LAUSR

Background/Hypothesis: The amino acid transporter SLC6A14 is upregulated in estrogen receptor (ER)-positive breast cancer, a subtype that represents 75-80% of all breast cancers. Obesity/overweight increases the risk of breast cancer due to estrogen generated from fat cells that fuel the growth of the ER-positive breast cancer. Previous studies from our lab have demonstrated that blockade of the amino acid transporter SLC6A14 by the small molecule α-methyltryptophan reduces the growth of ER-positive breast cancer in mouse xenografts of human breast cancer cells and in a spontaneous mouse model of ER-positive breast cancer. We have also discovered that α-methyltryptophan functions as a potent weight-loss agent. We believe that this compound would be effective for the treatment of ER-positive breast cancer, especially in obese/overweight women. α-methyltryptophan is metabolized by aromatic amino acid decarboxylase. Therefore, combination of this compound with carbidopa, a well-known inhibitor of this enzyme, might potentiate the anticancer efficacy of α-methyltryptophan. We tested this idea in the present study using a syngeneic mouse model of ER-positive breast cancer using the mouse breast cancer cell line AT3. Results: A syngeneic tumor-cell transplant mouse model was used for ER-positive breast cancer. AT3 cells were injected into the mammary fat pad of C57BL/6 mice. This allows to monitor the growth of AT3 tumor growth in an immunologically competent mammary tissue environment. Drug treatment in drinking water was started after tumor growth was noticeable (100 mm3). There were four groups: (i) control; (ii) α-methyltryptophan at 0.5 mg/ml; (iii) carbidopa at 0.25 mg/ml; (iv) α-methyltryptophan at 0.5 mg/ml + carbidopa at 0.25 mg/ml. Tumor growth was monitored every three days. The mice were killed after 4 weeks of treatment. Tumors were excised and weighed. These studies showed that α-methyltryptophan and carbidopa were independently effective in reducing the tumor (48% reduction, p<0.05 for α-methyltryptophan; 50% reduction, p<0.05 for carbidopa), but the combination was the most effective (92% reduction, p<0.01). These effects were evident irrespective of whether the monitored parameter was tumor weight or tumor volume. Conclusion: The combination treatment significantly decreased the tumor size and volume compared to carbidopa and α-methyltryptophan alone. We do not know yet if the improved efficacy of the combination of the two drugs is due to a simple additive effect or due to a synergistic effect. Studies have shown that carbidopa promotes degradation of ER, indicating that carbidopa has its own independent anticancer effect that is relevant to ER-positive breast cancer. Further studies are needed to differentiate between the effect of carbidopa as an independent anticancer agent and its ability to potentiate the anticancer efficacy of α-methyltryptophan by preventing its metabolic degradation. Citation Format: Sirin Falconi, Sabarish Ramachandran, Vadivel Ganapathy. Carbidopa/α-methyltryptophan as an ideal combination therapy for breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2785.