PARP Inhibitor Adds Nearly 5 Months to Breast Cancer Survival (BRCA/discussions) : Internal Medicine News

PARP inhibition: targeting the Achilles' heel of DNA repair..PARP inhibition: targeting the Achilles' heel of DNA repair to treat germline and sporadic ovarian cancers

A review of PARP inhibitors: from bench to bedside — Ann Oncol

Conclusion: PARP inhibitors show promise as a powerful therapeutic tool, especially in the management of BRCA-associated breast and ovarian cancers but also in tumours where BRCA genes may be dysfunctional. Clinical studies are ongoing and many translational questions remain unanswered that will help clarify how to determine the best way to use PARP inhibitors.

Search of: parp | Open Studies - List Results - ClinicalTrials.gov

Found 33 studies with search of: parp | Open Studies

Clinical Care Options Oncology - Slideset: Research Update on PARP Inhibition: Emerging Data in Breast, Ovarian, and Other Cancers

Source: Research Update on PARP Inhibition: Emerging Data in Breast, Ovarian, and Other Cancers

William J. Gradishar, MD, FACP, reviews the mechanism of PARP inhibition and its rationale as a therapeutic pathway and describes recent data using novel PARP inhibitors.

To download for use as a self-study resource or in your own noncommercial talks.

Download slides on recent data in PARP inhibitors in breast, ovarian, and other solid tumors.


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abstract/Cochrane Collaboration review: DNA-repair pathway inhibitors for the treatment of ovarian cancer (PARPs...AZD2281)

Plain language summary

Are DNA repair inhibitors as effective and harmless compared to conventional chemotherapy in the treatment of ovarian cancer?
Ovarian cancer is the sixth commonest cancer in women world-wide and remains a leading cause of death, with an annual incidence of 6.6 cases per 100,000 women and an annual mortality rate of 4.0 deaths per 100,000 women. Most ovarian cancers (90%) are epithelial ovarian cancer and arise from the surface of the ovary. Epithelial ovarian cancer typically occurs in post-menopausal women, with a peak incidence around the age of 60, although it does occur in younger women, often associated with genetic predispositions. The onset of this disease is insidious and 75% of women present with advanced stage disease (stage III or IV) when the 5 year survival is around 30%. Treatment consists of debulking surgery and platinum-based chemotherapy, with or without taxanes. Although initial response to chemotherapy is good, most women will relapse, requiring further chemotherapy treatment and develop cancer that is resistant to chemotherapy.

Conventinal chemotherapy acts on all rapidly dividing cells by damaging DNA. Cancer cells divide very rapidly, which is why chemotherapy works better on cancer cells than normal cells. However, there is no inherent selectivity for normal calls and so rapidly dividing cells, such as gut lining, hair follicles and bone marrow, are also affected, leading to diarrhoea, mouth ulcers, hair loss, anaemia and susceptibility to infections.

All cells are equipped with a number of systems or pathways that repair DNA damage. If cells are unable to repair their DNA, the cell undergoes programmed cell death (apoptosis) in order to prevent an abnormal cell from dividing. Because being able to repair DNA is vital to cell survival, normal cells have more than one DNA-repair pathway, so that if one is lost cells can still repair themselves. Cancer cells often develop defects in these pathways, due to mutations, which may promote development of cancer (e.g. BRCA mutations). However, these same mutations mean that these cancer cells are more susceptible to DNA damage, such as that caused by chemotherapy, than normal cells. Novel therapeutical agents have been developed to inhibit DNA-repair pathways, which makes cells that already have faults in another DNA repair pathway due to a mutation, exquisitely sensitive to DNA damaging chemotherapy agents. The most common target for this type of novel anti-cancer agent are the DNA-repair enzymes called poly (ADP-ribose) polymerases (PARPs). PARPs are a family of related enzymes, which are involved in regulating various cellular processes, including DNA repair, cell death, and inflammation. PARP inhibitors therefore have a potentially wide range of applications.

Our objective was to compare effectiveness and side effects of PARP inhibitors compared to conventional chemotherapy in women with ovarian cancer. The identification of a safe dose of AZD2281 (a PARP inhibitor) has been found by small non randomised trials, with encouraging results. For ovarian cancer, there are currently two ongoing RCTs, but outcome data are not yet available. Results of these trials are awaited to determine if DNA repair inhibitors have a role in addition to conventional chemotherapy in the treatment of ovarian cancer.

First-in-human trial of a poly(ADP-ribose) polymerase (PARP) inhibitor MK-4827 in advanced cancer patients (pts) with antitumor activity in BRCA-deficient and sporadic ovarian cancers (phase 1)

Results: 39 pts (male 10, female 29; median age 58 years; 11 BRCA mutation carriers) were treated...
Conclusions: MK-4827 is well tolerated, blocks PARP and has promising antitumor activity in both BRCA-deficient and sporadic cancers.

ASCO: Drug May Reactivate Chemo Effect in Ovarian CA - Olaparib (PARP)

"Chemotherapy resulted in an overall response rate of 42% in this heavily pretreated patient population, including a 55% response rate for carboplatin and/or a taxane," said Ang. "If these results are confirmed in a larger patient population, they could remain an option for these patients, even if they have demonstrated prior resistance."

ORC Oncology report - fill out form to receive copy of the report

Note: once the form is filled out the paper uploads a pdf file of the report automatically

ORC’s Oncology Report examines three important Oncology issues: Assessing the Impact of Revised NSCLC Staging, Genetically Linked Breast Cancer and PARP-1 Inhibitors and Reactions to New Mammogram Recommendations. Submit the information below and download the full report.

5 min podcast - Dr Ashworth - BRCA/PARPs

Podcast – A Breakthrough in BRCA-Mutated Cancers
11. May, 2010 in Podcast

Alan Ashworth, who helped discover the BRCA2 breast cancer gene in 1995, says understanding basic biology can help researchers find targeted cancer treatments. He shares about his research with PARP inhibitors to treat BRCA-mutated cancers.

media item: Magee-Womens Hospital - ovarian cancer recruitment - ABT-888/PARP

Drug Tested Against Women's Cancers
Pittsburgh Post-Gazette (PA) - Apr. 14, 2010

Apr. 14--Magee-Womens Hospital of UPMC is recruiting patients with recurrent ovarian, fallopian tube or peritoneal cancers who have already had chemotherapy for a national, Phase 2 clinical trial of the drug ABT-888.

ABT-888 works by targeting the PARP family of enzymes, which are responsible for a wide variety of cancer cell processes, principal investigator Kristin Zorn said. The PARP pathway is one of the mechanisms used by cancer cells to repair damage caused by chemotherapy....cont'd

quick check - PARP clinical trials (ovarian,BRCA,solid tumours)

Jan 2009 full free access - Development of PARP inhibitors in oncology; Expert Opinion on Investigational Drugs + Expert Opinion

Note: highly technical but worth reviewing (BRCAness, sporadic, specific therapies (combination/single agent/+radiotherapy), those in clinical studies (Table 1),
differing cancers etc