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

据美国癌症协会估计，2020年美国新增膀胱癌病例为80,400例。尽管在治疗策略上取得了最新进展，但大多数膀胱肿瘤在2-5年内复发，许多进展为肌肉侵袭性疾病，这构成了转移的高风险。显然，临床上显然需要开发具有新的作用机制的新药物，以发挥更高的疗效和最小的毒性来预防早期膀胱癌的进展。与许多其他癌症一样，膀胱癌从发病到转化为恶性细胞也需要相当长的时间(~20年)。大约一半的膀胱癌是首次发现的，而癌症仍然局限于膀胱壁的内层(非侵袭性或原位癌)，因此大大增加了成功的化学预防拦截的机会。在超过40%的膀胱癌中发现PI3K/AKT/mTOR通路的突变、拷贝数改变或RNA表达变化等基因改变，提示mTOR抑制剂可能阻止膀胱癌的进展。埃维洛莫斯(RAD001)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洛格，可与其他药物联合用于治疗晚期乳腺癌。 炎症在膀胱癌的发生发展中也起着重要的作用。在大鼠膀胱癌形成模型中，抗炎非甾体类抗炎药萘普生对预防膀胱癌非常有效。然而，较高剂量的非类固醇抗炎药与不良副作用有关。为了避免或减少这种不良反应，可以探索替代剂量方案。例如，在预防膀胱癌方面，间歇性/短期频繁剂量的萘普生已被证明与每日剂量一样有效。 临床准备药物的使用将大大缩短从临床前开发阶段到预防临床试验开始所需的时间。靶向互补通路可能比单一药物标准治疗剂量策略获得更好的疗效，后者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，可以重新用于预防膀胱癌。这些已经在临床上用于治疗癌症和其他疾病的“临床准备”药物提供了预防方案，如果能够在预防环境中建立有利的毒性曲线，这些预防方案可能会在更短的时间内准备好用于临床翻译。这些临床上可用的药物的替代给药模式--包括较低的、可能毒性较低的剂量--代表了一种可行的药物开发方法，用于预防膀胱癌。 该任务顺序的首要目标是通过使用致癌物诱导的大鼠膀胱癌模型，通过连续给药和间歇给药计划，对mTOR抑制剂伊维洛莫斯与非甾体抗炎药萘普生联合给予的化学预防效果进行临床前评估。

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.