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Low-toxicity Retinoids to Prevent the Recurrence of ER- Breast Cancer
Risk, Prevention and Epidemiology
Selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs) are two FDA-approved classes of drugs used to prevent the recurrence of estrogen receptor-positive (ER+) breast cancers. However, no preventive agents are available for adjuvant therapy of estrogen receptor-negative (ER-) cancers. Preclinical in vivo studies showed that 9-cis-retinoic acid (9cRA) and retinoids like Targretin that selectively target the nuclear retinoid X receptors (RXRs) are effective in the prevention of ER+ mammary cancers either alone or in combination with SERMs or AIs. Additionally 9cRA and Targretin prevent ER- cancers in transgenic mouse models, but due to significant toxicities these retinoids are not suited for chemoprevention. We have designed and evaluated two new classes of RXR-selective retinoid agonists (rexinoids). The least-toxic rexinoid, 9cUAB30, does not display common lipid toxicities that have plagued the clinical use of other retinoids for cancer prevention, but it is very effective in preventing ER+ cancers. 9cUAB30 is now approaching a Phase I human trial as a new chemopreventive agent (to determine toxicity and pharmacokinetics). We propose to evaluate 9cUAB30 and our most potent rexinoid, 9cUAB111, in preclinical studies aimed at determining their potential in treating and preventing ER- breast cancers in humans. In Specific Aim 1, 9cUAB30 and 9cUAB111 (each RXR-selective agonists) will be synthesized at quantities sufficient for in vivo evaluation. The two rexinoids have already been characterized in vitro. In Specific Aim 2, the two rexinoids will be studied for their capacity to reduce cancer cell proliferation or increase cell apoptosis in established ER- MMTV-erb2 cancers, and evaluated in vivo for their potencies as agents to inhibit the growth of these ER- cancers. In Specific Aim 3, 9cUAB30 and 9cUAB111 will be evaluated in a long-term (18 month) study to evaluate their capability of preventing the formation of ER- cancers in the MMTV-erb2 transgenic model. The preclinical data provided by these studies will be used to support further clinical development of 9cUAB30 in costly Phase II clinical trials, and/or to support moving 9cUAB111 forward in the early stages of preclinical toxicity/pharmacology studies needed for an IND application.
Two classes of drugs are used to prevent breast cancer that grows rapidly in response to estrogen. Selective estrogen receptor modulators (e.g., tamoxifen) and aromatase inhibitors (e.g., Arimidex) significantly reduce the chances of estrogen-receptor positive (ER+) breast cancer recurrence. However, for breast cancers that do not respond to estrogen (ER- cancers), there are no low-toxicity drugs available to prevent disease in these patients (African American women compose an unusually high proportion of ER- patients). Vitamin A derivatives hold great promise in preventing both ER+ and ER- breast cancers since their mechanism of action is not dependent on blocking estrogen. Instead these compounds, named retinoids, prevent cancer cells from proliferating and encourage them to die, thus suppressing cancer progression. The purpose of this research is to determine if either of two structurally different retinoids (9cUAB30 or 9cUAB111) is suitable for the prevention of ER- breast cancer. First, we will synthesize enough of each retinoid to perform the needed evaluation of these compounds in animals. The chemistry has already been developed to make large quantities of 9cUAB30. However, we will need to optimize the synthesis of 9cUAB111 to generate sufficient quantities to complete the subsequent studies. We will next study if either retinoid prevents ER- cancer cells from proliferating in animals, and then decide if the retinoids are capable of stopping ER- tumors from growing. The final study will evaluate if either retinoid can prevent the appearance of ER- cancers in mice that have been genetically altered to produce ER- cancers. This study is costly due its length and the amount of retinoid needed to treat the mice. In 2007, 9cUAB30 will start the first round of evaluation in humans for toxicity and pharmacology. Positive results from these studies will be used to support continued human evaluation in expensive Phase II trials as a new agent to prevent ER- disease (as well as enhancing SERMs/AIs in ER+ cancer).