Cancer therapy: Targeting in the field of metabolic rewiring
Monday, June 30, 2014
Of more than 100,000 carcinogen point mutations, 350 are known to influence cancer phenotype. However, 30 years of intensive research on cancer biology and large amounts of grant money invested have translated into few novel treatments.
Part of this difficulty in highlighting suitable drug targets could be the large number of passenger mutations in comparison to driver mutations. Also, multiple driver mutations are required for the development of most common cancers.
This raises many questions regarding the true value of development of multiple potential new therapeutics just to prove they cannot provide effective treatment for cancer. Perhaps we have missed the point. Metabolic reprograming of cancer cells could be yet another key to a more effective treatment for cancer.
Cancer is a multifactorial disease. It is well known that oncogenes' gain of function and tumor suppressors' loss of function are among the factors causing cancer. However, it is clear that there must be additional factors involved in the process of tumorigenesis. Reprogramming of energy metabolism is one of these factors.
Cancer is well known to cause major changes in cellular bioenergetics. Some of these changes include: glycolysis, glutaminolytic flux, lipid and amino acid metabolism and mitochondrial biogenesis, as well as induction of pentose phosphate pathway and macromolecule biosynthesis.
Considering the proven critical role of metabolic reprogramming for tumorigenesis, cancer bioenergetics has become a promising and rapidly-growing field. Several compounds have been developed for selective inhibition of metabolic enzymes with a critical role in tumor development. These are in various stages of clinical trial and will probably find their way into the market in less than a decade.
Some of these compounds at the preclinical stage include: 3-bromopyruvate, phloretin, 3PO, BPTES, 968 and FX11, affecting glycolysis, glucose transport, glutaminolysis and lactate production. Some of these compounds at phase 1 clinical trial include: dichloroacetate and AZD-3965, which target lactate production.
Some other compounds have been subject to ongoing clinical trials with promising initial data, including: 2-deoxyglucose, IDH1/2 inhibitors, PKM2 inhibitors, PKM2 activators and metformin, which target glycolysis, biosynthesis and energy production pathways.
One compound has even been approved for leukemia targeting asparagine and glutamine availability for cancer cells. L-asparaginase basically promotes asparagine and glutamine degradation, limiting the supply of these amino acids for cancer cells.
Furthermore, some other compounds have been listed in the literature as potential drugs/compounds targeting cancer metabolism pathways and mode of action, including: fasentin, clotrimazole, lodacetate, fluoride, buthionine, S'R'sulfoximine, 6-aminonicotinamide, chloroquine, c93, FAS3', rotenone, γ-TOS, oligomycin, resveratrol, L- γ-glutamyl-P-nitroanilide (GPNA) and aminoxyacetic acid (AOA).
These target glucose uptake, glycolytic flux, oxidative phosphorylation, stromal fuel supply, fatty acid synthesis, glutamine uptake, reactive oxygen species synthesis, ATP synthesis, mTor activation and transamination.
These observations highlight the promising potential for cancer metabolic pathway targeting.
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