Abstract C050: Vitamin B6 restriction impairs pancreatic cancer progression

Abstract Introduction: Cancer cells utilize altered metabolism to sustain their rapid growth, and understanding how these metabolic changes aid in tumor development could enhance current treatment approaches. Vitamins are essential micronutrients necessary in small quantities to support the proper functioning and metabolism of our organs and systems. Despite the recognized importance of vitamins in maintaining overall health, there is no direct evidence linking vitamin metabolism to pancreatic ductal adenocarcinoma (PDAC). Methods: PDAC animal models, organoid models, 3D-culture models, and LC-MS/MS-based metabolomic analysis were used to explore the role of vitamin B6 (VB6) in pancreatic cancer. Results: Our data showed that 1) Patients with PDAC exhibit lower levels of circulating vitamin B6 compared to healthy individuals of the same age. Additionally, vitamin B6 levels are reduced in the interstitial fluid of KPC (KrasG12D/+; p53R172H/+; Pdx1-Cretg/+) tumors and in the blood of mice with KPC tumors compared to healthy mice of the same age; 2) PDAC cells metabolize VB6 more rapidly than non-cancerous pancreatic epithelial cells; 3) VB6 restriction impairs PDAC cell proliferation in vitro and PDAC tumor growth in vivo; 4) VB6 depletion decreases key metabolites of the one-carbon pathway necessary for PDAC cell growth; 5) Inhibiting the one- carbon pathway mimics the effects of a vitamin B6 deficiency on PDAC cell proliferation. And knocking down VB6-dependent enzymes SHMT1/2 negates the pro-growth impact of VB6. Conclusion: Our research suggests that VB6 plays a key role in regulating various metabolic processes essential for the growth of PDAC cells. By focusing on inhibiting VB6-dependent enzymatic reactions, we may uncover new therapeutic strategies for treating PDAC. Citation Format: Chunbo He, Kamiya Mehla. Vitamin B6 restriction impairs pancreatic cancer progression [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr C050.