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PARP Inhibitors in Ovarian Cancer

gdpawel's picture
gdpawel
Posts: 549
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/

LaundryQueen's picture
LaundryQueen
Posts: 682
Joined: Mar 2011

I appreciate the information. I read somewhere that the FDA cannot keep up with the demand for combinations of therapy that the oncologists want to study.

gdpawel's picture
gdpawel
Posts: 549
Joined: May 2001

Yes. The FDA, recently issued draft guidelines designed to encourage companies to work in tandem to develop two or more new drugs to be used in combination to treat cancer. Janet Woodcock, director of FDA’s Center for Drug Evaluation and Research told a group of venture capitalists, drug company executives, and foundation representatives at a meeting that if companies want to work together, they shouldn’t wait for the final guidelines to be issued.

One can't remember phase I-II trials of combinations of drugs which had not received prior FDA approval. Cocktails that mix drugs still in development wouldn't have been possible just five years ago.

However, cell culture assay labs have always tested new drugs in combination with each other, simultaneously measuring direct antitumor activity and antivascular activity.

Cocktails have become standard treatment in many oncological protocols: concoctions of two or more powerful cytotoxic agents which supposedly will attack the tumor in different ways. The ability of various agents to kill tumor and/or microvascular cells (anti-angiogenesis) in the same tumor specimen is highly variable among the different agents. There are so many agents out there now, doctors have a confusing array of choices. They don't know how to mix them together in the right order.

Data show conclusively that patients benefit both in terms of response and survival from drugs and drug combinations found to be 'active' in functional profiling assays even after treatment failure with several other drugs, many of which are in the same class, and even with combinations of drugs found to have low or no activity as single agents, but which are found in the assay to produce a synergistic and not merely an additive anti-tumor effect.

Sources:
FDA.gov
Weisenthal Cancer Group, Huntington Beach, CA and Departments of Clinical Pharmacology and Oncology, Uppsala University, Uppsala, Sweden. Current Status of Cell Culture Drug Resistance Testing May, 2002.

Rookerbird's picture
Rookerbird
Posts: 100
Joined: Feb 2011

Thank you for your post. I'm likin' this concluding statement:

Data show conclusively that patients benefit both in terms of response and survival from drugs and drug combinations found to be 'active' in functional profiling assays even after treatment failure with several other drugs, many of which are in the same class, and even with combinations of drugs found to have low or no activity as single agents, but which are found in the assay to produce a synergistic and not merely an additive anti-tumor effect.

gdpawel's picture
gdpawel
Posts: 549
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.

LaundryQueen's picture
LaundryQueen
Posts: 682
Joined: Mar 2011

gdpawel

I appreciate your continued contributions to this board. I don't know what your motivation is to keep us posted; however, it is good to know that you and others are keeping up with the research and sharing it with us.

I have had a gut feeling for some time that there should be more "chemo cocktails" for OVCA such as those used for other malignancies. When dealing with something that "morphs" into drug resistant forms, it makes sense to use a multi-pronged approach.

The "multi-pronged approach" includes lifestyle changes for me.

Would you be on the look out for research using alternating chemo drugs (which may be too toxic to use in combination)? I can imagine there may be some benefit to that approach.

Thanks again and may God bless you.

gdpawel's picture
gdpawel
Posts: 549
Joined: May 2001

LaundryQueen

My motivation is the satisfacton of knowing that I've helped to increase the knowledge of informed consent. My bailiwick has been my wife's experience as a cancer patient and my research on cell function analysis, which has no boundaries across cancer types.

Yes, environmental influences can cause the suppression of some gene functions and the activation of others. Our knowledge of genomic complexity tells us that genes and parts of genes interact with other genes, as do their protein products, and the whole system is constantly being affected by internal and external evironmental factors.

What do I mean by environmental influences? The totality of surrounding conditions - the milieu of the cell. What affects the milieu of the cell? Toxins, viruses, carcinogens, diet, essentially everything that our cells are exposed to. Detoxification, followed by the creation of a healthy milieu with appropriate diet and supplements benefits cancer patients.

Patients should receive less toxic, less mutagenic therapy with agents such as high-dose tamoxifen, targeted drugs such as Iressa, Tarceva and anti-angiogenic therapy with agents such as Avastin. Of course, there are a number of new classes of drugs that target VEGF, like Avastin at the protein level. At the tyrosine kinase level (Nexavar, Sutent) and at the intracellular metabolic pathway mTOR (Afinitor, Torisel).

Assay-directed therapy could provide clinical benefit.

Greg

Tethys41's picture
Tethys41
Posts: 1054
Joined: Sep 2010

This is all great information. Thanks so much for posting, Greg.

LaundryQueen's picture
LaundryQueen
Posts: 682
Joined: Mar 2011

Greg: I hope your wife is doing well. Thanks for your contributions to "Cancer College."

carolenk's picture
carolenk
Posts: 909
Joined: Feb 2011

Dear Greg

Just want to let you know that I appreciate your continued attendence to this board and hope your wife continues to do well.

I was thinking that you could be Professor Greg for our Cancer College! LOL!

take care and be well,

Carolen

gdpawel's picture
gdpawel
Posts: 549
Joined: May 2001

I wasn't going to bring this issue up, but since another has mentioned if my wife was doing well, I need to say that my dearly beloved spouse is still with me in spirit, helping me go over all this split pea soup of cancer medicine. Many times we may think our thoughts are our own, but more often than not, they emanate from our passed on loved-ones. Through these thoughts, the best parts of our creative character come forth. I could not have done my ten years of cancer research without the guidence of my wife. She has inspired each and every avenue of my search for truth. She is intermingled within my own mind. And she was a mensa on earth.

carolenk's picture
carolenk
Posts: 909
Joined: Feb 2011

I understand what you are saying & I believe your beloved wife is helping all of us.
I am grateful for the teaching team. Hugs to both of you.

Carolen

lindaprocopio's picture
lindaprocopio
Posts: 2022
Joined: Oct 2008

I follow your posts everywhere, gdpawel, with careful attention and great interest. Please know you have a fan in me, and that I appreciate the research you provide and the conclusions you draw. You have helped me numerous times to make treatment decisions over the past 2 1/2 years. Thank you, my friend.

gdpawel's picture
gdpawel
Posts: 549
Joined: May 2001

Split Pea Soup Recipe

Ingredients
a.. 1 lb (2 1/4 cups) green split peas
b.. 1 large onion, peeled and chopped
c.. 2 celery stalks, chopped
d.. 1 large leek, chopped
e.. 1 large carrot, chopped
f.. 1 large clove of garlic, halved
g.. 1 herb bouquet*
h.. 2 well-rinsed ham hocks
i.. Salt and Pepper
j.. Optional garnish - small toasted croutons (avoid for gluten-free version)**, chopped parsley or chives
*Herb Bouquet: Tie 3 cloves garlic, 4 allspice berries, 2 bay leaves, 1 teaspoon thyme, 8 sprigs parsley in rinsed cheesecloth or place in bouquet garni muslin bag.

**To make toasted croutons, take 2 or 3 slices of day-old French or Italian loaf bread, cut into cubes. Let dry out a bit (can put in 200 degree oven for 10 minutes to help dry). Melt a tablespoon or two of butter on medium high heat in a large skillet. When hot, add the bread cubes, spread out in a single layer. Let toast on one side and then turn to other sides. Add more butter if necessary. Alternatively you can toss the cubed bread with olive oil and let toast in a 350°F oven until lightly browned.

Method
1 Pick over the peas and remove any stones. Wash and drain peas. Place in a 4 quart pan with the vegetables, herb bouquet, ham hocks and 2 1/2 quarts of water. Bring to a simmer. Skim the scum off the top of the soup for several minutes, until the scum ceases to rise. Cover loosely and simmer about 1 1/2 hours, or until peas are tender, stirring occasionally in case they stick to the bottom of the pan.

2 Remove the ham hocks and herb bouquet from the soup. Purée the soup with a blender. An immersion blender works great for this; if you are using a regular blender, take care to workin batches and only fill the blender halfway if the soup is still hot, and hold down the lid while blending. If you want an exceptionally smooth soup, pass the purée through a sieve.

3 Return the purée to the pot and heat to serve. Add salt and pepper to taste. Ladle into warm bowls and garnish with croutons and parsley or chives.

If you want, don't discard the ham hocks, but cut away the outer skin and remove the meat from the bones. Dice the meat and serve with the soup.

Makes 2 quarts. Serves 6.

[understand this!?] LOL!!!

lindaprocopio's picture
lindaprocopio
Posts: 2022
Joined: Oct 2008

If only pea soup would kill cancer!! When various chemos ruined my taste buds or made my bowels all yukky, pea soup was one thing that always tasted good and felt good in my belly. Please tell me this is the 'magic bullet' I've been looking for!!

LOL!

Hissy_Fitz's picture
Hissy_Fitz
Posts: 1869
Joined: Sep 2009

Sounds great! I have a huge ham bone left over from Easter.

Carlene

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