Cancer metabolism

Question 1

One-carbon metabolism is central to many cancer-related processes. Which of the
following therapeutic approach/drug leverages that vulnerability?
a) Methotrexate
b) Cisplatin
c) Surgery
d) Neoadjuvant anti-PD-1
e) Radiotherapy

Answer 1

a) Methotrexate

Question 2

Which of these metabolites is an oncometabolite?
a) isocitrate
b) alpha-ketoglutarate
c) s-adenosylselenocyteine
d) s-adenosylphenylalanine
e) D-2-hydroxyglutarate

Answer 2

e) D-2-hydroxyglutarate

Question 3

The phosphoinositide 3-kinase pathway is frequently deregulated in cancer. However, inhibitors targeting the phosphoinositide 3-kinase pathway performed poorly in clinical trials. How response to phosphoinositide 3-kinase pathway inhibitors can be enhanced?
a) Combination with high fat diet
b) Combination with a ketogenic diet
c) Combination with methotrexate
d) Combination with checkpoint blockade
e) Combination with histidine

Answer 3

b) Combination with a ketogenic diet

Question 4

What are the key hallmarks of cancer as outlined in 2000?

Answer 4

The hallmarks identified in 2000 include resisting cell death, inducing angiogenesis, enabling replicative immortality, activating invasion and metastasis, evading growth suppressors, and sustaining proliferative signaling

Question 5

According to the 2011 udpate, what additional features characterize cancer

Answer 5

The 2011update adds features such as deregulating cellular energetics avoidinc immune destruction, promoting tumor related inflammation, and contributing to genome instability and mutation

Question 6

Define the Warburg effect in cancer metbolism

Answer 6

The warburg effect refers to the tumors favoring anaerobic glycolysis over oxidative phosphorylatio, for energy prodution, even in the presence of oxygen, leading to increased lactate production and providing glycolytic intermediates for tumor growth

Question 7

How does the warburg effect support tumor growth

Answer 7

Through anaerobic glycolysis, tumors generate glycolytic intermediates that serve as building blocks for tumor growth and metastases, supporting various nalabolic pathways that promote rapid growth

Question 8

Explain the metabolic differences within tumors and implications

Answer 8

Tumor cells distant from blood vessels, experience nutrient scarcity and exhibit a different metabolism, undergoing autophagy, utilizing specific nutrients like branched-chain amino acids (BCAA) and undergoing beta oxidation of fatty acids contrasting with cell nearer to the tumor periphery

Question 9

How do changed in angiogenesis affect cancer metabolism

Answer 9

Angiogenic processes alter the tumors nutrients supply, leading to disequilibrium in cellular metabolism. As new blood vessels supply nutrients and remove lactate from the tumor microenvironment the tumors metabolic dynamic change

Question 10

Detail the role of glucose and glutamine in supporting cancer metabolism

Answer 10

Glucose supports one-carbon metabolism, aiding nucleotide biosynthesis and methylation. Glutamine provides a carbone backbone for various building blocks necessary for tumor growth

Question 11

What are the pros and cons of standard cell cultures enriched with glutamine and glucose for studying cancer metabolism

Answer 11

Pros include cost-effectiveness, easy measurement of flux and levels, and compatibility with high-throughput genetic and chemical screens
Cons include the absence of cellular heterogeneity, lack of microenvironmental physical factors (like ECM), and the use of non-physiological supplied nutrients.

Question 12

Describe the advantages and limitations of 3D tissue culture or mouse models in studying cancer metabolism.

Answer 12

3D culture or mouse models use more glucose, mimicking the production of lactate. Pros involve better representation of physical microenvironments
cons include limited cell heterogeneity, incomplete representation of physical factors, non-physiological nutrient supplies, higher costs, and less tractability for high-throughput experiments.

Question 13

What is FDG-PET used for in cancer imaging, and why might it fail for some tumors?

Answer 13

FDG-PET visualizes glucose uptake and anabolic processes. It can fail for tumors not avid for glucose; for instance, prostate cancer relies less on glucose and uses alternative substrates like lipids or acetate, requiring PET/CT imaging with acetate or choline tracers

Question 14

Explain the impact of nucleotide biosynthesis inhibitors on rapidly dividing cells and highlight specific chemotherapy medications targeting this pathway.

Answer 14

Drugs inhibiting nucleotide biosynthesis affect normal rapidly dividing cells (e.g., intestinal cells). Chemotherapy medications such as Pemetrexed, 6-MP, 6-TG, 5-FU, and Methotrexate target nucleotide biosynthesis pathways in cancer.

Question 15

What are the consequences of IDH mutants in cancer metabolism, and how do they affect cellular functions?

Answer 15

IDH mutants convert a-KG to D-2-hydroxyglutarate, disrupting metabolic homeostasis and depleting the a-KG pool, leading to a broken TCA cycle. They affect DNA methylation via TETs and IDH1, impacting histone demethylation, CpG islands, and gene regulation. Clinically, IDH1/2-mutants are targetable.

Question 16

What does metabolomics measure, and what comprehensive information does it provide in cancer studies?

Answer 16

Metabolomics measures and interprets changes in the metabolome, encompassing small molecules (MW < 1500 Da) in biofluids, cells, tissues, or organisms. It offers functional information and integrates genetic, transcriptomic, and proteomic variation, along with the exposome, for phenotype characterization.

Question 17

What are the categories of approaches used in studying metabolism?

Answer 17

Approaches are categorized as static (global untargeted/targeted metabolic profiling like NMR, GC-MS, LC-MS/MS), dynamic (fluxomics utilizing 13C or 1H fluxes), and imaging (MS-based imaging, MR-spectroscopy imaging, Positron Emission Tomography).

Question 18

What are the applications of metabolic studies in disease research and treatment?

Answer 18

Metabolic studies offer insights into disease biology, aid in identifying therapeutic targets, assess drug safety, efficacy, and mechanisms of action, provide biomarkers for target engagement, patient diagnosis, prognosis, and therapy selection, assist in pharmacometrics modeling, and even support surgeries via tools like the i-knife for real-time tissue analysis.

Question 19

What components and factors constitute the tumor microenvironment?

Answer 19

The tumor microenvironment includes cancer cells, lymphocytes, neurons, adipocytes, TAMs (tumor-associated macrophages), ECM (extracellular matrix), vasculature, nutrients, oxygen, metabolic waste, and pH variations. Lactate, produced under hypoxic conditions, affects redox balance, angiogenesis, the TCA cycle, bioenergetics, and biosynthesis.

Question 20

How does the tumor microenvironment affect nutrient availability and impact T cell function?

Answer 20

Cancer cells often consume more glucose and tryptophan, depriving other cells in the microenvironment and impacting T cell function. TAMs uptake tryptophan and arginine, further depriving T cells.

Question 21

How does diet influence tumor growth, and what experimental evidence supports this?

Answer 21

Diet impacts tumor growth differently depending on cancer stage and cellular genetic makeup. Studies on mice with PTEN and/or PTPN1 deficiency show increased cell proliferation with a high-fat diet. Dietary restriction affects cell proliferation differently based on genetic alterations (PTEN loss vs. hyperactive Ras).

Question 22

In what ways does a high-fat diet affect cancer progression in specific oncogene-driven models?

Answer 22

A high-fat diet fuels prostate cancer progression by altering the metabolome and amplifying oncogenic programs like MYC. Reverting to a normal diet can normalize transcriptomic profiling.

Question 23

What happens when diet and exercise improve before surgery?

Answer 23

Patients tend to walk further post-operatively compared to their pre-operative walking distance.

Question 24

How does radiation therapy affect cancer cells?

Answer 24

Ionizing radiation causes double-strand breaks that can kill non-replicating cancer cells. It’s used in prostate cancer treatments before or after surgery and can be administered systemically.

Question 25

What dietary elements are linked to radiotherapy’s effectiveness?

Answer 25

Radiotherapy is linked to folate and methionine cycles, which rely on nutrients from the diet such as dietary methionine (found in eggs, poultry, shrimp) and folate-rich elements (Vitamin B9).

Question 26

What does 5-fluorouracil (5-FU) do in cancer treatment?

Answer 26

5-FU is an antimetabolite drug used in colorectal cancer. It inhibits thymidylate synthase, affecting RNA and DNA incorporation. Combined with methionine restriction, it limits tumor growth more effectively.

Question 27

How does Methotrexate (MTX) function in cancer therapy?

Answer 27

MTX inhibits DNA, RNA, thymidylate, and protein synthesis. Cells lacking SLC, a transporter for MTX, or FTCD, involved in histidine catabolism, show resistance. Dietary histidine supplementation can impact MTX sensitivity in tumors.

Question 28

What is the impact of PI3K inhibitors in cancer treatment?

Answer 28

Hyperactivity of the PI3K pathway increases cell proliferation and survival in cancer. Combining PI3K inhibitors with a ketogenic diet or SGLT2 inhibition improved survival compared to using the inhibitors or diet alone.

Question 29

What does PD-1 checkpoint blockade do for the immune system?

Answer 29

It releases the natural brake on T cells, enabling them to recognize and attack tumors by blocking the interaction between PDL1/PDL2 with PD1, thereby reactivating T cells for tumor clearance.

Question 30

How does diet-induced obesity affect PD1 expression on T cells?

Answer 30

Diet-induced obesity increases PD1 expression on CD8 T cells, leading to T cell exhaustion and decreased T cell proliferation over the long term.

Question 31

What impact does PD1 expression have on T cells regarding targeting tumors?

Answer 31

If PD1 is not expressed on T cells, they cannot effectively target anything. PD1 expression is necessary for T cells to recognize and target tumors.

Question 32

How does obesity and PD-L1 checkpoint inhibition affect tumor growth?

Answer 32

Mice treated with anti-PDL1 on a high-fat diet showed a decrease in tumor growth and metastases compared to the control group. Obesity is suggested as a potential mediator of immune dysfunction and tumor progression, which can be reversed by PDL1 checkpoint inhibition, making the therapy more effective, especially in obese patients.