The PARP Inhibitors: Down But Not Out | Page 2

Jane de Lartigue, PhD
Published Online: Tuesday, July 31, 2012
Fast-forward to January 2011, when disappointing news emerged that the impressive phase II results with iniparib had failed to translate into a survival benefit in phase III testing of patients with metastatic TNBC.

This was followed by another blow in December, when AstraZeneca announced it would not be pursuing its PARP inhibitor olaparib in phase III trials in patients with serous ovarian cancer. This decision followed indications from an interim analysis of a phase II study that the observed PFS benefit did not translate into an overall survival (OS) benefit.

While this certainly has had a detrimental impact on the development of the leading PARP inhibitors, it does not necessarily spell the end for these therapeutic agents. Researchers are now beginning to backtrack a little to try and achieve a greater understanding of the precise mechanism of action of the PARP family. Furthermore, Sanofi is still continuing its iniparib development program, and AstraZeneca is pursuing olaparib for the treatment of other types of cancer, including BRCA1/2-deficient breast cancer.

Several recent studies also have shown that iniparib does not share the same mechanism of action as other PARP inhibitors and may, in fact, not be a true PARP inhibitor. Iniparib is also one of the weaker inhibitors of PARP. Therefore, the negative results that have plagued iniparib may not necessarily translate into a broad-spectrum failure of all PARP inhibitors. Additionally, TNBC is a biologically heterogeneous disease, which may account for the differences observed in phase II versus phase III clinical testing.

Researchers also are beginning to explore new PARP inhibitor designs. As previously mentioned, most currently target the catalytic domain, which is conserved among all PARPs. A recent study of the structure of PARP1 indicated that its enzymatic activity could in fact be blocked without interfering with the catalytic site itself. Multiple binding domains on the PARP1 protein come together to bind DNA damage, and targeting these sites could provide a more PARP1-specific inhibition, without affecting essential function of other PARP family members, thus avoiding potential unwanted side effects.

Finally, various other target cancers in addition to ovarian and breast cancer are now being examined. Researchers are attempting to expand the potential applications of PARP inhibitors by identifying and treating cancers that display other BRCA-like defects: abnormalities in other critical components of the HR DNA repair pathway that would make them susceptible to PARP inhibition.

Potential BRCA-like defects that have been identified thus far include mutations in the Fanconi anemia pathway genes, which encode proteins central to DNA damage response; the ataxia telangiectasia-mutated (ATM) gene; and the commonly mutated tumor suppressor gene phosphatase and tensin homolog (PTEN). Some other potential mechanisms of developing BRCA-like defects include epigenetic alterations, such as increased methylation of the BRCA gene promoter, or increased expression of proteins that inactivate the BRCA proteins.

This year’s American Society of Clinical Oncology (ASCO) annual meeting revealed some of the alternative target cancers in which PARP inhibitors are now being investigated. These included small cell lung carcinoma (SCLC) and neuroblastoma.

Jane de Lartigue, PhD, is a freelance medical writer and editor based in the United Kingdom.

Key Research

  • Addioui A, Belounis A, Cournoyer S, et al. Preclinical study of a PARP inhibitor in neuroblastoma. J Clin Oncol. 2012;30(suppl; abstr 9570).
  • Byers LA, Nilsson MB, Masropour F, et al. Investigation of PARP1 as a therapeutic target in small cell lung cancer. J Clin Oncol. 2012;30(suppl; abstr 7096).
  • Gradishar WJ. Research update on PARP inhibition: emerging data in breast, ovarian, and other cancers. Clinical Care Options Oncology website. Published April 29, 2010. Accessed July 3, 2012.
  • Guha M. PARP Inhibitors stumble in breast cancer. Nature Biotech. 2011;29(5):373-374. Jones P. Profiling PARP inhibitors. Nature Biotech. 2012;30(3):249-250.
  • Kummar S, Chen A, Parchment RE, et al. Advances in using PARP Inhibitors to treat cancer. BMC Medicine. 2012;10:25.
  • Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med. 2012;366(15):1382-1392.
  • Weil MK, Chen A. PARP inhibitor treatment in ovarian and breast cancer. Curr Probl Cancer. 2011;35(1):7-50.
  • Yap TA, Sandhu SK, Carden CP, et al. Poly(ADP-ribose) polymerase (PARP) inhibitors: exploiting a synthetic lethal strategy in the clinic. Ca Cancer J Clin. 2011;61:31-49.

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