PARP inhibitor?

[Cal-Gal]

Just saw a story on the news about this treatment for triple negative breast cancer--not sure I understand it-or what it targets
---and
wondered if any of you know if this is for
ER/PR- which many of us are double negative-but HER2 postive---??

thanks

[Soccermom]

This article from FORCE explains PARP (Poly ADP-Ribose Polymerase) inhibitors and their mechanism...


PARP Inhibitor research presented at ASCO 2009 Annual Conference

Three promising but early research studies on a class of drugs called PARP Inhibitors which may work preferentially for hereditary cancers were presented at the 2009 American Society of Clinical Oncology Annual Conference (http://www.asco.org) in Orlando.
One session presented results from a clinical trial for breast cancer patients with "triple-negative" cancers: cancers which do not express estrogen receptors, progesterone receptors, or the Her2neu protein. This study is particularly relevant to our community since "triple negative breast cancers" are the most common type of breast cancer in BRCA 1 mutation carriers. Approximate 85% of BRCA 1 mutation carriers who have breast cancer have triple negative disease.Some BRCA2 carriers and women with non-hereditary breast cancer (especially African-American women) also develop triple-negative disease.
This randomized phase II study looked at the BiPar Sciences PARP Inhibitor BSI 201 in women with triple negative breast cancer which had metastasized (spread beyond the breast and lymph nodes). Women in the study with metastatic breast cancer were chosen randomized to be in one of two groups: one group that received the chemotherapy combination Gemcitabine and Carboplatin and the other group that received those two chemotherapies in combination with the PARP Inhibitor BSI 201 as an intravenous injection. Three times as many women in the PARP inhibitor arm of the study had improvement of their cancer compared to those who received chemotherapy alone. Women on the arm of the study that included PARP inhibitors went about 3 ½ months longer on average than those on chemotherapy alone without their disease progressing and lived about 3 ½ months longer on average than those on chemotherapy alone. Also the group that received the PARP Inhibitors along with the chemotherapy had no higher side-effects than the group on chemotherapy alone.
A second study investigated the AstraZeneca PARP Inhibitor drug formerly known as AZD2281 and now known by the name “olaparib." This phase II clinical trial studied women with known BRCA 1 or BRCA 2 mutations and metastatic breast cancer. In this study the PARP Inhibitor was given as a “single agent” (ie- with no other treatment) to women who had already received previous courses of chemotherapy and had progression of their cancer on prior treatments. Olaparib is an oral medication and women in the study were given one of two doses: a low dose (100 mg 2 times/day) or a high dose (400 mg 2 times/day). The higher dose led to one woman having a complete response (ie-there was no measurable cancer during treatment) and 10 partial responses (the cancer was measurably smaller or did not increase) for an overall response rate of 41%. The response rate with the lower dose was 22%. Most of the side effects were not severe and included primarily fatigue and nausea. Women who responded favorably to treatment included women with BRCA 1 and women with BRCA 2 mutations suggesting that the medication works for both mutation carrier populations. This particular study used the PARP Inhibitor alone. The presenters reported on one woman in the study who had lung metastasis and is still on the medication whose cancer has not progressed in the 18 months since she started the study.
A third study similar to the one presented above investigated olaparib for advanced ovarian cancer in BRCA mutation carriers. This phase II clinical trial studied women with known BRCA 1 or BRCA 2 mutations and recurrent ovarian cancer. In this study the PARP Inhibitor was given as a “single agent” (ie- with no other treatment) to women who had already received several previous courses of chemotherapy and had progression of their cancer on prior treatments. As in the breast cancer study, women in this trial were given one of two doses: a low dose (100 mg 2 times/day) or a high dose (400 mg 2 times/day). 33 were evaluable at 400 mg bd and 24 at 100 mg bd. The overall response rate was 33% at the higher dose(400 mg twice daily) and 12.5% at 100 mg twice daily dose. Of the women on the high dose, 58% experienced clinical benefit and 17% of the women on the lower dose experienced clinical benefit. Side effects were mild, and included nausea (44%); fatigue (35%); and anemia (14%). More serious side effects were rare and comprised primarily of nausea and low white blood cells. The researchers showed that olaparib is well tolerated and active in women with advanced ovarian cancer.
Although exciting, there is more research that is needed. Larger (phase III) studies will help show if PARP inhibitors can extend the life of women with advanced cancer. Future studies on women with early stage disease will be needed to determine if these medications might be used to prevent recurrence in women with early stage cancer.
Currently there are some open PARP inhibitor studies for women with BRCA mutations and cancer but not many.

[Soccermom]

http://clinicaltrials.gov/ct2/results?term=PARP+inhibitors

[Cal-Gal]

guess this applies to BRCA/1&2 positive---I am negative--

[gdpawel]

As our understanding of cancer biology continues to advance, this disease has come to be understood as many different diseases. As seen in the most recent PARP clinical trial, mutations work with other proteins. Genes do not operate alone within the cell but in an intricate network of interactions.

The cell is a system, an integrated, intereacting network of genes, proteins and other cellular constituents that produce functions. One needs to analyze the systems’ response to drug treatments, not just one or a few targets (pathways).

In the functional profiling platform, where they can understand how PARP inhibitors enhance the effects of drugs and drug combinations, the excellent results with PARP inhibitors and BRAC mutants have been followed by striking response and survival data combining PARP inhibitors with carbo-platinum and gemcitabine.

PARP inhibitors by inhibiting DNA damage response can enhance the effects of ionizing radiation, mustard alkylators, topoisomerase inhibitors, platins, and intercalating agents. To date, they have observed good activity for the PARP inhibitors as single agents in BRAC1 positive patients, and in some triple negative patients.

At Rational Therapeutics, Inc., in Long Beach, California, they’ve explored the biology of PARP inhbitors in breast and other cancers. In these investigations, the lab applies the functional profiling platform to understand how PARP inhibitors enhance the effects of drugs and drug combinations.

More interesting, will be the results combining the PARP inhibitors with mustard alkylators, platins, and drug combinations to optimize PARP inhibitor combinations.

This work is ongoing in triple negative and BRAC positive patients as well as other tumor types where the PARP inhibitors may prove useful in the future. The PARP inhibitors are turning out to be very useful, but you don't necessarily have to enter a clinical trial to fine that out.

http://www.rationaltherapeutics.com/

http://healthinfoispower.wordpress.com/2010/11/17/parp-inhibitor-mk-4827-shows-anti-tumor-activity-in-first-human-clinical-study/

[gdpawel]

The Sunday, April 3, 2011, experimental and molecular therapeutics poster session at the AACR 102nd annual meeting included Dr. Robert Nagourney's Rational Therapeutics presentation on signal transduction inhibitors. Using MEK/ERK and PI3K-MTOR inhibitors he explored the activities, synergies and possible clinical utilities of these novel compounds.

The findings were instructive. First, it saw a good signal for both compounds utilizing the Ex-vivo Analysis of Programmed Cell Death (EVA-PCD) platform (functional profiling). Second, it saw disease-specific activity for both compounds. For the MEK/ERK inhibitor, melanoma appeared to be a favored clinical target. This is highly consistent with expectations. After all, many melanomas carry mutations in the BRAF gene, and BRAF signals downstream to MEK/ERK. By blocking MEK/ERK, it appeared that his lab blocked a pathway fundamental to melanoma progression. Indeed, MEK/ERK inhibitors are currently under investigation for melanoma.

For PI3K inhibitors, the highest activity was observed in uterine cancers. This has interest, because uterine carcinomas are often associated with a mutation in the PTEN gene. PTEN is a phosphatase tumor suppressor that functions to block activation of the PI3K pathway. Thus, mutations in the tumor suppressor unleash PI3K signaling, driving tumors to grow and metastasize. Blocking PI3K provided a strong signal, indicating that this approach may be very active in tumors associated with these oncogenic events.

The third point of interest in the report was, perhaps, its most important. Specifically, that the lab can explore those diseases where MEK-ERK, PI3K and mTOR signaling are less established targets. Cancers of the lung, ovary, colon or breast all manifested profiles of interest. When they combined both pathway inhibitors in a process called horizontal inhibition, renal cell carcinoma popped up as the best target. These results, though exploratory, suggest a superior approach for drug development, allowing the lab to identify important leads much faster than the clinical trial process.

Source: Rational Therapeutics, Inc.

Poster from Rational Therapeutics Session at 2011 AACR Meeting

http://robertanagourney.wordpress.com/2011/04/28/poster-from-rational-therapeutics-session-at-2011-aacr-meeting/