PARP Inhibitors (PARPi) in Clinical Development

Alice Chen, M.D.

Poly (ADP-ribosyl)ation (PAR) occurs after single or double-stranded DNA damage and represents the posttranslational modification of histones and other nuclear proteins by Poly ADP-Ribose Polymerase (PARP).  Eighteen different putative PARP homologues have been identified (Ame et al., 2004).  Though most members’ functions are not clearly understood, PARP-1 and PARP-2 have been clarified.  PARP-1 functions as a DNA damage sensor for both single- and double-stranded DNA breaks.  PARP-2 is a similar nuclear protein that plays an important role in base excision repair (BER) by homo- or hetero-dimerization PARP   with PARP-1.  Knockout of PARP-1 is sufficient to significantly impair DNA repair following damage via radiation or cytotoxic insult.  The residual PARP-dependent repair activity is due to PARP-2 (10%).   PARP is ubiquitously expressed in almost all types of eukaryotic cells, but PARP activity is increased in the nuclei of actively proliferating cells (Donawho et al., 2007).  Overexpression of PARP in cancer cells is linked to drug resistance and the overall ability of cancer cells to survive genotoxic stress.  Inhibition of PARP sensitizes tumor cells to cytotoxic agents that induce DNA damage that would normally be repaired through the BER system.  In addition to the potential of PARPi to enhance the effects of DNA-damaging cytotoxic agents, recent reports suggest that PARPi have single agent activity against breast cancer gene (BRCA)-deficient cells (Bryant et al., 2005; Farmer et al., 2005; De Soto and Deng, 2006; De Soto et al., 2006; Rubinstein, 2008). There are currently eight PARPis in various phases of development.  The first phase 0 performed under the Exploratory IND in the US was with ABT 888, a PARPi.  Several PARPi are in phase III. 

References

Ame, J.C., C. Spenlehauer, and G. de Murcia.  (2004).  The PARP superfamily.  Bioessays.  26:882-893.
Bryant, H.E., N. Schultz, H.D. Thomas, et al.  (2005).  Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase.  Nature.  434:913-917.
De Soto, J.A., and C.X. Deng.  (2006).  PARP-1 inhibitors: are they the long-sought genetically specific drugs for BRCA1/2-associated breast cancers?  Int J Med Sci.  3:117-123.
De Soto, J.A., X. Wang, Y. Tominaga, et al.  (2006).  The inhibition and treatment of breast cancer with poly (ADP-ribose) polymerase (PARP-1) inhibitors.  Int J Biol Sci.  2:179-185.
Farmer, H., N. McCabe, C.J. Lord, et al.  (2005).  Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy.  Nature.  434:917-921
Rubinstein, W.S.  (2008).  Hereditary breast cancer: pathobiology, clinical translation, and potential for targeted cancer therapeutics.  Fam Cancer.  7:83-89.