How Human Tissue Samples are Shaping Cancer Therapy
Posted 24th September 2018 by Kate Barlow
Thanks to advancements in human tissue sample procedures, we have been able to make major breakthroughs in cancer research. In the twenty-first century, epidemiological and clinical evidence have supported the claim that changes in metabolism can affect oncogenesis and tumour response to therapy.
It has been observed that metabolic conditions such as hyperglycemia, obesity, hyperlipidemia, and insulin resistance are directly associated with increased risk of cancer development as well as the acceleration of tumour progression. These findings indicate that statins and metformin may help decrease cancer-related deaths.
Phenformin is a drug used to treat diabetes that can help with anticancer effects, but it was discontinued in the late 1970s, due to the high occurrence of lactic acidosis. Globally, Metformin is the most commonly used antihyperglycemic agent because it has an optimal pharmacokinetic profile:
- 50 – 60% of absolute oral bioavailability
- Slow absorption
- Negligible binding to plasma protein
- Broad tissue distribution
- No hepatic metabolism
- Limited drug interactions
- Rapid urinary interaction
In addition, it has an exceptional safety profile, as only a very small percentage of individuals have had any side effects. Statins also have a great safety profile and are widely used.
Cancer and Cellular Metabolism
There has been an increased amount of evidence suggesting that malignant transformation is directly linked to changes in metabolism. Metabolic rearrangements have been linked with the inactivation of tumour suppressor genes and activation of proto-oncogenes. However, the accumulation of metabolites such as fumarate, succinate, and 2-hydroxyglutarate (2-HG) drives oncogenesis through the signal transduction cascades. Conclusively, these observations support the notion that signal transduction and intermediate metabolism are associated.
a) Oncogenes and Metabolism
Cancer causes signaling pathways from oncogenic drivers to provoke metabolic alterations. For example, the expression of the PKM2, an M2 isoform of pyruvate kinase, encourages the alteration of glycolytic intermediates in the direction of anabolic metabolism, while regulating both the transcriptional and post-transcriptional program that leads to the addiction of glutamine.
b) Oncosuppressors and Metabolism
There are some oncosuppressor proteins that can regulate cellular metabolism. The inactivation of tumour suppressor p53 occurs in more than 50% of all neoplasms, causing a variety of metabolic consequences that could potentially stimulate the Warburg effect. P53 can suppress the transcription of GLUT4 and GLUT1 and stimulate the expression of the apoptosis regulator, TIGAR, TP53 induced glycolysis, SCO2, glutaminase 2 (GLS2) and many other pro-autophagic factors. It also interacts physically with glucose-6-phosphate-dehydrogenase (G6PD) and with RB1-inducible coiled-coil 1 (RB1CC1).
c) Oncometabolites and Oncoenzymes
Metabolites can contribute to oncogenesis when mutations such as fumarate hydratase (FH) and succinate dehydrogenase (SDH) are present and are linked to sporadic and familial types of cancer. Once the enzymatic activity of SDH and FH are disrupted, succinate and fumarate accumulate and oncogenesis can occur as a result.
Targeting Cancer Metabolism
The metabolic targets for cancer are seen as a promising source for new drug targets. Some different approaches have resulted in the identification of several agents that can help with targeting glucose metabolism for cancer therapy. There are also some concerns about the uniformity between malignant cells and non-transformed cells that are undergoing proliferation.
a) Targeting Bioenergetic Metabolism
Some cancer-associated alterations such as the Krebs cycle, glycolysis, glutaminolysis, mitochondrial respiration, and fatty acid oxidation have been studied as potential sites for drug therapy.
b) Targeting Anabolic Metabolism
The anabolic metabolism in cancer cells increases the output of nucleotides, proteins, and protein biosynthesis pathways to help with the generation of new biomass in rapidly proliferating normal and malignant cells. A high metabolic flux through the pentose phosphate pathway is vital to cancer cells as it generates ribose-5-phosphate and nicotinamide adenine dinucleotide phosphate (NADPH).
c) Targeting Other Metabolic Pathways
Other pathways involved in the adaptation to metabolic stress may also provide drug targets for cancer therapy. This applies to autophagy, hypoxia-inducible factors 1, and nicotinamide adenine dinucleotide metabolism. A competitor of nicotinamide phosphoribosyltransferase (NAMPT), known as FK866, has antineoplastic effects in murine tumour models.
The extensive metabolic rewiring in malignant cells has provided a large number of possible drug targets. Some agents that target metabolic enzymes have been in use for decades, while others are still being developed. The use of metabolic modulators could be complicated by the similarities of highly proliferating normal cells and the metabolism of malignant cells. There might be a chance to harness the antineoplastic activity of these drugs clinically. While efforts have been primarily focused on merging metabolic modulators and targeted anticancer drugs, there is a growing opinion that metabolism and signal transduction are independent, if not separate, entities.
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Geneticist Inc. is a next-generation biorepository based in Los Angeles. At Geneticist’s biorepository we collect biomaterial from verticals such as Dermatology, Oncology, Immunology, & Infectious Diseases.
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