PPAR Modulators as Apoptosis Sensitizers for Breast Cancer

Institution: The Burnham Institute for Medical Research
Investigator(s): John Reed, M.D., Ph.D. - John Reed, M.D., Ph.D. - John Reed, M.D., Ph.D. - John Reed, M.D., Ph.D. -
Award Cycle: 2002 (Cycle VIII) Grant #: 8WB-0079 Award: $456,924
Award Type: STEP Award
Research Priorities
Detection, Prognosis and Treatment>Innovative Treatment Modalities: search for a cure

Initial Award Abstract (2002)
Current therapies for breast cancer predominantly rely on cytotoxic drugs that have limited therapeutic windows, which causes significant long-term side effects for patients. A need exists to explore natural (i.e., endogenous) pathways for controlling tumor growth. The aim is to induce cancer cells to commit suicide, called apoptosis, using relatively non-toxic methods. Our previous studies of chemical compounds that modulate the activity of endogenous receptors involved in lipid signaling have revealed the existence of a cellular pathway for sensitizing tumor cells. In particular, this process of inducing cell death mimics that used by the immune system for fighting cancers. By understanding more about this pathway and identifying the most appropriate chemicals that selectively trigger it, we may eventually uncover novel chemo-preventive strategies for breast cancer.

Pharmacological agents which bind nuclear receptors of the steroid/retinoid super-family have shown promise as potential apoptosis-sensitizers in carcinomas of the breast and other tissues. Preliminary data indicate that several classes of PPAR (peroxisomal proliferator activated receptor) modulators can regulate levels of specific anti-apoptotic proteins in epithelial cancer cell lines. The end result is that these cells become sensitized to apoptotic stimuli, particularly cytokines of relevance to immune responses (e.g., TNF, Fas, and TRAIL). This is a particularly promising approach for breast cancer, because breast cancer frequently does not stimulate an effective immune response. However, the underlying cellular mechanisms of breast cancer apoptosis might still, if they could be "activated" by alternate methods, be utilized for effective therapy.

We will explore the hypothesis that chemical compounds previously recognized as PPAR modulators have a second, independent activity as sensitizers of tumor cells to certain types of apoptotic stimuli. Our preliminary data suggests that certain PPAR modulatory drugs, can induce rapid degradation of the anti-apoptotic protein FLIP. The PPAR modulators include, thiazolidinediones (currently used for Type II diabetes), triterpenoids, and certain naturally-occurring prostaglandins. Our research will complement ongoing clinical trial work on a member of the TNF-family, called TRAIL, that is inhibited by FLIP. Thus to summarize, we hope to test the potential of a variety of PPAR compounds for creating a "permissive state" for cell death induction in breast cancer. We will conduct these experiments in cell lines and animal models of human breast cancer.

The overall goal of our work is to identify new, less-toxic therapies for prevention and treatment of breast cancer.

Final Report (2004)
The basis of this project was our research published in 2002 (J. Biol. Chem., 277 (25): 22320-22329) that uncovered a potentially promising way of inducing programmed cell death (apoptosis) in cancer cells via a TNF (tumor necrosis factor) pathway, termed TRAIL, that often preferentially kills tumor cells, sparing normal tissues. However, there is an intrinsic resistance mechanism to TRAIL, called FLIP. We reported that compounds that interact with the PPAR-? (peroxisome proliferator-activated receptor-?) would sensitize cells to TRAIL and enhance the tumor-specific killing effect. This PPAR-? system to permit apoptosis via TRAIL worked because PPAR-?, when activated, would serve to degrade FLIP by a ubiqutination process. PPAR-? is associated with multiple myeloma and many other cancers, as well as chronic inflammation and diabetes. PPAR-??also activates gene transcription in along with coactivators.

The aims of the CBCRP project was to investigate a class of chemicals ("drugs"), called triterpinoids, that we suspect may be capable of promoting or inducing breast cancer cells though the mechanism described above. Initially we tried to produce analogs of the parent triterpinoid, called CDDO, but the molecular structure was difficult to modify. Then, we screened a large (60,000+) chemical library and identified several compounds that were amenable to medicinal chemistry and acted through the PPAR and other, as yet unknown, pathways for apoptosis. These compounds will be investigated in future projects. Next, we have obtained recombinant purified TRAIL and performed experiments in animal models (xenografts) of human breast cancer to better understand the potential synergy between TRAIL and the mechanism of our CDDO derivatives. These experiments are very positive (i.e., tumor growth was suppressed), and the compounds appear to be well tolerated in animals. The preliminary results for this research has been presented at the American Association of Cancer Research in Orlando in 2004.

Altogether, our research efforts lay a foundation for eventual clinical testing of a new type of therapy for breast cancer that seeks to sensitize tumor cells to eradication by the immune system and mimic the cell death mechanism employed by the immune system to eliminate breast cancer cells. This new therapy is expected to be effective even in breast cancers that have become resistant to chemotherapy or hormonal therapy, because it taps into a different pathway for cell death.

An inducible pathway for degradation of FLIP protein sensitizes tumor cells to TRAIL-induced apoptosis.
Periodical:Journal of Biological Chemistry
Index Medicus: J Biol Chem
Authors: Kim Y, Suh N, Sporn M, Reed JC.
Yr: 2002 Vol: 277 Nbr: 25 Abs: Pg:22320-9