Can PARP Inhibitors be Tested Using the EVA-PCD Assay?

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.

Our 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 our 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). We have studied small molecule inhibitors of PARP for many years, and more recently, we have expanded these investigations to include BSI201 (iniparib) and AZD2281 (olaparib). Both of which are undergoing clinical investigations. We will be reporting our 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. We see activity in BRCA+ patients and some triple negative breast cancers. We have also identified synergy with other classes of drugs. The compounds are a welcome addition to our cancer therapy armamentarium and continue to be actively studied in the EVA-PCD 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 our successful work with other classes of compounds.

About Dr. Robert A. Nagourney
Dr. Nagourney received his undergraduate degree in chemistry from Boston University and his doctor of medicine at McGill University in Montreal, where he was a University Scholar. After a residency in internal medicine at the University of California, Irvine, he went on to complete fellowship training in medical oncology at Georgetown University, as well as in hematology at the Scripps Institute in La Jolla. During his fellowship at Georgetown University, Dr. Nagourney confronted aggressive malignancies for which the standard therapies remained mostly ineffective. No matter what he did, all of his patients died. While he found this “standard of care” to be unacceptable, it inspired him to return to the laboratory where he eventually developed “personalized cancer therapy.” In 1986, Dr. Nagourney, along with colleague Larry Weisenthal, MD, PhD, received a Phase I grant from a federally funded program and launched Oncotech, Inc. They began conducting experiments to prove that human tumors resistant to chemotherapeutics could be re-sensitized by pre-incubation with calcium channel blockers, glutathione depletors and protein kinase C inhibitors. The original research was a success. Oncotech grew with financial backing from investors who ultimately changed the direction of the company’s research. The changes proved untenable to Dr. Nagourney and in 1991, he left the company he co-founded. He then returned to the laboratory, and developed the Ex-vivo Analysis - Programmed Cell Death ® (EVA-PCD) test to identify the treatments that would induce programmed cell death, or “apoptosis.” He soon took a position as Director of Experimental Therapeutics at the Cancer Institute of Long Beach Memorial Medical Center. His primary research project during this time was chronic lymphocytic leukemia. He remained in this position until the basic research program funding was cut, at which time he founded Rational Therapeutics in 1995. It is here where the EVA-PCD test is used to identity the drug, combinations of drugs or targeted therapies that will kill a patient's tumor - thus providing patients with truly personalized cancer treatment plans. With the desire to change how cancer care is delivered, he became Medical Director of the Todd Cancer Institute at Long Beach Memorial in 2003. In 2008, he returned to Rational Therapeutics full time to rededicate his time and expertise to expand the research opportunities available through the laboratory. He is a frequently invited lecturer for numerous professional organizations and universities, and has served as a reviewer and on the editorial boards of several journals including Clinical Cancer Research, British Journal of Cancer, Gynecologic Oncology, Cancer Research and the Journal of Medicinal Food.

2 Responses to Can PARP Inhibitors be Tested Using the EVA-PCD Assay?

  1. It is interesting about alkylating agents that can induce cell death injury in extensive poly ADP ribosylation. Melphalan is a bifunctional alkylator that creates inter- and intra-strand DNA cross-links. In a recent study by Dr. William D. Foulkes (a.k.a. McGill University), et al, in a pharmaceutical screen, Melphalan was shown to be selectively toxic to BRCA2-deficient breast cancer cell lines and produced a longer relapse-free survival in mice than did cisplatin or olaparib (one of the PARP inhibitors). There is increasing evidence to consider BRCA mutation status when selecting chemotherapy regimens, and Melphalan treatment for BRCA-related ovarian cancer merits further investigation. Focusing attention on long-term survivors may provide new mechanistic insights into the biology of chemo-responsiveness (J Clin Pathol doi:10.1136/jcp.2010.086405).

    This has pith my curiosity because Chlorambucil (Leukeran) is the other oral-dose alkylator agent used for ovarian cancer patients. My wife was treated for her original stage IV ovarian primary in 1972 with total abdominal hysterectomy and Leukeran. By giving chemotherapy more often, at lower doses, it can prevent the regrowth of blood vessels that feed tumors (angiogenesis). She went 24 years before ever developing a recurrence. Although the BRCA 1 and BRCA 2 genes were discovered in 1994 and 1995, we did not test for them when she had her recurrence in 1996. However, it was likely she had Lynch Syndrome. She had a family history of colon cancer and her first bout with cancer was when she was 40 years of age. Even though a syndrome-type cancer may make one more susceptible to developing certain cancers, it may render one more hypersensitive to chemotherapeutics. A curse and a blessing at the same time.

  2. Jaerou Kim says:

    Thank you for your valuable post. We have decided to share it with our global physician audience at PhysicianNexus.com: http://physiciannexus.com/forum/topics/can-parp-inhibitors-be-tested

    Jaerou Kim
    Team Member
    http://www.PhysicianNexus.com
    Physicians Comparing Treatments Worldwide

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