MBCC: PARP Inhibitors for Breast Cancer—Which Subpopulation to Target? - Cancer Network (BRCA, triple-negative breast...)

MBCC: PARP Inhibitors for Breast Cancer—Which Subpopulation to Target? - Cancer Network

"Speaking at the 29th Annual Miami Breast Cancer Conference, Jorge S. Reis-Filho, PhD, MD, professor of medical pathology at the Institute of Cancer Research in London, England, described the rationale of applying poly (ADP-ribose) polymerase inhibitors (PARP) to breast cancer patients.

Tumors that have a loss of function in DNA-repair genes such as BRCA1 and BRCA2, and homologous recombination, as Dr. Joyce O'Shaughnessy described during her session on emerging triple-negative breast cancer therapies, may be particularly sensitive to PARP inhibitors.

Reis-Filho highlighted that sequencing tumors may not be enough to characterize whether tumors have intact DNA-repair pathways—tumors also have epigenetic changes that regulate homologous recombination......"

abstract: Evaluation of Iniparib as a PARP Inhibitor (BRCA2....)

Evaluation of Iniparib as a PARP Inhibitor:

Purpose:

Poly(ADP-ribose) polymerase (PARP) inhibitors are undergoing extensive clinical testing for their single-agent activity in homologous recombination (HR)-deficient tumors and ability to enhance the action of certain DNA-damaging agents. Compared with other PARP inhibitors in development, iniparib (4-iodo-3-nitrobenzamide) is notable for its simple structure and the reported ability of its intracellular metabolite 4-iodo-3-nitrosobenzamide to covalently inhibit PARP1 under cell-free conditions. The present preclinical studies were conducted to compare the actions iniparib with the more extensively characterized PARP inhibitors olaparib and veliparib.

Results:

Consistent with earlier reports, olaparib and veliparib selectively induced apoptosis and inhibited colony formation in cells lacking BRCA2 or ATM. Moreover, like earlier generation PARP inhibitors, olaparib and veliparib sensitized cells to the topoisomerase I poisons camptothecin and topotecan. Finally, olaparib and veliparib inhibited formation of pADPr in intact cells. In contrast, iniparib exhibited little or no ability to selectively kill HR-deficient cells, sensitize cells to topoisomerase I poisons, or inhibit pADPr formation in situ. In further experiments, iniparib also failed to sensitize cells to cisplatin, gemcitabine, or paclitaxel.


Conclusions:

While iniparib kills normal and neoplastic cells at high (>40 μmol/L) concentrations, its effects are unlikely to reflect PARP inhibition and should not be used to guide decisions about other PARP inhibitors.  

Clin Cancer Res; 18(6); 1655–62. ©2012 AACR.

March 7th /text and/or podcast: PARP Inhibitors and the Challenges of Developing Ovarian Cancer Therapeutics - Cancer Network Dr's Ledermann/Birrer

Blogger's Note: podcast and/or text available, registration required (free)
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PARP Inhibitors and the Challenges of Developing Ovarian Cancer Therapeutics - Cancer Network

Jonathan Ledermann, Cancer UK, London; Michael Birrer, Harvard Medical School, Dana-Farber Institute

AUDIO:
Right-click to download MP3

PODCAST 

PARP Inhibitors and the Challenges of Developing Ovarian Cancer Therapeutics

Interviewed by Anna Azvolinsky, PhD | March 7, 2012

---

Ovarian cancer is notoriously difficult to treat because it is usually diagnosed at an advanced stage, and because of the high variance in the types of mutations that are found in individual tumors. This creates hurdles for the development of efficacious treatments.
CancerNetwork presents an interview with two prominent ovarian cancer researchers from both sides of the Atlantic. Dr. Jonathan Ledermann is professor of medical oncology at the UCL Cancer Institute in London, England. He treats gynecological cancers and is heavily involved in ovarian cancer clinical trials. Dr. Michael Birrer is a professor of medicine at the Harvard Medical School and is part of the Dana-Farber/Harvard Cancer Center where he also treats gynecological cancers and leads an effort to molecularly characterize gynecological cancers.......

                           ~~~~~~~~~~~~~~~~~~~~~

"CancerNetwork: Despite promising results at ASCO last year, with one of the PARP inhibitors, olaparib, showing positive progression-free survival (PFS) benefit, the phase II trial was stopped in mid December because this PFS benefit was not likely to translate to an overall survival benefit. I would like to get both of your perspectives on this and then what the future holds for other PARP inhibitors in development.



Dr. Ledermann: Mike Birrer will want to comment on this, but can I just correct you on a point of fact. The phase II trial was not stopped. In fact it is still going. There are still patients on treatment, and it has not been unblinded. What the company that manufactures olaparib, which is one of the PARP inhibitors, said in their press release was they were not going to continue development of olaparib in high-grade serous ovarian cancer because, as you said, the interim analysis of survival didn’t show the benefit they wanted to see in relation to the benefit in PFS that I reported at the ASCO conference. But the trial is still continuing and a final analysis will be done probably toward the end of this year."

open access: Nature Reviews: Key Advances in Medicine - Ovarian Cancer/Markman page 15-16

Key Advances in Medicine (book)


Nature Reviews Clinical Oncology  (page 15)S11 ovarian cancer | Mutations and non-inferiority analyses show a way forward Maurie Markman      (page 15-16)






Highly clinically relevant ovarian cancer clinical research in 2011 focused on an increased understanding of the biology of the malignancy, limitations of strategies for early detection and screening, and the provocative reports of alternative primary and second-line management strategies.

"Although there were a number of very interesting
preliminary reports of therapeutic
advances in ovarian cancer in 2011 (for
example, bevacizumab in the first-line and
second-line management of the malignancy,
and olaparib  (Blogger's Note: links to Olaparib (parp inhibitor) - Cancer Research UK)  as maintenance therapy for
high-grade serous cancers), as of the writing
of this commentary these studies have not
appeared in the peer-reviewed oncology literature......."

Key advances
■■ There are currently no evidence-based
data supporting the clinical utility of any
ovarian cancer screening strategy in
non‑high-risk populations1
■■ Provocative data suggest there may be a
clinically meaningful difference between
the presence of a BRCA1 or a BRCA2
mutation in influencing outcome in ovarian
cancer6
■■ Under specific circumstances (for example,
neuropathy) it might be reasonable to
substitute pegylated liposomal doxorubicin
for paclitaxel in the front-line chemotherapy
management of ovarian cancer7

Markman, M. Nat. Rev. Clin. Oncol. 9, 69–70 (2012); published online 20 December 2011; doi:10.1038/nrclinonc.2011.200

                                   ~~~~~~~~~~~~~
"The articles included in Nature Reviews Key Advances in
Medicine were originally published in the February 2012
issues of the eight clinical Nature Reviews journals. The journals’
editors commissioned international experts to write a short
essay highlighting up to five key papers that made the biggest
contribution to their field in 2011."

Feb 9th: The Maze of PARP Inhibitors in Ovarian Cancer - Cancer Network

Blogger's Note:  full access, free subscription

Conclusion

"While consideration of chemoprevention with PARP inhibitors is on the horizon, many knowledge gaps exist regarding these agents. Although the trials in EOC provided some answers regarding the activity of PARP inhibitors, they raised many other questions. These questions may actually complicate the picture as newer agents in this drug class make their way to the clinical arena. A collaborative approach among the researchers is needed to systematically answer these questions so we are better equipped to provide effective treatment to the BRCA-deficient patients. It is noteworthy that The Cancer Genome Atlas Group analysis did reveal other commonly deregulated pathways in this disease—such as RB, RAS/PI3K, FOXM1, and NOTCH—that might provide future opportunities for therapeutic targeting while the story of the PARP inhibitors continues to unfold."


 

media: (PARP inhibitors) Researchers: Breast Cancer Drug May Treat Other Cancers

medical news: New Class of Cancer Drugs Could Work in Colon Cancers with Genetic Mutation (PARP inhibitors/MRE11 gene/Lynch Synrome))

15% of colorectal cancers have mutation that responds to PARP inhibitors

Newswise — ANN ARBOR, Mich. — A class of drugs that shows promise in breast and ovarian cancers with BRCA gene mutations could potentially benefit colorectal cancer patients with a different genetic mutation, a new study from the University of Michigan Comprehensive Cancer Center finds.

Working in cell lines from colorectal cancer patients, researchers found that a new class of drugs called PARP inhibitors worked against tumors with mutations in the MRE11 gene.

PARP Inhibitor Active in Ovarian Cancer (preliminary studies MK4827) upload date March 22nd

New test for ovarian cancer patients - RAD51 assay (UK)

Note: search blog for additional RAD51 information/studies

abstract: 6-thioguanine selectively kills BRCA2-defective tumors and overcomes PARP inhibitor resistance

"...Altogether, our data show that 6TG efficiently kills BRCA2-defective tumors and suggest that 6TG may be effective in the treatment of advanced tumors that have developed resistance to PARP inhibitors or platinum-based chemotherapy."

abstract: Cochrane Collaboration review: DNA-repair pathway inhibitors for the treatment of ovarian cancer (PARP inhibitors)

"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."

Main results
The search strategy identified 473 unique references of which 461 were excluded on the basis of title and abstract. The remaining 12 articles were retrieved in full, but none satisfied the inclusion criteria. However, two ongoing randomised phase II clinical trials were identified from the clinical trials databases that met our inclusion criteria, but no preliminary data were available.


Authors' conclusions

There are to date no published RCT data on the effectiveness and side effects of DNA-repair pathways inhibitors used alone or in association with conventional chemotherapy in the treatment of ovarian cancer. On-going trials have been identified and results are awaited and will be included in future updates of this review.

Somatic Mutations in BRCA1 and BRCA2 Could Expand the Number of Patients That Benefit From Poly (ADP Ribose) Polymerase Inhibitors in Ovarian Cancer

ABSTRACT

Purpose
The prevalence of BRCA1/2 mutations in germline DNA from unselected ovarian cancer patients is 11% to 15.3%. It is important to determine the frequency of somatic BRCA1/2 changes, given the sensitivity of BRCA-mutated cancers to poly (ADP ribose) polymerase-1 (PARP1) inhibitors and platinum analogs.

Conclusion
BRCA1/2 somatic and germline mutations and expression loss are sufficiently common in ovarian cancer to warrant assessment for prediction of benefit in clinical trials of PARP1 inhibitors.

research: BRCA-Negative Ovarian Cancer Responds to Monotherapy With PARP Inhibitor | Cancer Survivors Network

Note: detailed article on PARP's/BRCA "....Interest in PARP inhibition was perhaps best reflected by the question an attendee at the packed session put to Dr. Gelmon.

"My problem is, as a practicing oncologist, I see these great, wonderful results, in a very difficult population of patients with ovarian cancer," he said. "I want to know when I can get my hands on some. There are patients dying today because of this lack of access.""

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

Note:  free access/register

Research Update on PARP Inhibition: Emerging Data in Breast, Ovarian, and Other Cancers
	Interactive Virtual Presentation In this Interactive Virtual Presentation, 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. Throughout this presentation, you will be invited to vote on treatment options for specific patient cases. After voting, you can graphically view how others have voted while Dr. Gradishar provides an evidence-based rationale for the choices. To begin this Interactive Virtual Presentation, click here. Downloadable Slideset The slideset that accompanies this Interactive Virtual Presentation is available for use as a self-study resource or in your own noncommercial talks. To download, click here. This CME-certified Interactive Virtual Presentation is located online at: http://clinicaloptions.com/Oncology/Treatment%20Updates/PARP%20Inhibition.aspx