Abstract
Rexinoids are ligands which activate retinoid X receptors (RXRs), regulating transcription of genes involved in cancer-relevant processes. Rexinoids have anti-neoplastic activity in multiple preclinical studies. Bexarotene, used to treat cutaneous T cell lymphoma, is the only FDA-approved rexinoid. Bexarotene has also been evaluated in clinical trials for lung and metastatic breast cancer, wherein subsets of patients responded despite advanced disease. By modifying structures of known rexinoids, we can improve potency and toxicity. We previously screened a series of novel rexinoids and selected V-125 as the lead based on performance in optimized in vitro assays. To validate our screening paradigm, we tested V-125 in clinically relevant mouse models of breast and lung cancer. V-125 significantly (p < 0.001) increased time to tumor development in the MMTV-Neu breast cancer model. Treatment of established mammary tumors with V-125 significantly (p < 0.05) increased overall survival. In the A/J lung cancer model, V-125 significantly (p < 0.01) decreased number, size, and burden of lung tumors. Although bexarotene elevated triglycerides and cholesterol in these models, V-125 demonstrated an improved safety profile. These studies provide evidence that our screening paradigm predicts novel rexinoid efficacy and suggest that V-125 could be developed into a new cancer therapeutic.
Highlights
Rexinoids are ligands which activate retinoid X receptors (RXRs), regulating transcription of genes involved in cancer-relevant processes
We have found that applying principal component analysis (PCA) in our prior work[35,36] with rexinoids has helped to visualize active rexinoids with improved therapeutic potential, and to that end, we have conducted a Principal component analysis (PCA) with V-125 and the nine other novel rexinoids (Fig. 1) to visualize where they group relative to each other as well as bexarotene and LG100268
The PCA analysis resulted in three groups—A, B, and C—in which rexinoids clustered according to their activities in in vitro assays
Summary
Rexinoids are ligands which activate retinoid X receptors (RXRs), regulating transcription of genes involved in cancer-relevant processes. Bexarotene elevated triglycerides and cholesterol in these models, V-125 demonstrated an improved safety profile These studies provide evidence that our screening paradigm predicts novel rexinoid efficacy and suggest that V-125 could be developed into a new cancer therapeutic. While retinoids are active in this model[14,15], they cause headaches and mucocutaneous toxicity in patients as a result of binding to the retinoic acid receptor (RAR)[16] These side effects are not observed with the rexinoids that do not bind to RAR17. SERMs are an effective treatment and prevention option for ER + breast cancer, but fewer strategies exist for hormone receptor negative breast cancers, despite high morbidity and mortality With their enhanced efficacy coupled with a favorable toxicity profile, rexinoids may be useful for cancer treatment and for prevention. The more potent rexinoid LG100268 and a SERM were highly effective at delaying tumor development in a similar murine model of HER2 + breast cancer, while the combination of a SERM and LG100268 completely prevented tumor development over a 50 week period of treatment[20]
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