Abstract C025: Enhanced efficacy of gemcitabine analogs and AZD 1775 combination therapy in patient-derived organoids

Abstract Pancreatic cancer (PCa), specifically Pancreatic Adenocarcinoma (PDAC), is projected to become the second leading cause of cancer related death by 2040. Currently, the 5-year survival rate for pancreatic cancer is between 7% - 12%. The standard treatment options for PDAC are chemotherapy and surgical resection. However, pancreatic cancer presents multiple challenges to successful treatment. First, PDAC is usually diagnosed in the advanced stages of the disease, even if diagnosed early only a small fraction of patients are eligible for surgical resection, about 13% - 15%. Second, PDAC is characterized by a stiff extracellular matrix. This stiffness can lead to poor vascularization, diminished immune responses and cell migration/metastasis. Finally, PDAC is notorious for being extremely resistant to chemotherapy regiments. In addition to these challenges, health disparities add to the dismal prognosis of pancreatic cancer. Examples of these disparities include unequal access to healthcare facilities and screenings, awareness of disease risk factors and symptoms and socioeconomic factors. Differences in genetics can influence the various outcomes seen in PDAC in terms of health disparities. Certain genetic mutations, some more prevalent in certain ethnic groups, can increase the risk for PDAC. Variation in tumor heterogeneity and genetic factors impacting drug metabolism can influence patient outcomes. To overcome some of these challenges, we have developed and tested novel gemcitabine analogs, conjugated with various fatty acid chains in collagen-based 3D gel, Patient Derived Organoid (PDO) models. The collagen-based gel allows tuning of the physical stiffness by varying the gelatin percentage, creating a more realistic tumor microenvironment with the intratumoral pressure can be upwards of 10 kPa. We have tested the gemcitabine analogs on patient derived cells, G43 and G46, from black and white patients respectively, in both soft and stiff matrices. Our results indicated that medium to long fatty acid chains (8, 10 and 18 carbon chains) have increased effectiveness, especially in softer matrices. Comparatively, G46 cells exhibited higher drug resistance across all environments than G43 cells. Recent studies have shown that combining Gemcitabine with AZD 1775, a WEE1 inhibitor may have synergistic effects. We tested the combinations of Gemcitabine analogs and AZD-1775 on both G43 and G46 patient derived cells in 2D and 3D environments. Our data suggests that short to medium length fatty acid chains (2-8 carbons) provide optimal combinational effectiveness. The combined treatment also demonstrated promising results in increasing treatment effectiveness in G46, which are typically chemoresistant. Further studies will examine the influence that tumor microenvironment may have on PDAC response to the combination therapy, as well as intrinsic difference between black patient-derived cells and white patient-derived cells and their sensitivity or resistance to treatment. Citation Format: Jonathan Barajas, Edward Agyare, Xueyou Zhu, Sherise Rogers, Ba Xuan Hoang, Bo Han. Enhanced efficacy of gemcitabine analogs and AZD 1775 combination therapy in patient-derived organoids [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C025.