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.

美国癌症协会预计 2020 年美国新增膀胱癌病例为 80,400 例。尽管治疗策略取得了最新进展，但大多数膀胱肿瘤会在 2-5 年内复发，并且许多进展为肌肉侵袭性疾病，这带来了很高的转移风险。显然，临床上显然需要开发具有新颖作用机制的新药物，以最小的毒性发挥更高的功效，以预防早期膀胱癌的进展。与许多其他癌症一样，膀胱癌从发生到转变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局限于膀胱壁内层（非侵袭性或原位癌）时首次发现的，从而显着增加了成功化学预防拦截的机会。超过 40% 的膀胱癌中发现了 PI3K/AKT/mTOR 通路中的突变、拷贝数改变或 RNA 表达变化等基因改变，这表明 mTOR 抑制剂可以预防膀胱癌的进展。依维莫司 (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 Rapalog，可与其他药物联合用于治疗晚期乳腺癌。 炎症在膀胱癌的发展中也起着重要作用。在膀胱肿瘤发生的大鼠模型中，抗炎 NSAID 萘普生对于预防膀胱癌非常有效。然而，较高剂量的非甾体抗炎药会带来不良副作用。为了避免或减少此类不良副作用，可以探索替代给药方案。例如，对于预防膀胱癌，间歇/短期频繁给药萘普生已被证明与每日给药一样有效。 使用临床准备好的药物将显着缩短从临床前开发阶段到预防性临床试验开始所需的时间。针对互补途径可能会比单一药物标准治疗剂量策略取得更好的疗效，而单一药物标准治疗剂量策略可能会增加副作用的风险或导致肿瘤耐药性的发展。依维莫司和萘普生均已获得 FDA 批准，可重新用于预防膀胱癌。这种“临床就绪”药物已经在临床上用于治疗癌症和其他疾病，如果可以在预防环境中建立有利的毒性特征，则可以在更短的时间内为临床转化做好准备。这些临床就绪药物的替代给药方式——包括较低的、可能毒性较小的剂量，代表了预防膀胱癌药物开发的可行方法。 该任务顺序的总体目标是使用致癌物诱导的大鼠膀胱癌模型，通过连续与间歇给药方案，评估 mTOR 抑制剂依维莫司与 NSAID 萘普生联合用药的临床前化学预防功效。