HER2 overexpression renders human breast cancers sensitive to PARP inhibition

gdpawel · 10-08-2013, 11:45 PM

Poly ADP ribose polymerase (PARP) is a nuclear enzyme associated with response to DNA damage. Following single strand DNA breaks, the enzyme attaches a backbone of ADP and ribose that serves to initiate DNA repair. Certain classes of chemotherapeutics, specifically alkylating agents, can induce injury that results in extensive poly ADP ribosylation resulting in the exhaustion of intercellular pools of NAD and ATP ultimately leading to cell death.

Although PARP inhibitors have recently entered the clinical cancer literature mostly relating to the treatment of BRCA+ and triple negative patients, neither PARP nor PARP inhibitors are new to the cancer researcher community, according to Dr. Robert Nagourney, medical director at Rational Therapeutics, one of the pioneers of the functional profiling technique.

His group first became interested following a 1988 study by Distelhorst from Case Western Reserve (Distelhorst CW, Blood 1988 Oct;72(4):1305-09) that described a mechanism of cell death that correlated with their work in childhood leukemia. Previously, investigators at Scripps Clinic had described PARP’s role in response to 2CDA (Seto, S., et al. J Clin. Invest. 1985 Feb;75(2):377-83). His group has studied small molecule inhibitors of PARP for many years, and more recently, they have expanded these investigations to include BSI201 (iniparib) and AZD2281 (olaparib). Both of which are undergoing clinical investigations. Nagourney will be reporting their findings with these PARP inhibitors at the 2011 ASCO meeting (Nagourney, R., et al Proceedings Amer Soc Clin Oncol. 2011).

PARP inhibitors are easily studied and provide interesting signals in the tissue studied. They have seen activity in BRCA+ patients and some triple negative breast cancers. They have also identified synergy with other classes of drugs. The compounds are a welcome addition to the cancer therapy armamentarium and continue to be actively studied in the cell-based functional profiling platform.

Of interest is the recent failure of the iniparib plus Carboplatin & gemcitabine Phase III trial to meet progression-free and overall survival goals in triple negative breast cancer patients (Zacks Investment Research on January 31, 2011). This failure may reflect the need to apply predictive methodologies to select candidates for these drugs, similar to Nagourney's successful work with other classes of compounds.

gdpawel · 10-08-2013, 11:47 PM

NIH researchers discover new mechanism of action for class of chemotherapy drugs

Bethesda, Maryland

Monday, November 05, 2012

The National Institutes of Health (NIH) researchers have discovered a significant new mechanism of action for a class of chemotherapy drugs known as poly (ADP-ribose) polymerase inhibitors, or PARP inhibitors. They have also identified differences in the toxic capabilities of three drugs in this class which are currently being tested in clinical trials. The study was conducted at the National Cancer Institute (NCI), part of NIH.

In recent years, drugs classified as PARP inhibitors have been shown to be promising anticancer agents for breast and ovarian cancer. Members of the PARP family of proteins are involved in a number of critical cellular processes, including DNA damage repair and programmed cell death. Prior to this study, PARP inhibitors were thought to work primarily by blocking PARP enzyme activity, thus preventing the repair of DNA damage and ultimately causing cell death.

In this study, scientists established that PARP inhibitors have an additional mode of action: localizing PARP proteins at sites of DNA damage, which has relevance to their anti-tumour activity. The trapped PARP protein–DNA complexes are highly toxic to cells because they block DNA replication. When the researchers tested three PARP inhibitors for their differential ability to trap PARP proteins on damaged DNA, they found that the trapping potency of the inhibitors varied widely.

"Critical to our research is that, while PARP inhibitors had been assumed to be of equivalent potency based on the degree to which they elicit PARP inhibition, we now know that they are not equivalent with respect to their potency to trap PARP," said Yves Pommier, MD, PhD., NCI Centre for Cancer Research. "Our findings suggest that PARP inhibitors should be categorized according to their potency to trap PARP, in addition to their enzyme inhibition abilities."

The PARP family of proteins in humans includes PARP1 and PARP2, which are DNA binding and repair proteins. When activated by DNA damage, these proteins recruit other proteins that do the actual work of repairing DNA. Under normal conditions, PARP1 and PARP2 are released from DNA once the repair process is underway. However, as this study shows, when they are bound to PARP inhibitors, PARP1 and PARP2 become trapped on DNA. The researchers showed that trapped PARP–DNA complexes are more toxic to cells than the unrepaired single-strand DNA breaks that accumulate in the absence of PARP activity, indicating that PARP inhibitors act as PARP poisons.

In collaboration with James Doroshow, MD, deputy director for clinical and translational research at NCI, the investigators used PARP assays (ways of measuring PARP activity in cells and tissues) to compare three PARP inhibitor compounds that are currently in clinical testing: MK-4827, olaparib, and veliparib.

The scientists found that the three PARP inhibitors differed in their ability to inhibit PARP enzyme activity, with olaparib being the most potent inhibitor, followed by veliparib and then MK-4827. However, in terms of toxicity, MK-4827 was the most potent, followed by olaparib and then veliparib. Moreover, PARP1 complexes with MK-4827 and olaparib were shown to be more tightly bound to DNA than complexes with veliparib.

These findings suggest that there may be two classes of PARP inhibitors, catalytic inhibitors that act mainly to inhibit PARP enzyme activity and do not trap PARP proteins on DNA, and dual inhibitors that both block PARP enzyme activity and act as PARP poison.

"Our findings suggest that clinicians who use PARP inhibitors in clinical trials should carefully choose their drug, because we now suspect results may differ, depending upon the PARP inhibitor used," said Junko Murai, MD, PhD., NCI Centre for Cancer Research. "As a next step, we are working to categorize other leading PARP inhibitors based upon both PARP trapping and PARP inhibition."

This work was supported by the Intramural Programme of NCI and by the Japan Society for the Promotion of Science (JSPS) Core-to-Core Programme. First author Junko Murai is a JSPS fellow working at NCI Centre for Cancer Research. Funding was provided by NCI grant Z01 BC 006150-19LMP.

The National Cancer Institute (NCI) leads the National Cancer Programme and the NIH effort to dramatically reduce the burden of cancer and improve the lives of cancer patients and their families, through research into prevention and cancer biology, the development of new interventions, and the training and mentoring of new researchers.

NIH, the nation's medical research agency, and is a component of the US Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases.