Lesson 10 Venetoclax and p53

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• Venetoclax


  Next generation drug, still orally bioavailable but less toxic to platelets because targets Bcl-2 but not Bcl-xL
• Venetoclax is effective in mouse models, reduced platelet toxicity
• Venetoclax was given at 100 mg/kg/day for 21 days in a mouse model of B cell lymphoma harbouring the t(14;18) translocation
• Venetoclax dose escalation study design tested doses of 100-400mg, 150-1200mg, or 20mg in 58 patients with CLL and 9 with SLL

  
• Tumour lysis syndrome


  Large numbers of cancer cells are killed rapidly, ions and metabolic by-products are released into circulation, body cannot cope, can lead to acute renal failure and be fatal
• The study was re-started, using lower doses and lead-in dosing to manage tumour lysis syndrome

  
• In the phase I clinical trial, Venetoclax showed efficacy as a sole agent, particularly in patients with p53 deletion
• In the phase III randomised controlled trial, relapsed/refractory CLL patients receiving Venetoclax plus an antibody had better progression-free survival and overall survival compared to those receiving chemotherapy plus the antibody

  
• Venetoclax was approved and subsidised in Australia as of March 2019
• In a phase I trial for follicular lymphoma, Venetoclax showed a 38% overall response rate, despite high Bcl-2 levels, likely due to resistance from the Bcl-2 relative Mcl-1
• Molecules targeting Mcl-1 are now being developed for treating cancers whose survival depends on Mcl-1 activity
• P53 is a transcription factor

  
• P53


  • Induces expression of apoptotic proteins, eg the Bax-activator Puma to promote apoptosis
  • Induces cell cycle arrest, DNA repair genes

  
• P53 is the most commonly mutated gene in human cancers (>50%)
• P53


  A tumour suppressor
• Typical age of onset and type of cancer

  • Infancy: Adrenocortical carcinoma
  • Under five years of age: Soft-tissue sarcomas
  • Childhood and young adulthood: Acute leukaemias and brain tumours
  • Adolescence: Osteosarcomas
  • Twenties to thirties: Premenopausal breast cancer
• Li Fraumeni syndrome (LFS)


  • Cancer predisposition
  • Heterozygous mutation in p53. Tumours often result when second allele is mutated
  • 100% of females and 75% of males develop cancers
• Regulation of p53 activity

  1. DNA damage/stress

  2. Kinases activated

  3. Phosphorylated p53 (stable)

  4. Unphosphorylated p53

  5. p53-Ub (degraded)

  6. Cell cycle arrest proteins

  7. DNA repair proteins

  8. Lots of other proteins

  
• In LFS patients, all cells in their body harbour one defective p53 allele
• LFS is rare, but about half of all spontaneous cancers (which are the vast majority of cancers) also have p53 mutations
• In about ~60% of p53-mutant cancers, both alleles are disabled
• In the remaining 40%, only one p53 allele is mutated
• P53


  • A transcription factor
  • Acts as a tetramer
  • DNA-binding domain
• Most mutations occur in the DNA binding domain
• Mutant proteins are assembled into tetramers with the normal proteins
• Mixed tetramers can't bind DNA so can't induce target genes
• One mutant allele can act in a dominant way (preventing wildtype protein from doing its job)
• Most p53 tetramers in heterozygous cells are inactive
• Cells from many cancers contain high levels of mutant p53 (some also express wild type)
• If we could re-activate even a small portion of the mutant p53, perhaps apoptosis would be triggered in the cancer cells

  
• Some mutants are inactive at 37°C but are active at 32°C
• In vitro, chaperones (eg glycerol) encourage mutant p53 proteins to adopt conformations that resemble wild type, and boost activity

  
• It is generally easier to block function than restore it...and lots of compounds kill cells via mechanisms independent of p53 restoration
• P53 mutations are typically point mutations, not loss of expression

  
• Targeting mutant p53 for cancer therapy: disappointing so far
• Some (all?) of these drugs' anti-cancer activities have been proposed to result from other, p53-independent mechanisms