medsunman, I'll give a bit more detail on the molecular aspects of Rexinoid (Targretin) / SERM (Evista) synergies. Animal data has been quite encouraging. Although the various SERMs can have structural differences, they all target the estrogen receptor (ER). The compounds have been called anti-estrogens, but since their effect can vary, depending on the cell type, they have more recently been called TSEs (Tissue Specific Estrogens) or SERMs (Selective Estrogen Receptor Modulators).
ER is a sex steroid and it is structurally related to the IRs that LGND targets (Retinoic Acid Receptor, RAR; Retinoic Acid X Receptor, RXR; Peroxisome Proliferation Activated Receptor, PPAR; Androgen Receptor, AR; Thyroid Hormone Receeptor, TR; Vitamin D Receptor, VDR;
Gluccocorticoid Receptor, GR; etc). RXRs form heterdodimers with many of the receptors and the heterodimer is really the activated transcription factor, so it's pretty easy to understand why an RXR activator like Targretin would synergize with a PPAR activator like Rezulin.
However, it's not clear that RXRs for heterodimers with ERs, so the synergy between Targretin or Panretin and Tamoxifen or Evista isn't as obvious from the molecular viewpoint. Howevere, the synergy has been demonstrated in many systems now. For breast cancer prevention in rats, Panretin has been shown to synergize with Tamoxifen and Evista. Targretin has also been shown to synergize with Tamoxifen in prevention trials. Moreover, Targretin has been shown to synergize with Tamoxifen to cause established breast tumors to disappear in rats.
The above data is important because of the potential human applications. Panretin is in two Phase I/II trails with Tamoxifen to treat breast cancer. The upcoming presentation at ASCO is expected to show "Striking" prevention results for women treated for 3 years with Evista.
LLY and LGND recognize this potential synergy for the treatment or prevention of breast cancer, so a research program targeting rexinoids and SERMs was set up under the recent LLY/LGND Alliance. Turk's info seems to also implicate LGGND with Evista based by the serum estrogen clues.
It sounds like the media will be excited about the Evista prevention data to be presented at ASCO in May. By then, I suspect that more will be known about the LLY compound, and shortly thereafter, details about the implications for the research program may be more obvious. |
