Abstract:
Introduction: The rationale for combination therapy in treating cancer is to use drugs with different mechanisms of action, thereby reducing the likelihood that resistant cancer cells will develop. CLX-155A is an oral prodrug conjugate hydrolyzed by intestinal enzymes to yield 5’-DFCR and valproic acid. 5’-DFCR is an intermediate in generating 5-FU, a clinically proven antimetabolite, producing DNA and RNA damage in cancer cells. Valproic acid is an approved antiseizure medication known to produce antitumor activity due to its epigenetic modulating histone deacetylase inhibitory activity. Thus, CLX-155A differs from capecitabine, an approved oral prodrug of 5-fluorouracil (5-FU), used to treat metastatic breast and colorectal cancer. Hepatic carboxyl esterases hydrolyze capecitabine to yield intermediate 5’-DFCR, which the tumor will convert to 5-FU. Variability in therapeutic levels of 5-FU and severe neurologic (e.g., hand-foot syndrome), gastrointestinal, and hepatic toxicities have limited the use of capecitabine in treating solid tumors. Unlike capecitabine, CLX-155A yields 5-FU, independent of liver metabolism. Due to the combined activity of 5’-DFCR and valproic acid, CLX-155A can offer the potential for greater potency for anticancer effects. Hence, this preclinical work compares the efficacy of CLX-155A in a triple-negative human breast cancer xenograft model in nude mice as monotherapy and in combination with paclitaxel.
Methods: This study involved Foxn1 athymic nude female mice (7-8 weeks) implanted subcutaneously with MDA-MB-231 human triple-negative breast cancer (5 million cells/site) in the dorsal right flank. The study randomized these animals into different treatment groups (N=10 per group) as vehicle control, CLX-155A (1000 mg/kg/day), capecitabine (1000 mg/kg/day), CLX-155A plus paclitaxel (15 mg/kg) or capecitabine plus paclitaxel (15 mg/kg). Animals underwent oral treatment once daily for eight consecutive days. The combination groups received paclitaxel by intravenous route on study days 1, 3, and 6. Investigators recorded tumor volumes thrice weekly and observed clinical signs of toxicity, mortality, and body weights until study day 8. Later, animals were observed for tumor regrowth pattern and body weight recovery under post-treatment observation till day 25. The tumor growth inhibition (TGI) percentage analysis involved calculation based on the tumor volume on a given day compared to the vehicle control group.
Results: All test groups exhibited significant tumor growth inhibition (***p<0.001; day 3-day 6). The capecitabine group and capecitabine + paclitaxel treatment group showed a %TGI of 115% and 143%, respectively, on Day 9. CLX-155A group and CLX-155A combination treatment group exhibited greater anticancer efficacy with higher %TGI of 145% and 167% on day 9. The study did not observe any notable regrowth of the tumors during the post-dose observation period in any of the groups. However, mortalities and moderate to severe body weight loss occurred in all the dose groups. The combination groups showed a higher degree of toxicity than the groups that received the drugs alone. At the end of the study, the number of surviving animals in the treatment groups was 5/10 (Capecitabine), 3/10 (CLX-155A), and 2/10 each in the combination groups.
Conclusion: CLX-155A showed significant antitumor activity in triple-negative breast cancer cell-derived tumor xenografts alone and with paclitaxel. The efficacy of CLX-155A was better than that observed with capecitabine alone or in combination with paclitaxel. The dose levels evaluated in this study for the test compounds alone and in combination with paclitaxel were higher than the maximum tolerated doses, as evidenced by a high incidence of mortality, significant body weight loss, and associated clinical signs of toxicity. While these initial data indicate that CLX-155A may have improved efficacy, regulators will require additional dose-ranging efficacy in the xenograft model further to characterize the CLX-155A's efficacy and safety profile.
Audience Take Away Notes:
- The audience will be able to use such data to evaluate the candidacy of CLX-155A for phase 1/2 study investigation in solid tumors, such as breast and colon cancer, where clinicians might use capecitabine.
- This research will add knowledge about antimetabolites, capecitabine, and their role in solid tumors, which academics can teach in both pharmacology and therapeutics class settings.
- This research offers an avenue to examine drug design strategies to improve the therapeutic window of newer antimetabolite candidates for use in solid tumors.
- This effort creates awareness about the antimetabolite and capecitabine alternatives. Such awareness will help clinicians reevaluate the current and future roles of antimetabolites and capecitabine based on their therapeutic benefits and toxicity profiles, which might limit current use, particularly that of capecitabine.
