December 8, 2023

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Nature: The history of tumor therapy targeting metabolism

Nature: The history of tumor therapy targeting metabolism


Nature: The history of tumor therapy targeting metabolism


100 years ago, Warburg discovered that tumor tissue undergoes metabolic changes. More than 70 years ago, Sidney Farber discovered the use of antifolate drugs to treat childhood leukemia. Twenty years ago, research discovered the relationship between oncogenes and metabolism.

However, in the past decade, the progress of therapeutics targeting tumor metabolism has been slow.

Only a few metabolism-based anticancer drugs have been approved for clinical trials.

The development of drugs targeting tumor metabolism often does not take into account non-tumor stromal cells and immune cells, but they have a critical role in tumor progression and maintenance.

By exploring immune cell metabolism, it may be possible to avoid undesirable off-tumor targeting during metabolic drug development.

Therefore, the metabolic characteristics of non-tumor cells and tumor cells in the tumor microenvironment must be considered in drug design.


Recently, researchers from the Wistar Institute and Ludwig Cancer Institute published a review article entitled Targeting cancer metabolism in the era of precision oncology in Nature Reviews | Drug Discovery .

This review summarizes recent advances, milestones, and setbacks in targeting tumor metabolism, and discusses future directions for the field.


Nature: The history of tumor therapy targeting metabolism


Sidney Farber published his seminal paper in The New England Journal of Medicine in 1948, in which he found that antifolates could provide relief from childhood acute lymphoblastic leukemia, before which ALL was commonly fatal.


Thirty years before this article was published, Otto Warburg discovered that tumors can utilize aerobic glycolysis, which can convert glucose into lactate, known as the “Warburg effect.” However, the discovery of aerobic glycolysis has not yet been successfully exploited in the clinic.


The use of 2-deoxyglucose, which inhibits glycolysis, also induces adverse side effects and has limited therapeutic effect.


In 11 children treated with activated folic acid, clinical symptoms worsened, Farber noted. He then collaborated with chemist Yellapragada Subbarow to synthesize the antifolate aminopterin and found that the inhibitor could relieve ALL in children, thus laying the foundation for tumor chemotherapy.


Currently, another folate antagonist, methotrexate, is used with I-asparaginase, with cure rates as high as 90%. A variety of drugs targeting nucleotide metabolism have also been approved for clinical use.


The recently approved drug targeting mutant isocitrate dehydrogenase in acute myeloid leukemia AML is a milestone in the precise targeting of tumor metabolism and establishes that metabolic therapy works.


The ideas of Warburg and Farber were gradually replaced in the 1980s by oncogenes and tumor suppressor genes, which were considered major targets for human tumor therapy. Molecular biology takes center stage at this stage, and tumor drivers targeting oncogenes have sparked research interest.


The focus on targeting metabolism has been replaced by a variety of potent kinase-targeting drugs. Research on the links between oncogenes, tumor suppressors, and metabolism began to emerge in the 1990s, which also led to a renewed focus on tumor metabolism.


The recent rise of immunotherapy has highlighted the importance of the tumor immune microenvironment, the center of tumor metabolism, where cells in all microenvironments are involved in tumor growth.


This review covers the basics of tumor metabolism and summarizes emerging small molecule drug development.




Metabolism: Basic Concepts and Weaknesses


Glucose, amino acid and fatty acid metabolism : Glucose is the main source of energy and the carbon skeleton for biosynthesis. Insulin and glucagon are the main molecules that regulate glucose levels in both fed and fasted states.

To maintain cellular homeostasis, glucose is converted to pyruvate through glycolysis. Pyruvate enters the mitochondria via the pyruvate carrier, where it is further oxidized by the tricarboxylic acid cycle TCA. The carbon skeleton and ATP are produced by glycolysis and mitochondrial oxidative metabolism.

Mitochondrial pyruvate carriers are tumor-suppressive, suggesting an important role for glycolysis in tumorigenesis. Amino acids and fatty acids are also taken up by cells to maintain function and structure.

Essential and non-essential amino acids enter cells through transporters for carbon metabolism, nucleic acid and protein synthesis.

Branched-chain amino acids can be used as an energy source and are converted into keto acids by mitochondrial branched-chain a-ketoacid dehydrogenase complexes, which enter the TCA cycle for oxidation.

Fatty acids and cholesterol are packaged in the liver and transported to peripheral tissues for uptake, storage or metabolism.

Fatty acid oxidation is a major source of energy. Complete oxidation of a 16-carbon fatty acid yields 129 ATP molecules, while a single glucose yields 38 ATP.


Nucleotide synthesis : The rate of tumor cell proliferation depends on nucleotide synthesis mediated by TCA cycle intermediates, pentose phosphate pathway-derived ribose, and amino acids that yield purine and pyrimidine nucleotides.

Sidney Farber specifically pointed out that one-carbon metabolism is critical for nucleic acid synthesis. These pathways contain multiple potential therapeutic targets.

However, normal tissue proliferation also depends on these pathways, so myelosuppression, gastrointestinal mucosal damage, and alopecia are common clinical manifestations of nucleotide synthesis-targeted chemotherapy.

Driven by RAS-RAF-MEK-ERK and PI3K-AKT-mTOR signals, proliferating cells import nutrients such as amino acids, activate mTORC1, induce transcriptional reprogramming of MYC and other transcription factors, and promote growth signal-related gene expression as well as protein and ribose body synthesis.

Oncogene-driven tumor cell growth-related genes are constitutively expressed. Normal proliferating cells will stop proliferating and return to the G0/G1 state when they sense nutrient deficiency, while tumor cells will die when they are nutrient deficient.


Weaknesses in tumor cell metabolism : Although tumor cells are more susceptible to inhibition by different metabolic pathways, these pathways are also exploited by immune cells, especially activated T cells.

Inhibition of specific nutrient transporters disrupts the targeting of antitumor drugs. Metabolic inhibition of CTL and NK cells attenuates the tumor suppressive effects of other targeted drugs. Therefore, it is most important to study therapeutic approaches targeting tumor metabolism in the context of the immune system.

In particular, solid tumors such as pancreatic cancer have more non-tumor cells than tumor cells. In contrast, hematological tumors, especially rapidly proliferating acute leukemia cells that rely on metabolism. Studies using CRISPR-cas9 screening have uncovered a number of tumor cell-type-specific weaknesses.

Integrative metabolomics and CRISPR-cas9 screening identified asparagine synthase as a weak point in solid tumor cell lines, which also suggests that the therapeutic pathway for I-asparaginase can be extended from ALL to solid tumors.

Also of note is the effect of diet on tumors. Multiple studies using different mouse tumor models have shown that diet is critical in the sensitivity of tumor metabolism to therapy, as it affects nutrient availability.




Metabolism-Based Drug Development


A key factor to consider when targeting metabolism is drug specificity.

The combination of medicinal chemistry and structural biology can be used to develop highly specific drugs, and crystallographic studies determine how molecules interact with their targets.

Among them are several highly specific metabolic inhibitors, acting at catalytic and allosteric sites.

The hydrophobic pockets commonly found in metabolic enzymes are a major challenge in targeting active sites. However, because tumor cells will remodel metabolic pathways, resulting in drug resistance, it will also reduce the effect of precise targeted therapy.

Therefore, combination therapy or treatments that block multiple pathways have advantages over monotherapy.

Metabolic tracer-based imaging techniques can be used to monitor drug activity in vivo.

The development of targeted metabolic drugs requires a combination of medicinal chemistry, structural biology, and pharmacokinetics and pharmacodynamics.





Metabolic target


Aerobic Glycolysis :

Inhibition of glucose uptake is a therapeutic approach.

STF-31 is a small molecule inhibitor that inhibits GLUT1. In vivo experiments have demonstrated that it has anti-tumor effects, but it has off-target effects.

STF-31 also inhibits the nicotinamide phosphoribosyltransferase NAMPT1, which also suggests that GLUT1 is not the only inhibitory target.

Despite reports that lactate is also an important energy source for tumors, this claim is controversial.

It has been found that blocking SLC16A family members MCT1 or MCT4 leads to the accumulation of intracellular lactate, thereby reducing the recycling of NADH to NAD+ and inhibiting glycolysis. Therefore, inhibition of MCT1 or MCT4 may have anti-tumor therapeutic effects.


Glutamine Metabolism :

Glutamine is highly abundant in plasma, ten-fold higher than glucose. Glutamine is transported into cells by ASCT2 and converted to glutamate by deamination by mitochondrial glutaminase.

It is then converted into α-ketoglutarate by glutamate dehydrogenase and enters the TCA cycle. Mouse model studies have shown selective tissue dependence on glutamine.

Therefore, there are tissue differences in targeting glutamine. The ASCT2 antagonist V-9302 has in vivo antitumor activity and can inhibit breast cancer by enhancing T cell activation.

V-9302 combined with the glutamine inhibitor CB-839 reduces liver cancer cell growth.


Fatty acid synthesis :

Although some tumors are dependent on fatty acid oxidation, highly specific inhibitors of fatty acid oxidation are currently lacking.

This review focuses on fatty acids and inhibitors that have been developed to maturity.

Inhibition of fatty acid oxidation with stomoxir has off-target effects, but it has inhibitory activity in mice with MYC-induced breast cancer.

Inhibition of palmitoyltransferase CPT1A by ST1326 has inhibitory activity in a mouse lymphoma model, but whether there is an off-target effect is unknown.


Amino acid metabolism :

Many clinically approved metabolic drugs target nucleotide metabolism, especially to interrupt DNA synthesis.

The antifolate therapy developed by Sidney Farber is the first to target tumor metabolism.

Recently, attention to one-carbon metabolism has begun to rise.

Methotrexate targets the dihydrofolate reductase DHFR and plays a key role in the development of tumor chemotherapy.

Pemetrexed appeared later, targeting thymidylate synthase and formamide ribonucleotide converting enzyme, for the treatment of non-small cell lung cancer.




Targeting tumor immunometabolism


A hallmark of successful application in the field of tumor metabolism is the FDA approval of mutant IDH2 and IDH1 inhibitors for the treatment of AML.

There are other inhibitors in clinical trials and pending approval.

However, the possible effects of these drugs on the tumor microenvironment are unknown.

Drugs targeting immune cell metabolism are not covered in this review, an emerging field that holds promise for new oncology metabolic drugs. More and more in-depth studies are needed on how metabolized drugs affect the tumor immune microenvironment.

The tumor immune microenvironment is extremely complex and varies with the composition of various cells, and the effects of these cells on tumor cells are also complex.

Tumor cells can produce immunosuppressive metabolites, such as adenosine, 2-hydroxyglutarate, lactate, and methylthioadenosine, which hinder tumor immunotherapy.

The composition of different types of tumor immune microenvironment is different, desmoplastic pancreatic cancer has a high abundance of stromal cells, and leukemia has a large number of circulating tumor cells.

Stromal cells provide nutrients to tumor cells, while immune cells such as M2 macrophages and MDSCs can suppress anti-tumor immune responses mediated by CD8+ CTL and NK cells.

Targeted metabolic therapy needs to find synergistic targets in tumor cells and immune cells to produce synergistic effects.

Therefore, it is crucial to study how targeting various metabolic enzymes affects T cell function.




Future direction

Numerous metabolic enzymes have been targeted in the study of tumor-targeted therapies, but the responsiveness of specific tumor types to inhibitors, single agents or in combination with other treatments, remains to be elucidated.

However, targeting specific metabolic enzymes, the plasticity of tumor metabolism can also become a major challenge.

Regardless of future developments, focusing on targeting tumor metabolism while synergistically enhancing anti-tumor immunity is the most desirable outcome.






Nature: The history of tumor therapy targeting metabolism

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Important Note: The information provided is for informational purposes only and should not be considered as medical advice.