Cancer and metabolism, pt.2

Cancer and metabolism, pt.2

1. Role of metformin (antidiabetic drug) in cancer

   • Increases glucose uptake in adipocytes
   • Increase in lipid oxidation in muscle cells
   • Decrease in liver glucose production
     • Decreased insulinaemia (insulin signals via the insulin receptor -> acitvates both PI3K and Ras pathways)
       • Activation of Akt and MAPK -> activation of mTOR -> cell gorwth and protein synthesis (with inhibited apoptosis and autophagy)
   • Direct effects of metformin
     • Inhibits mTOR by...
       • Inhibition of complex 1 (inhibtion of oxidative phosphorylation) -> activation of AMPK (AMP-dependent kinase)
         • AMPK activates TSC1/2 -> inhibits mTOR
       • Inhibits RagGTPase (an activator of mTOR)
       • Activates p53 -> activates REDD1 -> inhibtis mTOR

2. alpha-ketoglutarate derivatives

   • Competes with succinate and fumarate for prolyl hydroxylase
     • In cancer... succinate and fumarate inhibit prolyl hydroxylase
       • No hydroxylation of HIF1-alpha and therefore no degradation (via VHL ubiquitination)
         • Using alpha-ketoglutarate derivatives (alpha-ketoglutarate is the normal substrate) overcomes and reverses this prolyl hydroxlation inhibition
       • Due to loss of SDH and FH

3. mTOR (ser/thr kinase) antagonists

   • Licensed for reneal cell cancer
   • e.g. evrolimus, temsirolimus
   • Activated mTOR (by GFs, amino acids, energy status, oxygen)
     • Protein synthesis
     • Apoptosis inhibition (cell survival)
     • Metabolism
     • By RTKs -> activation of Ras or PI3K pathway -> activation of mTOR
       • mTOR is a member of the PI3K family - therefore an effective treatment may include the dual blockade of both PI3K and mTOR

4. Amino acid metabolism and blood cancers

   • Asparagine as a target
     • Guinea-pig serum caused regression of lymphoma in a mouse model (Kidd, 1953) - active substance was L-asparaginase
       • L-asparaginase (produced in E. coli) now given in childhood ALL
       • All cells need asparagine for survival
         • Lymphoma cells (e.g. ALL) have repressed asparagine sythetase and therefore cannot synthesise asparagine - rely on asparagine from an outside source
   • Arginine as a target
     • Arginine is an essential amino acid - without it cells will die
       • If diet is deficient normal cells can synthesise argininosuccinate (made into arginine) by the enzyme argininosuccinate synthase (ASS1)
         • Using cellular aspartate+ citrulline
         • Several cancers (melanoma, hepatocellular carcinoma (HCC), mesothelioma and renal) lack ASS
           • Require an extracellular source
             • PEGylated (covalently added polyethylene glycol) arginine deaminase (ADI-PEG)
               • Converts arginine to citrulline and NH3
               • Promising signs in phase I/II trials in HCC and metastatic malignant melanoma (MMM)
             • Without arginine cells undergo apoptosis
           • Methylation of the ASS promoter [EPIGENETIC]
             • Low ASS is a sign for chemoresistance (particularly to platinum based drugs - cisplatin) and poor prognosis
               • Seen in MMM, HCC, osteosarcoma, mesothelioma, renal, pancreatic and prostate cancers
             • De-methylation as a treatment?
           • Indicates a poor prognosis

5. Malignant pleural mesothelioma (MPM)

   • Invariably fatal
     • 80% of cases linked to earlier asbestos exposure
       • Long delay between exposure and disease
     • After diagnosis, survival is between 9-12 months
   • ~2000 deaths each year
   • NICE guideline treatment - Platinum (cisplatin) and anti-folate (methotrexate)-based therapy (gives an extra 3 montsh at best)
     • Both inhibit enzymes involved in nucleotide synthesis for DNA and RNA
   • Other treatment - pemexetred (alimta)
     • Inhibits all enzymes involved in nucleotide synthesis: thymidylate synthase, dihydroxyfolate reductase (DHFR) and GARFT
       • Gives 12 months survival (in combination with standard therapy)
   • ASS expression in MPM
     • Many MPM cell lines have a low expression of ASS1
       • Associated with a poorer prognosis - 5 months (over 12 months in ASS+ve MPM)
       • Use of ADI-PEG 20 (arginine deaminase) reduces tumour size in MPM
         • ADAM trial
         • Szlosarek, 2013
           • Describe that the affects of ADI-PEG are neutralised by antibodies against it
             • Need to produce a less-antigenic version of ADI (human derived?)
           • Also describe the methylation of the ASS1 promotor in many MPM cell lines
             • Leading to supressed ASS1 transcription

6. Summary

   • Metabolism is dysregulated and is a key hallmark of cancer involved in invasion, metastasis, angiogenesis, survival etc.
   • Targeting cancer metabolism is an exciting area of current research and may provide novel therapeutic approaches
   • PREVENTION (E.G. CALORIFIC RESTRICITON) IS BETTER THAN THE CURE!