CSN Login
Members Online: 19

PARP Inhibitors in Breast Cancer

gdpawel's picture
gdpawel
Posts: 545
Joined: May 2001

Some cell-based assay labs have explored the biology of PARP inhibitors, alone and in combination, in actual human tumor primary culture micro-speheroids (microclusters), in breast, ovarian 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.

As seen with PARP inhibitors, mutations work with other proteins. Genes do not operate alone within the cell but in an intricate network of interactions.

To date, one lab has observed good activity for the PARP inhibitors as single agents in BRCA1 positive patients and in some triple negative patients. Work is ongoing with these BRCA1 positive patients as wells as other tumor types where the PARP inhibitors may prove useful in the future. The PARP inhibitors are turning out to be very useful.

On April 3rd, Dr. Robert Nagourney, medical director at Rational Therapeutics and instructor in Pharmacology at the University of California, Irvine School of Medicine, will have a Poster Session at the 102nd Annual Meeting of the American Association for Cancer Research (AACR) in Orlando, Florida on the most recent findings on novel compounds that target two parallel pathways in cancer cells.

Dr. Nagourney will report the results of functional analysis with the mTOR/P13K and MEK/ERK inhibitors, BEZ235 and AZD6244, alone and in combination in human tumor primary culture micro-spheroids (microclusters): Exploration of horizontal pathway targeting. While the profiles of each drug alone are of interest, the profiles of the drugs in combination are better still.

The phenomenon of cross-talk defines an escape mechanism whereby cancer cells blocked from one passage, find a second. When clinical therapists have the capacity to block more than one pathway, the cancer cell is trapped and often dies.

This is what has been observed with these duel inhibitor combinations.

What is interesting is the fact that the activities cut across tumor types. Melanomas, colon cancers and lung cancers seem to have similar propensities to drive along these paths. Once again, we find that cancer biology is non-linear.

Moreover, cancers share pathways across tumor types, pathways that might not intuitively seem related. This is the beauty of cell-based functional profiling platform. It allows the exploration of drugs and combinations that most oncologists wouldn’t think of.

It is these counterintuitive explorations that will likely lead to meaningful advances.

Functional profiling measures biological signals rather than DNA indicators, which plays an important role in cancer drug selection and is demonstrably greater and more compelling data currently generated from DNA analyses.

The results of their investigation support the clinical relevance of targeting the MEK/ERK and PI3K/mTOR pathways and more importantly, suggest "dual" pathway inhibition (horizontal) to be a productive strategy for further clinical development. Disease specific profiles and sequence dependence are being explored and will be reported.

Most solid tumors reveal complex interactions between signal pathways that cross talk at points of commonality. To examine the clinical potential of BEZ235 and AZD6244 - inhibitors of PI3K and MEK/ERK pathways - they applied cell function analysis of programmed cell death to tumor micro-spheroids (microclusters) isolated from 24 patients. Drugs were tested alone and in combination.

According to researcher, Professor Alan Ashworth, director of the Breaktrhough Breast Cancer Research Centre in London, the BRCA1 and BRCA2 genes are involved in a repair pathway for double-strand DNA breaks that occur very close to each other. An elaborate mechanism called homologous recombination fixes some of these double-strand breaks, and BRCA2 and BRCA1 are critical for homologous recombination.

PARP is a very active enzyme involved in the repair of single-strand breaks in DNA or modified bases. It binds to DNA damage and adds multiple sugar molecules to the DNA that act as a beacon to recruit other components of DNA repair.

Emerging work on assays (PARP levels correlating with response to PARP inhibitors) have shown pretty good response with PARP inhibitors as single agents in BRCA1 positive patients and in some triple negative patients. There has been some results combining the PARP inhbitors with mustard alkylators, platins and drug combinations to optimize PARP inhibitor combinations.

These molecules have also been the subject of investigation using functional analysis in the laboratory of Dr. Nagourney. As will be reported in the Proceedings of the American Society of Clinical Oncology, Dr. Nagourney found activity for Olaparnib and Inaparib, in patients with BRCA mutation and in some triple negative breast cancer patients. This is a fertile area of investigation and a highly informative application of human tumor microspheroid analyses.

Source: Robert A. Nagourney, Paula Bernard, Federico Francisco, Ryan Wexler, Steve Evans, Rational Therapeutics, Long Beach, CA. Proceedings of AACR - Volume 52 - April 2011.

American Association of Cancer Research (AACR) Meeting 2011

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

cindycflynn's picture
cindycflynn
Posts: 1133
Joined: Oct 2009

This sounds very promising, especially for those with Triple Negative!

laughs_a_lot's picture
laughs_a_lot
Posts: 1368
Joined: Mar 2011

However at least part of what you are saying is this PARP enzyme works on a different protein attacking cancer from another angle. I think you are saying that it prevents the sneaky mets from finding another pathway to get to another part of the body to grow there. Would it be similar to having more than one mouse trap perhaps at a right angle with the first, so as to catch the nasty vermin? I like the idea of having more options or triple negatives

gdpawel's picture
gdpawel
Posts: 545
Joined: May 2001

LOL! You have a way with words. But I believe you've hit the proverbial nail right on the head!

laughs_a_lot's picture
laughs_a_lot
Posts: 1368
Joined: Mar 2011

Some times I have a hard time wading through the medical terminology. I think when I can link the difficult terms to real life situations that people can imagine better, that it allows the good news to travel to more waiting hearts. In my personal battle I am using several strategies that are not offered by the medical proffession, such as faith, positive thinking, meditaion. Since none of these other strategies cost me any money and don't cause any harm either, I feel like I am putting out other mouse traps for that nasty vermin. They may not be as effective as what medical science can do, however a combination of approaches often times gives a better result than the sum of the parts used.

carkris's picture
carkris
Posts: 4513
Joined: Aug 2009

Do the PARP inhibitors stop them when they mutate or are good to prevent mets? I asked about them with Heidi but was told they were for geneticlly positve cancers so far. We need more ammunition!

gdpawel's picture
gdpawel
Posts: 545
Joined: May 2001

carkris

The work above is ongoing in BRCA positive patients. They have observed good activity for the PARP inhibitors as single agents in BRCA1 positive patients. Those patients whose tumors do not mark for estrogen, progesterone, or HER2 on immunohistochemical or FISH analyses, appear to carry features that segregate them into a BRCA1-like biology. This is of great interest clinically for it offers the opportunity to treat these patients with drugs found active in the BRCA mutant populations.

laughs

You know, expressive writing - writing about ones deepest thoughts and feelings - may help change the way cancer patients think and feel about their disease. In one of the first studies published in an oncology journal about the benefits of writing therapy, researchers say those who immediately reported changes in thoughts about their illness also reported a better physical quality of life three weeks later.

Nancy P. Morgan, M.A., writing clinician and director of the Lombardi Comprehensive Cancer Center Arts and Humanities Program suggests expressive writing may enhance physical and psychological well-being. The study appeared in a February 2008 issue of The Oncologist.

laughs_a_lot's picture
laughs_a_lot
Posts: 1368
Joined: Mar 2011

This makes a lot of sense and I am glad there is a study to support this. I never really wrote until my "Johnny come lately" years in college. I do find that it allows me to process a lot of thoughts. I have found this true in my profession as well, as it allows me to be anylitical. I also allow my humble begginings to show in many of my assesments by using some rather colloquial terms. I think sometimes professional nomanclature is a barrier to people being able to glean information in a way that they can understand.

laughs_a_lot's picture
laughs_a_lot
Posts: 1368
Joined: Mar 2011

I just found out today that a clerical error was made at the surgical oncologists office. I was called several days prior to surgery and told I was positive for HER2. I'm chalking this up to clerical error. However, today on my trek into battle cancer land, (at the radiation oncologists office)I discovered the misscommunication. The surgeon just called back and confirmed I am triple negative. So now I will read this heady article again. I know they have already started thier 3rd clinical trial. I am praying for a miracle that ht BSL-201 drug gets FDA approval by 4/26 when I see the medical oncologist. I would like to see this drug added to my chemo meds.

gdpawel's picture
gdpawel
Posts: 545
Joined: May 2001

I see where Sanofi-aventis and its subsidiary, BiPar Sciences, announced on January 27th that a randomized Phase III trial evaluating Iniparib (BSI-201) in patients with metastatic triple-negative breast cancer (mTNBC) did not meet the pre-specified criteria for significance for co-primary endpoints of overall survival and progression-free survival.

Importantly, the results of a pre-specified analysis in patients treated in the second- and third-line setting demonstrate an improvement in overall survival and progression-free survival, consistent with what was seen in the Phase II study. The overall safety analysis indicates that the addition of Iniparib (BSI-201) did not significantly add to the toxicity profile of gemcitabine and carboplatin.

"While this trial did not meet its primary goal, we believe that the improvement in overall survival and progression-free survival in patients in the second- and third-line setting are important findings," said Dr. Debasish Roychowdhury, Senior Vice President and Head of sanofi-aventis Oncology. "We are conducting in-depth analysis to gain further insight into these Phase III results. Sanofi-aventis remains committed to improving outcomes for patients with triple-negative breast cancer where there is high unmet medical need."

Sanofi-aventis plans to discuss these data with United States and European health authorities in the near future. Full study results will be presented at an upcoming major oncology conference. Patients with questions are encouraged to consult with their treating physicians, or call 1-800-633-1610. The current clinical development program for Iniparib (BSI-201) continues in breast, lung and other cancers.

The study enrolled 519 women with mTNBC from 109 sites in the United States. Patients were randomized to receive a standard chemotherapy regimen (gemcitabine and carboplatin) on days one and eight of each 21-day cycle, with or without iniparib (BSI-201) 5.6 mg/kg, which was administered on days one, four, eight and 11 of each 21-day cycle. Patients in the study had received up to two previous lines of chemotherapy in a metastatic setting. The co-primary endpoints were overall survival and progression-free survival.

Iniparib (BSI-201) is a novel investigational anti-tumor agent with poly (ADP-ribose) polymerase (PARP) inhibitory activity in preclinical models. Iniparib (BSI-201) is in Phase III trials for patients with squamous non-small cell lung cancer, as well as in Phase II trials for patients with breast, lung and other cancers. Iniparib is the United States Adopted Name (USAN) for the investigational agent BSI-201.

However, these molecules have also been the subject of investigation using functional profiling analysis in the laboratory of Dr. Nagourney. As will be reported in the Proceedings of the American Society of Clinical Oncology, Dr. Nagourney found activity for Olaparnib (AZD-2281) and Iniparib (BSI201), in patients with BRCA mutation and in some triple negative breast cancer patients. This is a fertile area of investigation and a highly informative application of human tumor microspheroid (microcluster) analyses.

laughs_a_lot's picture
laughs_a_lot
Posts: 1368
Joined: Mar 2011

I was looking several places for clinical trials. My disease has not progressed far enough for participation in the ones I found. That is lucky for me. However, if my luck turns in the other direction I probably want to particpate in the one of the clinical trials. I had planned on organ donation prior to getting bc but now I bet I cannot donate. If I am right participation in a clinical trial would be a way to further medical science and perhaps make life better for the future unfortunate recipients of TNBC.

gdpawel's picture
gdpawel
Posts: 545
Joined: May 2001

laughs

This just came out. Thought you'd like to read it.

Art in Oncology: How Patients Add Life to Their Days

http://jco.ascopubs.org/content/29/10/1392.full

Greg

laughs_a_lot's picture
laughs_a_lot
Posts: 1368
Joined: Mar 2011

Odly enough I have a lot of lanscaping I do. I put in a field stone patio in my yard in the city so that my fire pit would not be near vegetation. I have yet to complete parts of this project. I have made some raised beds in my yard in order to plant my own vegetables and one of them is also from feild stones. This summer I hope to build an arbor for my beans or other vegies to grow on.

gdpawel's picture
gdpawel
Posts: 545
Joined: May 2001

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.

laughs_a_lot's picture
laughs_a_lot
Posts: 1368
Joined: Mar 2011

It sounds like this is a different inhibitor than the PARP inhibitor. Am I correct on this assumption? Let me know so I can follow this and speak with my medical oncologist when I consult on 4/26.

I hoped that this would be a factor to fight triple negative bc. I told my daughter several days ago of the fact that I would want to participate in a clinical trial on this if I ever reached a stage of breast cancer that they were recruiting for. This would only likely be the case if tnbc returned either in the other breast or more likely elsewhere in the body. I it seems that the conventional success rate is 70% with chemo and radiation for getting to the 5 year mark. So no matter how you look at it I will either be a part of that 70% which would be good, or I may have a chance to participate in a clinial trial for a better cure for tnbc. Though being in that other 30% would be difficult for my family, if I could participate in a clinical trial it would mean that my life meant something above what it has meant up until now. I refuse to let the experience of having breast cancer be wasted by not turning it into a positive somehow. I have always been determined to make the best of every situation that I face in life.

gdpawel's picture
gdpawel
Posts: 545
Joined: May 2001

laughs

Don't forget, cancers of the lung, the ovary, the colon, the breast, all manifest profiles of interest. There has been some pretty good responses with PARP inhibitors as single agents in some triple negative patients. There has been some results in drug combinations to optimize PARP inhibitor combinations. The functional profiling platform measures biological signals (rather than DNA indicators) which cut across all tumor types. If there would be PARP inhibitors (single agent or in combination) that are synergistic (efective, cooperative) to your individual cancer cells, clinical response will occur. The functional profiling platform can be crucial for clinical response prediction.

Greg

laughs_a_lot's picture
laughs_a_lot
Posts: 1368
Joined: Mar 2011

And that is still ok as long as we still make some progress somewhere. Sure I would love to have it be the answer for triple negative bc. But the idea that it can be used accross several different kinds of cancer makes it even more valuable in the sense that the manufacturers of this would have a decent market for development of the drug. So no matter how you look at this it would still be good news in the long haul. It is just good news from a different angle so to speak.

Megan M's picture
Megan M
Posts: 3001
Joined: Dec 2009

Thanks for all of this info!

laughs_a_lot's picture
laughs_a_lot
Posts: 1368
Joined: Mar 2011

Since reading some of the posts here on Parp inhibitors I did some further researchon Triple Negative Breast Cancer. Wow there is a lot to know about TNBC than just the research on PARP inhibitors. I will admit that the PARP inhibitors hold out the most hope at preset to assist a sub group of those with TNBC. Hurrah!!!!!

One of the issue involved with TNBC is that there seem to be two (or perhaps more) sub groups within the diagnosis of TNBC. There are basal type cell TNBC and non basal cell type. Of course in addition of certain types of chemotherapy studied to advance treatment will depend on the type of sub group that the TNBC seems to fall into. None the less any move forward to differentiate the various sub groups within TNBC will be a move forward so that avenues can be persued for each sub group.

So even though not all subgroups can benefit from the PARP inhibitor it is still good news for those who can use it. Meanwhile they are looking at ways to classify the subgroups into more precise subgroups in order to move forward in treatement for those who will not be able to benefit from the PARP inhibitor.

gdpawel's picture
gdpawel
Posts: 545
Joined: May 2001

Dr. Joyce O’Shaughnessy reported Phase II data, first at the ASCO meeting, then in the NEJM, describing the efficacy of iniparib combined with carboplatin and gemcitabine in triple negative breast cancer (TNBC). Despite the enthusiasm that surrounded Dr. O’Shaughnessy’s initial observations, the confirmatory clinical trial using iniparib combined with carboplatin and gemcitabine, then compared with carboplatin and gemcitabine did not achieve statistical significance. That is, the trial was negative and the combo of iniparib with carboplatin plus gemcitabine was not proven superior.

Based on this, Dr. Robert Nagourney initiated a study of both iniparib and olaparib in human breast cancer specimens. His results were reported at the ASCO meeting. What happened? Quite a few things.

First, it turned out that iniparib, a member of the benzamine chemical family, at physiological concentrations achievable in humans is not a PARP inhibitor. This, in retrospect, should have been obvious because a full-dose PARP inhibitor, plus a potent combination of carboplatin plus gemcitabine would not likely be tolerable if PARP inhibition were achieved.

Second, the patients receiving the drug are probably not a homogeneous population. That is, some TNBC patients may be similar to the BRCA patients, while others may not have the DNA repair deficiencies associated with PARP inhibitor response.

Finally, Dr. Nagourney originally reported the carboplatin plus gemcitabine combination in breast cancer, as a split-dose doublet in 2008 (Nagourney, Clin Breast Cancer Research, 2008). He observed, in that original clinical trial, that even a lower starting dose of gemcitabine (i.e. 800mg/ml2 vs. the O’Shaughnessy 1000 mg/m2) resulted in significant toxicity and in his concluding comments in that paper, he suggested 600mg/ml2. At 1000 mg/m2, Dr. O’Shaughnessy’s trial nearly doubled his recommended dose in this patient population.

Dr. Nagourney, like other investigators, entered into his original studies of these molecules believing iniparib to be a PARP inhibitor. To his surprise, and in retrospect, a direct comparison of olaparib (AZD2281) to inapaprib (BSI201) revealed no correlation. He described this in his abstract, “Of interest, BSI201 & AZD2281 activity did not correlate in parallel analyses (R = 0.07, P > 0.5).” Thus, his human tumor primary culture analysis scooped the ASCO investigators.

What has been learned? First, iniparib is not a true PARP inhibitor. Second, the combination of platins plus gemcitabine in breast cancer is synergistic, highly active and can be toxic (particularly at the doses chosen for this trial). Finally, that TNBC, indeed all breast cancers, even more to the point, all cancers in general, are heterogeneous. That is precisely why the use of human tumor primary culture analyses are so instructive and should be incorporated into clinical trials for these and other targeted agents.

Source: Rational Therapeutics

laughs_a_lot's picture
laughs_a_lot
Posts: 1368
Joined: Mar 2011

Sometimes the best minds can overlook the obvious. One of the new things I did find out about TNBC is that the NCCN is now reccomending that all TNBc patients get tested for the BCRA genes. I think this is wise as perhaps the BCRA gene can be passed through the father much like the baldness gene gets passed on through the mother. The spread of TNBC to other female organs when one has the BCRA gene probably has the NCCN thinking that it is worth the cost of genetic testing for all TNBC patients than to risk another cancer that could easily be prevented by testing for the gene and then having a hysterectomy if you turn out positive for the gene. Of course this is pure speculation on my part rather than anything I can back up with research. This however makes common sense from a purely economic perspective and unfortuneatly this is often how the insurance companies make thier decsions on what they will and will not cover.

Heatherbelle's picture
Heatherbelle
Posts: 1218
Joined: Jun 2010

Thank you so much for sharing this. I recently tested positive for BRCA1, and am *almost triple negative - ER and Her2- but very weakly (1-4%) PR+ - so tamoxifen wasn't helping me. The double whammy I was hit with a few weeks ago upon finding out my BRCA1 status threw me for a loop, and I had actually heard something about this subject, but this conversation thread made it understandable and gives me hope.
*hugs*
heather

nandu
Posts: 1
Joined: Jul 2011

Hi,
My mom has 4 tumors in breast for last 22 years. Is there any hope to recover her with these medicines?
Please help…

Reg,
Narendra Sing

pinkpalette's picture
pinkpalette
Posts: 112
Joined: Jul 2011

Kudos for sending the link in this thread:

Art in Oncology: How Patients Add Life to Their Days
http://jco.ascopubs.org/content/29/10/1392.full

I agree. To use art - be it poetry, painting, collage, knitting, cooking, journaling, crafts, gardening, to name a few - as a way of coping with cancer - is a proactive way to express emotions and heal from within. If someone told you creating art could improve your total health, quality of life, psychological and physical health, wouldn't you give it a try. Whatever you enjoy doing, do it creatively. Learn something new. Express yourself, enjoy yourself and feel good about your creative accomplishment....and yourself.

pinkpalette

Subscribe with RSS
About Cancer Society

The content on this site is for informational purposes only. It is not a substitute for professional medical advice. Do not use this information to diagnose or treat a health problem or disease without consulting with a qualified healthcare provider. Please consult your healthcare provider with any questions or concerns you may have regarding your condition. Use of this online service is subject to the disclaimer and the terms and conditions.

Copyright 2000-2014 © Cancer Survivors Network