Breast cancer (BCa) is a major health problem with a steady growth in new cases and deaths worldwide. Although more women are surviving cancer in recent years, mainly due to early detection and improved early stage therapies, most cancers eventually turn hormone-independent and metastatic disease requires simultaneous treatment with anti-hormonal and chemotherapeutic drugs. Therefore, novel strategies are still necessary for the prevention and treatment of BCa. PPAR? and RXR? are nuclear hormone receptors overexpressed in BCa and have been validated as ideal targets for the chemoprevention and treatment of BCa. A number of PPAR? and RXR? ligands have strong anticancer activity and have been studied with promising results in animal models. The combination of PPAR? and RXR? activators has synergistic effects in vitro and the antitumoral response is stronger than that of either ligand alone. The natural PPAR? ligand 15-delta-prostaglandin J2 (15?PGJ2) is among the PPAR? agonists with strong growth inhibitory activity against cancer cells. Unfortunately, its mechanism of action has not been clearly defined most likely due to its high chemical reactivity which facilitates the interaction with numerous cellular targets. In our quest o find novel compounds with enhanced anti-tumoral properties and hopefully better therapeutic profiles, we have taken a medicinal chemistry approach to prepare a series of synthetic analogs of 15?PGJ2 with improved chemical stability. The focus of this proposal is the characterization of one of these synthetic analogs, CPG-4109, which shows strong antiproliferative activity in BCa cells. This compound is unique because it activates both PPAR? and RXR? with similar efficacy. Like 15?PGJ2, CPG-4109 also inhibits IKK2, a well-known therapeutic target in advanced BCa. Our working hypothesis is that activation of both PPAR? and RXR and the inhibition of IKK2 are the major actions required for optimal growth inhibitory activity of CPG-4109. Simultaneous activation of PPAR? and RXR mimics the synergistic effect observed when combining selective PPAR? and RXR ligands. We propose here to characterize the mechanism of action of CPG-4109 in BCa cells, with a special emphasis on the role of PPAR?, RXR? and IKK2 on CPG-4109-mediated apoptosis. Additionally, in vivo studies will answer important questions regarding the bioavailability, toxicity, and antitumor efficacy of CPG-4109. Results of this project will reveal CPG-4109 as an excellent lead molecule for future optimization efforts directed to improve the potency and selectivity against most relevant targets in BCa. This novel compound represents a unique opportunity to develop novel multi-targeted drugs, with a wider spectrum of signal transduction modulation and probably improved efficacy, less toxicities, reduced risk of drug-drug interactions and better patient compliance adhering to a long term therapy program.
The focus of this proposal is the characterization of the antitumoral activity of CPG-4109 both in vitro and in vivo in breast cancer (BCa) cells and in a mouse orthotopic xenograft model. This compound is a synthetic analog of the cyclopentenone prostaglandin 15?PGJ2 with strong growth inhibitory activity against ER+ and ER- BCa cells. CPG-4109 is unique in that it activates PPAR? and RXR? with similar efficacy and has improved chemical stability compared to the parental compound 15?PGJ2. Therefore, it is expected that CPG- 4109 will likely interact with a reduced number of cellular proteins, inducing a narrower range of biological responses and causing fewer side effects. An additional advantage of CPG-4109 is that it activates two proven targets for the chemoprevention and treatment of BCa, PPAR? and RXR?. Since liganded PPAR? and RXR? receptors recruit different subsets of transcriptional coactivators, the use of a single compound to activate both receptors may increase transcription (as there is less competition) and improve the growth inhibitory activity. In addition, CPG-4109 also inhibits IKK2, another therapeutic target for BCa, in particular with ER- phenotype. This type of BCa is characterized by constitutive NF?B activation, is generally highly invasive and metastatic and responds poorly to radio- and chemotherapy. Finally, the characterization of a compound that can target both PPAR?/RXR? and IKK signaling pathways can have a great impact in the future development of novel therapies for the chemoprevention and treatment of BCa, especially when an inflammatory component is involved. Targeting multiple signaling pathways may also facilitate its use in combination with other chemotherapeutic drugs at a lower dose, reducing the risks of drug-drug interaction and side effects.