In spite of the setbacks, researchers remain hopeful that a better understanding of the mechanism of action for PARP inhibitors will lead to effective treatment of a wide variety of cancers.
Two views of the protein structure of a PARP1 inhibitor complex.
Poly(ADP-ribose) polymerase (PARP) inhibitors, particularly Sanofi’s iniparib and AstraZeneca’s olaparib, have elicited both great excitement and significant disappointment in equal measure in recent years as researchers pursue these agents in the treatment of several types of cancer with poor prognoses.
In spite of the setbacks, researchers retain a sense of cautious optimism and remain hopeful that a better understanding of the mechanism of action of these agents will lead to a renovation of PARP inhibitors for effective treatment of a wide variety of cancers.
PARPs are a family of enzymes implicated in a host of key cellular processes, including chromosome stability, regulation of apoptosis, cell division, and transcriptional regulation and differentiation. A particularly important role of PARPs is in repairing DNA damage that results from everyday environmental stresses and DNA replication errors.
First identified in the early 1960s, the substrates upon which they act and the precise cellular functions of most members of the PARP family remain unknown. The best studied are PARP1 and PARP2 and, to date, these are the only two PARPs known to be involved in DNA repair.
A diverse range of DNA repair pathways are utilized in the cell; which pathway depends on the type of damage and the type of repair required. Through their enzymatic activity, the PARPs coordinate the base excision repair (BER) pathway to repair single-strand breaks (SSBs) in DNA. If SSBs go unrepaired, they can lead to a more dangerous form of DNA damage, the double-strand break (DSB). PARP1 has also been implicated in the homologous recombination (HR) and nonhomologous end-joining (NHEJ) pathways of DNA repair, both of which are used to repair DSBs.
PARP plays a central role in DNA repair, and researchers theorize that inhibiting PARP
would result in cancer cell death.
The potential anticancer activity of PARP inhibitors was first elucidated in 2005. Currently, PARP inhibitors are designed to target the catalytic site of PARP1 and inhibit PARP1 by greater than 90%. They are thought to function in the treatment of cancer by exploiting the concept of synthetic lethality.
Synthetic lethality occurs if two genetic mutations are nonlethal when they occur individually, but lead to cell death when they occur in combination. If PARP1 activity is impaired, other DNA repair pathways take over to repair the resulting DSBs. However, if PARP inhibitors are used in tumors that already have defects in these other DNA repair pathways, then the combination becomes synthetically lethal, as the tumor cell cannot repair either SSBs or DSBs. The theory is that this should lead to selective tumor cell death without impacting normal cells.
This was initially tested, and proved to be true, in breast and ovarian cancers that commonly have a mutation in the breast cancer type 1 susceptibility (BRCA1) and breast cancer type 2 susceptibility (BRCA2) genes. It is believed that BRCA1/2-mutated tumors have a defective HR DNA repair pathway.
Research interest has been especially piqued in the use of PARP inhibitors to treat a particularly problematic form of breast cancer, triple-negative breast cancer (TNBC). TNBC displays clinical and pathological similarity to BRCA1/2- mutated breast cancers and has a very aggressive profile and poor prognosis.
PARP inhibitors also have significant potential for improving the efficacy of chemotherapeutic agents. These agents cause DNA damage, which can be repaired by PARP activity. Therefore, inhibiting PARP should increase the tumor cell-killing potential of chemotherapy. Research has shown that this is true only for certain types of chemotherapeutic agents, including alkylating agents such as temozolomide, and that the use of these combinations is limited by the risk of increased toxic side effects, particularly myelosuppression.
Iniparib was the first PARP inhibitor to reach phase III clinical development. It elicited a great deal of excitement in 2009 with the report of very promising phase II data in a particularly difficult-to-treat form of breast cancer, triple-negative breast cancer (TNBC). Disappointingly, iniparib has subsequently failed to prolong progression-free survival (PFS) or overall survival (OS) in phase III trials in patients with TNBC.
Sanofi is still pursuing iniparib development. A study in non-small cell lung cancer (NSCLC) is in phase III, and results are expected to be available soon (NCT01082549). Phase II trials also are ongoing in ovarian cancer (NCT01033292) and glioblastoma (NCT00687765).
Olaparib is AstraZeneca's contribution to the PARP inhibitor pool. Until recently, olaparib was being actively investigated in patients with serous ovarian cancer. Phase II trials demonstrated that olaparib improved median PFS by 8.4 months versus 4.8 months with placebo in this patient population. However, in December 2011, AstraZeneca announced that it would not be pursuing phase III trials, as interim analysis of the phase II data suggested that the PFS benefit was unlikely to translate into an OS benefit, and attempts to identify a suitable dosage for use in these studies had not been successful.
Olaparib is still undergoing phase I and II clinical testing in a variety of other indications, including recurrent ovarian or TNBC (NCT01116648), advanced NSCLC (NCT01562210), and glioblastoma (NCT01390571).
(ABT-888; Abbott Laboratories)
A large and very important randomized phase II study of veliparib with and without chemotherapy in BRAC 1/2-mutation associated metastatic breast cancer has been launched internationally (NCT01506609). Phase I and II trials are ongoing in pancreatic cancer (NCT01585805), rectal cancer (NCT01589419), and myeloma (NCT01495351).
(CO-338; Clovis Oncology/Cancer Research UK)
Rucaparib is currently undergoing phase I/II testing as a single agent and in combination with cisplatin in patients with BRCA1/2-mutated breast and ovarian cancer (NCT01482715, NCT00664781).
This agent is undergoing phase I clinical testing in advanced hematological malignancies and recurrent tumors (NCT01399840, NCT01286987).
(Teva Pharmaceutical Industries)
CEP-9722 is being pursued in phase I/II trials alone or in combination with temozolomide or gemcitabine/cisplatin for solid tumors or mantle cell lymphoma (NCT01311713, NCT00920595, NCT01345357).
Merck's PARP inhibitor MK4827 is undergoing phase I evaluation as a single agent in advanced solid tumors or hematologic malignancies (NCT00749502), and in combination with temozolomide in advanced cancer (NCT01294735).
E7016 is being evaluated in phase I/II clinical trials in combination with temozolomide in patients with advanced solid tumors and melanoma (NCT01127178, NCT01605162).
There are a number of PARP inhibitors currently undergoing clinical testing (Above). In 2009, a significant amount of excitement was generated when the PARP inhibitor iniparib (BSI-201; Sanofi) demonstrated extremely promising results in phase II trials in patients with TNBC. Furthermore, clinical testing of olaparib (AZD2281; AstraZeneca) showed promise in patients with serous ovarian cancer, with reported improvements in progression-free survival (PFS).
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.