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.

美国癌症协会对2020年的膀胱癌病例的估计为80,400，大多数膀胱肿瘤都在2 - 5年内出现，并在肌肉侵入性疾病中进行了许多进展，这构成了Metastastas的高风险与许多其他癌症一样，膀胱癌的早期癌症也需要大量时间（〜20年）。在超过40％的膀胱癌症中，途径的压力变化显着增加。晚期乳腺癌。 Inti-isaid Naighloxen在ISAID Naghloxen NSAID Naproxen NSAID Naproxen的含尿液膀胱癌中的高度作用是在大鼠膀胱模型中，以避免或减少替代剂量的剂量。萘普生已被证明与每日剂量一样有效，以预防膀胱癌。 使用临床准备的药物将显着缩短临床前开发阶段所需的时间。肿瘤耐药性的发展。 - 就绪的药物 - 包括较低的，潜在的剂量，代表了预防膀胱癌的药物治疗方法。 该TOSK的总体有序地评估了一些MTOR抑制剂，该抑制剂使用NSAID，NAPROXEN，THUCE连续与间歇性剂量时间表使用致癌的大鼠膀胱膀胱癌癌症癌症模型。