Cancer and metabolism, pt.2

Role of metformin (antidiabetic drug) in cancer
1. Increases glucose uptake in adipocytes
2. Increase in lipid oxidation in muscle cells
3. Decrease in liver glucose production
  1. Decreased insulinaemia (insulin signals via the insulin receptor -> acitvates both PI3K and Ras pathways)
    1. Activation of Akt and MAPK -> activation of mTOR -> cell gorwth and protein synthesis (with inhibited apoptosis and autophagy)
4. Direct effects of metformin
  1. Inhibits mTOR by...
    1. Inhibition of complex 1 (inhibtion of oxidative phosphorylation) -> activation of AMPK (AMP-dependent kinase)
      1. AMPK activates TSC1/2 -> inhibits mTOR
    2. Inhibits RagGTPase (an activator of mTOR)
    3. Activates p53 -> activates REDD1 -> inhibtis mTOR
alpha-ketoglutarate derivatives
1. Competes with succinate and fumarate for prolyl hydroxylase
  1. In cancer... succinate and fumarate inhibit prolyl hydroxylase
    1. No hydroxylation of HIF1-alpha and therefore no degradation (via VHL ubiquitination)
      1. Using alpha-ketoglutarate derivatives (alpha-ketoglutarate is the normal substrate) overcomes and reverses this prolyl hydroxlation inhibition
    2. Due to loss of SDH and FH
mTOR (ser/thr kinase) antagonists
1. Licensed for reneal cell cancer
2. e.g. evrolimus, temsirolimus
3. Activated mTOR (by GFs, amino acids, energy status, oxygen)
  1. Protein synthesis
  2. Apoptosis inhibition (cell survival)
  3. Metabolism
  4. By RTKs -> activation of Ras or PI3K pathway -> activation of mTOR
    1. mTOR is a member of the PI3K family - therefore an effective treatment may include the dual blockade of both PI3K and mTOR
Amino acid metabolism and blood cancers
1. Asparagine as a target
  1. Guinea-pig serum caused regression of lymphoma in a mouse model (Kidd, 1953) - active substance was L-asparaginase
    1. L-asparaginase (produced in E. coli) now given in childhood ALL
    2. All cells need asparagine for survival
      1. Lymphoma cells (e.g. ALL) have repressed asparagine sythetase and therefore cannot synthesise asparagine - rely on asparagine from an outside source
2. Arginine as a target
  1. Arginine is an essential amino acid - without it cells will die
    1. If diet is deficient normal cells can synthesise argininosuccinate (made into arginine) by the enzyme argininosuccinate synthase (ASS1)
      1. Using cellular aspartate+ citrulline
      2. 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
Malignant pleural mesothelioma (MPM)
1. Invariably fatal
  1. 80% of cases linked to earlier asbestos exposure
    1. Long delay between exposure and disease
  2. After diagnosis, survival is between 9-12 months
2. ~2000 deaths each year
3. NICE guideline treatment - Platinum (cisplatin) and anti-folate (methotrexate)-based therapy (gives an extra 3 montsh at best)
  1. Both inhibit enzymes involved in nucleotide synthesis for DNA and RNA
4. Other treatment - pemexetred (alimta)
  1. Inhibits all enzymes involved in nucleotide synthesis: thymidylate synthase, dihydroxyfolate reductase (DHFR) and GARFT
    1. Gives 12 months survival (in combination with standard therapy)
5. ASS expression in MPM
  1. Many MPM cell lines have a low expression of ASS1
    1. Associated with a poorer prognosis - 5 months (over 12 months in ASS+ve MPM)
    2. Use of ADI-PEG 20 (arginine deaminase) reduces tumour size in MPM
      1. ADAM trial
      2. 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
Summary
1. Metabolism is dysregulated and is a key hallmark of cancer involved in invasion, metastasis, angiogenesis, survival etc.
2. Targeting cancer metabolism is an exciting area of current research and may provide novel therapeutic approaches
3. PREVENTION (E.G. CALORIFIC RESTRICITON) IS BETTER THAN THE CURE!

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Cancer and metabolism, pt.2

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