Abstract LB-230: Pt-Mal-LHRH, a newly synthesized compound attenuating breast cancer tumor growth and metastasis by targeting overexpression of the LHRH receptor

Abstract

In the United States, breast cancer affects 1 in 8 women during their lifetime. The National Cancer Institute estimated that this means 231,840 new breast cancer cases will arises in 2015, attributing to 40,290 mortalities. Survival of breast cancer and prognosis depends mainly on the type and aggressiveness of the cancer; invasive carcinomas contribute to the majority of cancer related deaths. As such, detection and early stage treatment of breast cancer is crucial to increasing prognosis and favorable outcome. Platinum based chemotherapeutics are widely accepted as a standard treatment for breast cancer. Current drugs on the market, including cisplatin and carboplatin, have been shown to effectively reduce tumor size and improve patient prognosis. However, many patients eventually relapse, developing new tumors that are chemo-resistant, along with exhibiting debilitating side effects, often leading to discontinuation of treatment. To combat this growing problem, we devised and synthesized a new analog of Carboplatin, entitled “Pt-Mal-LHRH”, to selectively target breast cancer cells overexpressing the LHRH receptor. Our initial results utilizing Pt-Mal-LHRH in-vitro showed a higher potency towards 4T1 (stage IV) breast cancer cells compared to those treated with Carboplatin. Cell viability was analyzed by an MTT assay, resulting in significant, (p>0.01), reduction in viable cancer cells treated with Pt-Mal-LHRH compared to those treated with Carboplatin. In addition, drug uptake was evaluated by ICP-MS after cells were treated with either Pt-Mal-LHRH or Carboplatin, displaying a 20-fold increase in 4T1 cellular uptake of Pt-Mal-LHRH compared to Carboplatin. We also found that Pt-Mal-LHRH selectively targets 4T1 breast cancer cells as there was a significant,(p>0.0001), decrease in 4T1 cell viability compared to normal mammary cells. In addition, Pt-Mal-LHRH showed a significant decrease in cell migration using an in-vitro scratch/cell migration assay. Subsequently, using an in-vivo mouse model, our findings showed a significant, (p>0.05), reduction in tumor volume in mice treated with Pt-Mal-LHRH (5 mg/kg/wk) through IP injection compared to those injected with Carboplatin. Furthermore, metastasis and tumor colonization in the lungs was significantly attenuated in Pt-Mal-LHRH treated mice compared to control and Carboplatin treated. Lastly, there was a slight decrease in lung weight and no difference in liver weight between treatment groups. Together, our data indicates that Pt-Mal-LHRH is potentially a more potent and selective chemotherapeutic agent than other platinum based drugs currently on the market, such as Carboplatin. Citation Format: Joseph D. Rollins, Lindsay Calderon, Margaret Ndinguri. Pt-Mal-LHRH, a newly synthesized compound attenuating breast cancer tumor growth and metastasis by targeting overexpression of the LHRH receptor. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-230.