Master Program in Molecular Biotechnology

CANCER METABOLISM

Cancer Metabolism

Academic year 2023/2024

Sommario del corso

• Course objectives
• Results of learning outcomes
• Program
• Course delivery
• Learning assessment methods
• Suggested readings and bibliography
• Teaching tools
• Course card

Course objectives

In the last ten years dysregulated metabolism has emerged as an hallmark of cancer and there is abundant interest in developing anti-cancer therapies by selectively targeting aberrant metabolic pathways. The aim of this course is to give an overview of the most recent advances in cancer 's metabolism with an eye at possible therapeutic interventions. In particular metabolism will be revisited in light of the adaptations imposed by the activation of oncogenes, the loss of tumor suppressors, or the mutations of metabolic genes. The imaging techniques available to detect deviations in metabolism will be presented. The translational value of these advances, both in diagnostic and therapeutic terms will be illustrated.

Results of learning outcomes

Program

• The fundamentals of cancer metabolism. Aerobic glycolysis: the Warburg effect.
• The alteration of the most common metabolic regulatory mechanisms. The principles of metabolic regulation altered in tumors. The revisiting of the "Warburg effect": the role of metabolic intermediates in tumorigenesis. The paradox of Peto.
• Metabolic reprogramming by oncogenes and tumor suppressors in cancer. The role of the LDH-A enzyme and lactate in cancerous metabolism.
• study of LDH-A inhibitors from pre-clinical use to the first clinical trials. What cancer is telling us about metabolism: C. Thompson's lecture and discussion
• the role of divergent glycolytic flows: the role of hexokinase 2 and phosphoglycerate dehydrogenase. In vitro and in vivo studies.
• The role of RAS in cellular metabolism. The discovery of KRAS-G12C inhibitors
• how we sense and control nutrient consumption (AA and glucose). The role of GCN2. The discovery of TOR. The pathways of mTORC1 and mTORC2. The role of mTOR in cell growth and homeostasis of glucose and AA.
• Insulin resistance, mTOR longevity and cancer. The 1st, 2nd and 3rd generation mTOR inhibitors. The squalene role in the cancerous metabolism of ALCL-ALK tumors positive.

• AMPK as the main regulator of the cell's energetic homeostasis. Interplay between mTOR and AMPK. Allosteric activators of AMPK in the treatment of diabetes and cancer: the anti-Warburg effect.
• The role of HIF in "metabolic reprogramming". SDH, FH mutations in cancer and their role in HIF regulation.
• IDH mutations in cancer. The role of TETs proteins in the epigenetic control of gene expression.
• The role of IDH and TET2 mutations in the control of hematopoiesis and in the onset of leukemias. 2HG as an oncometabolite. Molecular target therapy against IDH1/2 in AML. The resistance acquired at AG-221.
• Fructose metabolism in anoxia conditions. The possible therapeutic role of vitamin C in mutated colorectal RAS/BRAF. The role of alpha-ketogutarate in controlling self renewal processes of HSC and ESC.
• The role of P53 in the control of glycolysis, TCA and NADPH synthesis. The role of glutamine as a donor of amino groups and carbonaceous skeletons in the biosynthetic processes of cancer cells.
• Serine and glycine metabolism in tumor metabolism. The intersection with the TP53 pathway, the role of glycine decarboxylase. The predominant role of serine and the toxicity of glycine in the 1-C metabolism.

Course delivery

Original scientific articles will be illustrated during classes. Power point presentations of the lectures will be made available to the students.  A list of recent articles will be provided, from which each student will select a few for the oral presentation. A list of reviews will be also provided.

Learning assessment methods

Each student will provide an oral presentation (max 30 min), using power point slides, in which the most recent scientific articles, from a list proposed also by the teacher, will be discussed together. The students are invited to start their presentation with an adequate introduction. After the oral presentation there will be a session of questions based on the principal topics of the course. This presentation will provide a bonus (1 score max.) for the exam.

The exam will consist of:

-either a written test including 4 open questions (score from 0 to 7 according to the accuracy of the answer) and 4 multiple choice questions (score 1)

-Or an oral examination where each student will be asked questions on the main topics of the program carried out during classes.

Specifically, will be evaluated the capability to discuss in depth and properly the main topics of the course, including also logic, reasoning ability, criticism, quality of the exposure and the appropriateness in the use of scientific terminology

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