互补途径可能会比单一药物标准治疗剂量策略获得更好的疗效，这可能会增加副作用的风险或允许肿瘤耐药性的发展。依维莫司和萘普生都是FDA批准的，可以用于预防膀胱癌。已经在临床上用于治疗癌症和其他疾病的这种“临床就绪”药剂提供了预防选择，如果可以在预防环境中建立有利的毒性特征，则可以在短得多的时间范围内为临床转化做好准备。这些临床现成药物的替代给药模式-包括较低的，潜在的毒性较小的剂量，代表了预防膀胱癌药物开发的可行方法。 本任务指令的总体目标是使用致癌物诱导的大鼠膀胱癌模型，通过连续vs.间歇给药方案，临床前评价mTOR抑制剂依维莫司与NSAID萘普生联合给药的化学预防疗效。