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    Research Grants Awarded

    Combination Therapy Based on Novel Vitamin D Actions to Inhibit Breast Cancer Cell Growth

    Study Section:
    Treatment

    Scientific Abstract:
    Background: Calcitriol, the active form of vitamin D, has anti-cancer activity in breast cancer (BCa). Our recent novel findings in BCa cells are exciting and also point to two potential combination therapies. First, we found that calcitriol inhibits prostaglandin (PG) synthesis and action. Since PGs are major stimulators of BCa growth and resistance to apoptosis, inhibiting this pathway would be an effective therapy. We further postulate that combination therapy with non-steroidal anti-inflammatory drugs (NSAIDs) that also inhibit PGs will have synergistic activity to inhibit BCa cell growth allowing the use of lower and safer doses of NSAIDs and calcitriol, yet with greater potency. Second, we discovered that calcitriol selectively inhibits aromatase expression in BCa cells. Aromatase is responsible for the local production of estrogens in BCa and aromatase inhibitors (AIs) are currently the most effective therapy for women with BCa. We postulate that combination therapy of calcitriol with AIs will more effectively inhibit BCa growth. Objective: We will study two novel pathways of calcitriol action to inhibit BCa growth. We propose that calcitriol combination with NSAIDs or AIs will render the therapies more effective than the use of individual drugs and we expect the studies will pave the way to clinical trials. Specific Aims: 1. To evaluate the inhibition of PGs as one of the mechanisms for the anti-cancer activity of calcitriol. Combination therapy with NSAIDs will be assessed. 2. To study calcitriol actions to inhibit aromatase activity in BCa, bone and ovary cells. Combination therapy with AIs will be assessed. Study Design: Several BCa cell lines will be evaluated in culture. Calcitriol effects on the PG pathway will include measurement of cyclooxygenase-2, 15-PG dehydrogenase, PG receptors, PG levels and biological responses. Calcitriol effects on aromatase mRNA and enzyme activity will be studied. The effects of calcitriol with NSAIDs and AIs on BCa target gene regulation and cell growth will be assessed individually and in combination. Target genes to be evaluated include growth control genes and apoptosis related genes. Potential Outcome/ Research Benefits: Calcitriol inhibits both PGs and aromatase. These studies will evaluate drug combinations for therapy of BCa patients. Calcitriol, NSAIDs and AIs are approved drugs, orally active, safe and of modest cost. Progress to clinical trials to treat and/or prevent BCa can be swift.

    Lay Abstract:
    Background: Calcitriol, the hormonally active form of vitamin D, acts in the body like a steroid hormone. Calcitriol has anti-cancer activity in many cancers including breast cancer (BCa). Our recent findings indicate two novel pathways of calcitriol action. First, calcitriol inhibits the production and action of prostaglandins (PGs). Since PGs are major stimulators of BCa growth, their inhibition is potentially an effective therapy for BCa. We postulate that calcitriol combination therapy with nonsteroidal anti-inflammatory drugs (NSAIDs) that also inhibit PG production, will be synergistic, and will allow lower and safer doses of both drugs yet with increased potency. Second, we discovered that calcitriol inhibits aromatase expression in BCa cells. Aromatase is the enzyme that leads to local production of estrogens in the breast and aromatase inhibitors (AIs) are currently the most effective therapy for post-menopausal BCa. We postulate that combination therapy of calcitriol with AIs will be synergistic and make AIs plus calcitriol more effective. Objective: We propose to study two pathways of calcitriol action and combination therapy with NSAIDs and AIs to render the drugs more effective than either drug alone. These studies will pave the way to clinical trials of combination therapy. Specific Aims: 1. To evaluate the inhibition of prostaglandins (PGs) as a mechanism for the anti-cancer activities of calcitriol. Combination therapy with NSAIDs will be assessed. 2. To study calcitriol actions to inhibit aromatase activity in BCa, bone and ovary cells. Combination therapy with AIs will be assessed. Study Design: Several BCa cell lines will be evaluated in culture. Calcitriol effects on the PG pathway will include measurement of critical enzymes, PG receptors, PG levels and biological responses. Calcitriol effects on aromatase activity will be studied. The effects of calcitriol, NSAIDs and AIs on BCa target gene regulation and cell growth will be assessed individually and in combination. Important genes for growth of BCa cells will be evaluated. Potential Outcome/Benefits of the Research: Calcitriol inhibits both PGs and aromatase, actions that arrest BCa growth. These studies will evaluate calcitriol and combinations for therapy of BCa patients. Calcitriol, NSAIDs and AIs are approved drugs, orally active, safe and of modest cost. Progress to clinical trials to treat and/or prevent BCa can be swift.