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Targeting PPARgamma by CDDO: A Novel Therapy for Resistant Breast Cancer
Background: Drug resistance is a major obstacle in the treatment of breast cancer. We have identified the synthetic triterpenoid CDDO (2-cyano-3,12-dioxoolen-1,9-dien-28-oic acid) as a novel anticancer agent that causes growth arrest and apoptosis in breast cancer independently of HER2, estrogen receptor, or p53 status.
Objective/Hypothesis: The growth inhibition of resistant breast cancer cells by CDDO in vitro and in vivo will be characterized. The hypothesis is that CDDO induces anti-tumor effects in breast cancer cells independent of the known resistance factors, via activation of PPARgamma signaling and/or disruption of the redox homeostasis.
Specific Aims: 1) To determine the efficacy of CDDO alone, or in combination with retinoids and chemotherapy in preventing the growth of breast cancer cells in vitro, 2) to investigate PPARgamma-dependent and -independent mechanisms by which CDDO affects apoptosis and proliferation in breast cancer cells, 3) to test the therapeutic efficacy of CDDO in the orthotopic and metastatic mouse models in vivo.
Study Design: In Specific Aim 1, growth-inhibitory and pro-apoptotic effects of CDDO will be studied in matched parental and chemotherapy-resistant breast cancer cells, and in breast cancer cells isolated from the metastatic tumors in mice. The combinations of CDDO and RXR ligands/chemotherapy will be examined. In Specific Aim 2, PPARgamma-dependent and -independent mechanisms will be delineated by combined use of knockdown and overexpression approaches. Furthermore, the recently characterized PPARgamma-independent disruption of intracellular redox balance and glutathione depletion will be investigated in detail. Finally, the therapeutic efficacy of CDDO will be tested in the in vivo xenograft mouse model following establishment of the luciferase-expressing breast tumors (Specific Aim 3). Molecular endpoints of CDDO activity in breast tumors will be assessed including proliferation, induction of apoptosis, cyclin D1 and GSH depletion.
Potential Outcomes and Benefits of Research: We anticipate developing the synthetic triterpenoid CDDO in collaboration with CTEP/RAID at the National Cancer Institute, for use as a novel agent for the treatment of breast cancers. Pre-clinical information, including the ability of CDDO to induce growth arrest in resistant and metastatic breast cancer cells will contribute to the development process. The long-term goal of the proposed studies is to determine the molecular, biological and clinical effects of CDDO against breast cancer in humans.
Despite advances in the diagnosis and treatment of breast cancer, few patients with metastatic disease are cured. This project is aimed at developing a novel chemotherapy agent for the treatment of breast cancer.
CDDO (2-cyano-3,12-dioxoolen-1,9-dien-28-oic acid) is a synthetic analogue of the triterpenoid oleanolic acid (derived from Chinese oleander). We have demonstrated that CDDO inhibits the growth of breast cancer cells in culture, including those overexpressing the HER2 protein that are resistant to Herceptin. CDDO also depletes the intracellular antioxidant glutathione, which has been implicated in the resistance of breast tumors to chemotherapy. Preliminary data show favorable toxicology and pharmacokinetic properties for CDDO, and the National Cancer Institute is developing this compound for oral administration in a clinical setting.
The first specific aim will elucidate CDDO-induced growth inhibition in breast cancer cells that are resistant to chemotherapy or herceptin, and compare these effects with those observed in the sensitive cells. In addition, we will examine effects of CDDO on breast cancer cells isolated from the metastatic tumors in mice. It is known that "peroxisome proliferator-activated receptor gamma" (PPARgamma, one of CDDO’s targets) and another nuclear receptor, retinoid X receptor, form a complex. We will therefore test the therapeutic effects of combining CDDO with RXR-selective compounds and with commonly used chemotherapeutic agents.
The second aim will examine the specific mechanism(s) of CDDO’s action in breast cancer cells. PPARgamma is abundantly expressed in malignant but not in normal breast tissue. Thus, we will study downstream targets of PPARgamma activation by CDDO. Furthermore, we will examine the molecular basis leading to the depletion of glutathione by CDDO in breast cancer cells.
The last specific aim will test the anti-tumor effects of CDDO in a xenograft mouse model of breast cancer. In this model, we will employ several resistant breast cancer cell types, which grow in the mammary gland and develop metastasis. We will monitor both, effects on tumor growth and metastases, as well as the molecular changes in tumor cells.
We expect that CDDO will be effective in breast cancer chemotherapy especially in women whose tumors are resistant to conventional chemotherapy or herceptin. The results of these experiments will form the basis for future clinical trials in patients. If successful, the rationale of targeting signaling pathways should be applicable to a wide variety of human tumors.