Rexinoid testing in animal models of breast cancer and diabetes has been extensive. For breast cancer LGND used rats that develop breast cancer because of carcinogen treatment during development. This model allows for development of multiple "natural" tumors and is more representative of "natural" tumors in humans (tumors are heterogeneous and arise at different times), although of course the tumor is of rat origin. Other systems use human tumors injected into nude mice. Of course in this system the tumor is of human origin, but the nude mouse is a rather artificial system (the mice have a compromised immune system - a normal mouse would reject the injected tumor without treatment) due to the mouse's immune system and the fact that the human tumor used is grown in tissue culture for many years and may not be all that representative of the original human tumor or tumors arising in patient populations.
The animal data for Targretin was quite impressive. Tamoxifen was able to eliminate existing tumors and it was also able to prevent tumors from developing. Tamoxifen is the current hormonal treatment of choice for human breast cancer and it was just approved for breast cancer prevention. Targretin was also quite effective in the treatment and prevention of breast cancer in the animal model and it had fewer side effects (lack of induction of endometrial tissue growth), it synergized with Tamoxifen, and was effective in treating Tamoxifen resistant tumors.
For diabetes, Targretin and LGD1268 produced similar impressive results in two mouse models of diabetes and obesity. The compounds worked as monotherapy and in combination with Avandia and were effective with both models. In the mouse models, I believe that the elevated triglyceride levels were lowered as were glucose and insulin levels. Like Avandia, Targretin and LGD1268, sensitized the mice to insulin.
In the European diabetes trials, I believe that patients were also a able to more efficiently use glucose, but there is a problem with elevated triglycerides. The elevation is acceptable for patients with advanced breast cancer, but not acceptable for long term treatment of a chronic disease like type II diabetes. Similarly, the elevated triglycerides would also pose a problem for prevention approaches for diabetes or breast cancer in high risk individuals. |
