Abstract 1746: Optimizing Gemcitabine efficacy through chemical modification for the treatment of pancreatic cancer using PDX mouse model

Abstract

Abstract PURPOSE: Despite the remarkable advances in cancer treatment, the incidence rate of pancreatic cancer (PCa) for decades among African Americans (AA) has been 30% to 70% higher than other racial groups in the United States. Gemcitabine (Gem) remains the first-choice treatment for PCa. It is administered as monotherapy in patients with locally advanced and metastatic PCa; but, drug resistance develops over time. Gem treatment resistance coupled with poor pharmacokinetics (short half-life) has resulted in poor treatment outcomes. The purpose of this study is to enhance the anticancer efficacy and pharmacokinetic profile of Gem through chemical modification of Gem with stearic acid by using mice bearing tumors from AA and White pancreatic cancer patients. METHODS: The Gem was modified by conjugating the 4-amino group of Gem and stearoyl acyl derivative to form 4-(N)-stearoyl-gemcitabine (4NSG). 4NSG was developed into solid lipid nanoparticles (4NSG-SLN) and characterized using nuclear magnetic resonance (NMR), micro-elemental analysis, and high liquid chromatography (HPLC). Patient-derived primary pancreatic cancer cells from AA (PPCL-135 and PPCL-192) and Whites (PPCL-46 and PPCL-68) were used to evaluate the anticancer activity of Gem and 4NSG-SLN. We performed antitumor efficacy testing of Gem and 4NSG-SLN in a patient-derived xenograft (PDX) mouse model harboring pancreatic tumors from the same AA and White patients. RESULTS: The H-NMR spectra displayed an amide bond at 11ppm, confirming the conjugated bond between the 4-amino group of Gem and stearoyl derivative. The half-maximal inhibitory concentration (IC50 =12 ± 2.1µM) of 4NSG-SLN-treated PPCL-46 and (IC50 =22 ± 2.6µM) of 4NSG-SLN-treated PPCL-68 cultures were significantly higher than that of Gem treated PPCL-46 and PPCL-68 cultures respectively (IC50 = 56 ± 2.4 µM, IC50 = 57 ± 1.5 µM, p-value: p<0.001). We found a similar trend of higher growth inhibition of 4NSG-SLN treated PPCL-135 and PPCL-192 cultures (IC50 = 11± 1.3 µM; IC50 = 9 ± 1.1 µM) respectively, P< 0.001 (4NSG-SLN-PPCL-135 vs. Gem-PPCL-135) and P<0.001 (4NSG-SLN-PPCL-192-2 vs Gem-PPCL-192) compared with Gem treated PPCL-135 and PPCL-192 cultures (IC50 = 56 ± 1.8 µM; IC50 =57 ± 2.4 µM) respectively. The anticancer activity of 4NSG-SLN showed an enhanced efficacy in PPCL-46, PPCL-68, PPCL-135, and PPCL-192 treated cultures compared with their corresponding Gem treatments. In vivo studies, 4NSG-SLN treated mice bearing AA tumors showed significant tumor growth inhibition compared with GemHCl treated mice bearing AA tumors. A similar pattern was observed where 4NSG-SLN treated mice bearing White tumors showed significant tumor growth inhibition than GemHCl treated mice bearing White tumors. CONCLUSION: This study reveals that 4NSG-SLN may be a novel approach to significantly enhance the therapeutic efficacy of Gem in the treatment of pancreatic cancer. Citation Format: Andriana Inkoom, Edward Agyare, Nkafu Bechem Ndemazie, Taylor Smith, Bo Han, Jose Trevino Trevino. Optimizing Gemcitabine efficacy through chemical modification for the treatment of pancreatic cancer using PDX mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1746.