Lecture Notes: Cancer Metabolism and Epigenetics

Speaker Introduction

• Dr. Jason Lokasenna
  • Assistant Professor, Department of Pharmacology and Cancer Biology, Duke University
  • BA from Rutgers University (2003), PhD from MIT (2008)
  • Postdoctoral training at Harvard Medical School focusing on cancer metabolism
  • Positions at Cornell University, Duke University

Research Overview

• Focuses on cancer metabolism and its influence on cellular physiology
• Research areas include:
  • Metabolomics technologies applied to cancer biology, nutrition, and molecular physiology
  • Role of altered metabolism in cancer and chromatin states
  • Emphasis on 1-carbon metabolism, the TCA cycle, and histone methylation

Cancer Metabolism Basics

• Central Carbon Metabolism:
  • Nutrients from the environment undergo complex biochemistry to provide energy and materials for cell regeneration
  • Output leads to biological functions that confer fitness advantages
  • Interaction between metabolism and signal transduction pathways

One-Carbon Metabolism

• Nutrients processed to produce:
  • Nucleotides
  • Maintenance of cellular redox potential
  • Methyl groups for histone modification

Clinical Implications of Cancer Metabolism

Chemotherapeutic Agents Targeting Metabolism

• Common agents include Methotrexate, 5-FU, Pemetrexed, Gemcitabine
• Increasing understanding of molecular mechanisms behind their effectiveness

Repurposing Existing Drugs

• Example: Metformin, primarily for diabetes, showing potential therapeutic benefits in cancer

Role of Metabolic Enzymes

• Enzymes are druggable targets due to their catalytic sites and allosteric interactions

Lifestyle and Environmental Factors

• Diet and exercise can influence cancer metabolism and outcomes

Methodologies in Metabolomics

• Chromatography coupled with mass spectrometry for metabolite profiling
• Measurement of ~400 metabolites in ~30 minutes
• Isotopically labeled nutrients help track metabolic fluxes

The Warburg Effect

• A hallmark difference between normal and tumor cells
• Tumors exhibit high rates of glucose uptake and ferment glucose to lactate
• Historically noted by Otto Warburg

Hypotheses for Warburg Effect Advantages

1. Kinetic advantage: faster ATP production from glycolysis compared to oxidative phosphorylation
2. Immune evasion: lactate production may suppress immune responses
3. Support for anabolic processes: providing building blocks for new cells
4. Direct signaling functions to cellular machinery

Targeting the Warburg Effect

• Challenges in targeting glycolytic enzymes due to abundance and toxicities
• Investigating enzyme control properties such as GapDH in glycolysis
• Kinetic Acid identified as a potential GapDH inhibitor

One-Carbon Metabolism and Epigenetics

• One-carbon metabolism intersects with chromatin biology
• Influence of diet on metabolic pathways affects epigenetic modifications
• Low methionine diets show alterations in histone methylation in cancers

Dietary Interventions in Cancer

• Methionine restriction leads to beneficial metabolic effects in model organisms
• Human pilot studies show dietary adjustments can target one-carbon metabolism

Conclusion and Future Directions

• Continue exploring mechanisms of how diet influences metabolic pathways and chromatin
• Investigate therapeutic avenues targeting one-carbon metabolism in cancer

Acknowledgments

• Thanks to team members contributing to research efforts

Questions and Discussions

• Discussion on caloric intake, macronutrient composition, and their effects on cancer outcomes
• Considerations of epigenetic modifications and their dynamic nature in cancer biology.