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Project

Prevention of Urinary Bladder Cancer with Two Clinically-Ready Agents (Everolimus andNaproxen) When Administered in Combination

Funder: National Cancer Institute

Funding period
USD 710 K
Funding amount
Abstract
Urinary bladder cancer is a global health problem, making it the 9th most common cancer worldwide and sixth most common cancer in the USA. In spite of 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) (ACS 2017) thereby significantly increasing the chance for successful chemoprevention intervention. 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 unwarranted 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 (Lubet et al. Cancer Prev Res 2015). 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 alone or in combination with an NSAID, naproxen, through continuous vs. intermittent dosing schedules using a carcinogen-induced rat bladder cancer model.
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System

Categories
  • FOR (ANZSRC)

    1112 Oncology and Carcinogenesis

  • FOR (ANZSRC)

    1115 Pharmacology and Pharmaceutical Sciences

  • RCDC

    Biotechnology

  • RCDC

    Human Genome

  • RCDC

    Cancer

  • RCDC

    Genetics

  • RCDC

    Orphan Drug

  • RCDC

    Prevention

  • RCDC

    Rare Diseases

  • RCDC

    Urologic Diseases

  • HRCS HC

    Cancer

  • HRCS RAC

    5.1 Pharmaceuticals

  • HRCS RAC

    6.1 Pharmaceuticals

  • Health Research Areas

    Biomedical

  • Broad Research Areas

    Basic Science