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Introduction: South Asians (SA) have a two times greater prevalence of CAD and metabolic syndrome (MetS) than matched Europeans. Diet and physical activity may be best addressed through culturally-tailored interventions. The Stanford South Asian Translational Heart Initiative (SSATHI) was designed to help SA better understand and improve their risk factors. We tested the hypothesis that a team-based and culturally-tailored clinical intervention for SA would result in a reduction in MetS risk factors. Methods: Patients underwent an initial assessment consisting of fasting lipid profile, advanced lipid studies (lipid fractionation, lp (a), apoA1, apoB), inflammatory markers (high sensitivity CRP, homocysteine), and A1c. All non-diabetics underwent two-hour OGTT. Following initial assessment by a cardiologist, a registered dietician developed a personalized nutrition plan based on SA cuisine. Results: A total of 395 patients were seen between July, 2011 and July, 2019. Of these, 198 (50%) completed at least two cardiologist visits with baseline and follow up labs. Patients had an average age of 45.5 years and 86% were male. At baseline, SSATHI patients had a mean BMI of 26.4 (IQR = 23.9-28.8), 52% of patients had total cholesterol greater than 190 mg/dl, 21% had systolic BP > 140 mmHg, and 13% had diastolic BP > 90 mmHg. During an average follow-up of 11.8 ± 9.2 months, diastolic BP declined from 80.9 ± 9.32 to 78.9 ± 7.6 mmHg (p = 0.028), total cholesterol decreased from 190.4 ± 46.4 to 153.4 ± 63.7 mg/dl (p < 0.001), total triglycerides declined from 137.1 ± 87.1 to 100.2 ± 67.5 mg/dl (p < 0.001), and LDL declined from 120.4 ± 40.0 to 92.3 ± 46.4 mg/dl (p Conclusion: A team-based and culturally-informed program targeted to South Asian populations may help improve cardiometabolic risk factors but may be limited by program attrition and generalizability.

Molecular alterations in the histone methyltransferase EZH2 and the antiapoptotic protein Bcl-2 frequently co-occur in diffuse large B-cell lymphoma (DLBCL). Because DLBCL tumors with these characteristics are likely dependent on both oncogenes, dual targeting of EZH2 and Bcl-2 is a rational therapeutic approach. We hypothesized that EZH2 and Bcl-2 inhibition would be synergistic in DLBCL. To test this, we evaluated the EZH2 inhibitor tazemetostat and the Bcl-2 inhibitor venetoclax in DLBCL cells, 3-dimensional lymphoma organoids, and patient-derived xenografts (PDXs). We found that tazemetostat and venetoclax are synergistic in DLBCL cells and 3-dimensional lymphoma organoids that harbor an EZH2 mutation and an IGH/BCL2 translocation but not in wild-type cells. Tazemetostat treatment results in upregulation of proapoptotic Bcl-2 family members and priming of mitochondria to BH3-mediated apoptosis, which may sensitize cells to venetoclax. The combination of tazemetostat and venetoclax was also synergistic in vivo. In DLBCL PDXs, short-course combination therapy resulted in complete remissions that were durable over time and associated with superior overall survival compared with either drug alone.

Molecular alterations in the histone methyltransferase EZH2 and the antiapoptotic protein BCL2 frequently co-occur in diffuse large B-cell lymphoma (DLBCL). We hypothesized that EZH2 inhibition and BCL2 inhibition would be synergistic in DLBCL. To test this, we evaluated the EZH2 inhibitor tazemetostat and the BCL2 inhibitor venetoclax in DLBCL cells, 3D lymphoma organoids, and patient-derived xenografts (PDXs). We found that tazemetostat and venetoclax are synergistic in DLBCL cells that harbor both an EZH2 mutation and a BCL2/IGH translocation, as demonstrated by CI values Citation Format: Hanna Scholze, Regan E. Stephenson, Raymond Reynolds, Shivem Shah, Rishi Puri, Matthew R. Teater, Herman van Besien, Destini Gibbs-Curtis, Hideki Ueno, Salma Parvin, Anthony G. Letai, Susan Mathew, Ankur Singh, Ethel Cesarman, Ari Melnick, Lisa Giulino-Roth. Combined EZH2 and BCL2 inhibitors as precision therapy for genetically defined DLBCL subtypes [abstract]. In: Proceedings of the AACR Virtual Meeting: Advances in Malignant Lymphoma; 2020 Aug 17-19. Philadelphia (PA): AACR; Blood Cancer Discov 2020;1(3_Suppl):Abstract nr PO-53.