My wife is most likely to use PARP inhibitor in few weeks time, so I tried to put together some potential strategies that may synergize with PARP inhibitors. FYI, my wife is mTNBC and the parp inhibitor will be 9th line therapy. We just had NGS done on her met and found somatic BRCA2/ATM/ATR (low vaf).

Comments welcome and would love to continue updating the list. 

https://www.dropbox.com/s/cmwvy9nd3uusadg/parp_strategy.pdf?dl=0

Briefly speaking, main strategies are following;

1. Inhibit Drug Efflux (Just like other treatments)

1. • Talazoparib for example is a substrate of P-gp and BRCP1
2. Increase DNA/Oxidative Damage so that DNA repair starts the action

1. • For DNA damage, temozolimide may work while decitabine and similar also could work.
   • For oxidative damage, I think Daniel has put a list together somewhere.

      3. Inhibit Nucleotides Synthesis (so that DNA repair cannot be performed in abundant manner)

1. • While a bit risky and aggressive, leflunomide for example, is doing a clinical trial as a single agent in mTNBC
   • PPP may be also a target as well as glycolysis

      4. Inhibit HR pathway (which is the only remaining high-fidelity DNA repair) – some patients may                 already have defects in following genes.

• • MRN
  • ATM
  • ATR
  • BRCA1/2

       5. Inhibit DDR related Pathways

• • PI3K/AKT/MTOR
  • WNT
  • BET
  • HSP90
  • HDAC
  • Autophagy
  • MGMT/DNMT (DNA meth.)