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Old 04-14-2011, 09:42 AM
gdpawel gdpawel is offline
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Default PARP Inhibitors for Melanoma?

Patients with melanoma are now candidates for the antibody Yervoy (ipilimumab) and/or the B-Raf inhibitor PLX4720. The latter requires identification of a V600E b-RAF mutation. It would seem appropriate for patients to be given insights on those options. The problem in cell function analysis, is that Ipilimumab effects are modest and PLX responses are generally short-lived.

Some cell-based assay labs have explored the biology of PARP inhibitors, alone and in combination, in actual human tumor primary culture microspeheroids (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.

The Sunday, April 3, 2011, experimental and molecular therapeutics poster session at the American Association for Cancer Research (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 results of functional analysis with the mTOR/P13K and MEK/ERK inhibitors, BEZ235 and AZD6244, alone and in combination in human tumor primary culture microspheroids (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.

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.

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 explored and reported.

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 and some results combining the PARP inhbitors with mustard alkylators, platins and drug combinations to optimize PARP inhibitor combinations. 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: Robert A. Nagourney, Paula Bernard, Federico Francisco, Ryan Wexler, Steve Evans, Rational Therapeutics, Long Beach, CA. Proceedings of AACR - Volume 52 - April 2011.

Poster from Rational Therapeutics Session at 2011 AACR Meeting

[url]http://robertanagourney.wordpress.com/2011/04/28/poster-from-rational-therapeutics-session-at-2011-aacr-meeting/
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Old 05-02-2011, 10:53 AM
gdpawel gdpawel is offline
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Default Can the PARP Inhibitors be tested with the Functional Profiling Platform?

Poly ADP ribose polymerase (PARP) is a nuclear enzyme associated with response to DNA damage. Following single strand DNA breaks, the enzyme attaches a backbone of ADP and ribose that serves to initiate DNA repair. Certain classes of chemotherapeutics, specifically alkylating agents, can induce injury that results in extensive poly ADP ribosylation resulting in the exhaustion of intercellular pools of NAD and ATP ultimately leading to cell death.

Although PARP inhibitors have recently entered the clinical cancer literature mostly relating to the treatment of BRCA+ and triple negative patients, neither PARP nor PARP inhibitors are new to the cancer researcher community, according to Dr. Robert Nagourney, medical director at Rational Therapeutics, one of the pioneers of the functional profiling technique.

His group first became interested following a 1988 study by Distelhorst from Case Western Reserve (Distelhorst CW, Blood 1988 Oct;72(4):1305-09) that described a mechanism of cell death that correlated with their work in childhood leukemia. Previously, investigators at Scripps Clinic had described PARP’s role in response to 2CDA (Seto, S., et al. J Clin. Invest. 1985 Feb;75(2):377-83). His group has studied small molecule inhibitors of PARP for many years, and more recently, they have expanded these investigations to include BSI201 (iniparib) and AZD2281 (olaparib). Both of which are undergoing clinical investigations. Nagourney will be reporting their findings with these PARP inhibitors at the 2011 ASCO meeting (Nagourney, R., et al Proceedings Amer Soc Clin Oncol. 2011).

PARP inhibitors are easily studied and provide interesting signals in the tissue studied. They have seen activity in BRCA+ patients and some triple negative breast cancers. They have also identified synergy with other classes of drugs. The compounds are a welcome addition to the cancer therapy armamentarium and continue to be actively studied in the cell-based functional profiling platform.

Of interest is the recent failure of the iniparib plus Carboplatin & gemcitabine Phase III trial to meet progression-free and overall survival goals in triple negative breast cancer patients (Zacks Investment Research on January 31, 2011). This failure may reflect the need to apply predictive methodologies to select candidates for these drugs, similar to Nagourney's successful work with other classes of compounds.
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Old 06-05-2011, 09:29 PM
gdpawel gdpawel is offline
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Default Functional Analysis of PARP Inhibitors in Human Tumor Primary Cultures

Functional analysis of PARP inhibitors AZD 2281 and BSI-201 in human tumor primary cultures: A comparison of activity and examination of synergy with cytotoxic drugs.

Sub-category: DNA Repair and Apoptosis

Category: Developmental Therapeutics - Experimental Therapeutics

Meeting: 2011 ASCO Annual Meeting

Abstract No: e13599

Citation: J Clin Oncol 29: 2011 (suppl; abstr e13599)

Author(s): R. A. Nagourney, K. R. Kenyon, F. R. Francisco, P. J. Bernard, S. S. Evans; Rational Therapeutics, Long Beach, CA

Abstract:

Background:

Poly (ADP-ribose) polymerases (PARP) are activated in response to cellular injury. DNA damage from radiation and cytotoxic drugs results in the up-regulation of PARP 1/2, leading to base excision repair. PARP inhibition enhances chemotherapy and induces cell death by synthetic lethality in patients with deficient homologous repair (BRCA1/2 and ATM). PARP inhibitors in development include benzamides, phthalazinones and benzimidazoles. Our work with 3-aminobenzamide (3-AB) led to the study of BSI-201 and AZD 2281, in human tumor micro-spheroids, isolated from surgical specimens and cytologically (+) fluids.

Methods:

Delayed loss of membrane integrity, morphologic and metabolic measures of drug-induced programmed cell death (EVA/PCD) were applied in 45 human tumor specimens exposed to PARP inhibitors, alone and in combination with cytotoxics. Lethal concentrations (LC50) were interpolated from 5-point dose response curves. Synergy was assessed by median effect. Drug activity comparisons were performed by modified Z-score.

Results:

PARP inhibitors are active in human tumor micro-spheroids. Activities for AZD 2281 and BSI-201 are superior to 3AB favoring BRCA1/2 and triple-negative (TN) breast over wild type and ER/PR (+); (AZD avg LC50 12 vs. 60 ug/mL; BSI avg LC50 19 vs. 30 ug/mL). AZD2281 and BSI-201 reveal synergy with CDDP, CDDP and gemcitabine, and alkylators. Of interest, BSI-201 and AZD-2281 activity did not correlate in parallel analyses (Pearson Moment, r = 0.07, P > 0.5). A comparison of BSI-201 and AZD 2281 activity with CDDP or taxol, suggested correlation with CCDP but not with taxol.

Conclusions:

1) PARP inhibitors are active in human tumors favoring BRCA1/2 and TN breast. 2) Favorable interactions with DNA damaging agents are observed. 3) Activity profiles correlate more strongly with CDDP than taxol. 4) Direct comparisons suggest somewhat different activity profiles for BSI-201 vs. AZD-2281. 5) Individual activity/synergy profiles may provide opportunities for patient selection in the development of novel PARP combinations. Analyses in BRCA 1/2 and TN breast cancers are ongoing.

Supported by The Vanguard Cancer Foundation and The Nagourney Institute.

Synthetic lethality: beating cancer at its own game

[url]http://www.oncologypractice.com/fileadmin/content_pdf/co/JCSO_jan_35-39_Feature_DeLartigue.pdf
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Last edited by gdpawel : 02-09-2014 at 07:12 PM. Reason: additional info
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Old 06-21-2011, 10:28 AM
gdpawel gdpawel is offline
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Default The Evolutionary History Of The PARP Enzyme

The recently analyzed evolutionary history of the poly(ADP-ribose)polymerase (PARP) found these proteins in eukaryotes, a wide range of organisms - animals, plants, molds, fungi, algae and protozoa - whose cells contain complex structures enclosed within membranes. While PARP proteins can be found with any of these groups, they have been most extensively studied in mammals.

In these organisms, PARPs have key functions in DNA repair, genome integrity and epigenetic regulation. More recently it has been found that proteins within the PARP family have a broader range of functions that initially predicted.

Researchers used computers to identify 236 PARP proteins from 77 species across five of the six groups, and performed extensive phylogenetic analyses of the identified PARP regions.

PARPs are found in all eukaryotic groups for which sequence is available, but some individual lineages within groups have independently lost these genes. The PARP family can be subdivided into six branches or clades. Two of these clades were likely found in the last common eukaryotic ancestor. In addition, they have identified PARPs in organisms in which they have not previously been described.

Three main conclusions were drawn from the study:

First, the broad distribution and pattern of representation of PARP genes indicated to the researchers that the ancestor of all existing eukaryotes encoded proteins of this type.

Second, the ancestral PARP proteins had different functions and activities. One of these proteins likely functioned in DNA damage response.

Third, the diversity of the PARP family is larger than previously documented, suggesting as more eukaryotic genomes become available, this gene family will grow in both number and type.

Source: The study, "Evolutionary history of the poly(ADP-ribose) polymerase gene family in eukaryotes," was authored by Rebecca S. Lamb, PhD, an assistant professor of Molecular Genetics and Ohio State University colleagues Matteo Citarelli and Sachin Teotia and appeared in an issue of the journal BMC Evolutionary Biology. The work was supported by a grant from the Ohio Plant Biotechnology Consortium and by funds from the Ohio State University.
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Old 05-13-2012, 09:37 PM
gdpawel gdpawel is offline
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Default Cancer Medicine is a BIG Business

What can influence the treatment options for patients being treated for cancer? McKeeson to Purchase US Oncology.

[url]http://www.businesswire.com/news/home/20101101005861/en/McKesson-Purchase-Oncology-Transaction-Valued-2.16-Billion

US Oncology is a 1,200 doctor practice that gets discounts or rebates that they receive from drugmakers.

US Oncology, a corporation whose affiliated network of oncology physicians cares for approximately 15% of all newly diagnosed cancer patients each year in the United States.

Medicare accounts for 38% of US Oncology's net patient revenues.

Just this year, US Oncology picked up Cure Media Group and its flafshlip magazine Cure. The magazine goes out to all US Oncology-affiliated practices and over 720,000 cancer patients treated within that network. The majority of Cure's advertisers are pharmaceutical companies.

The PARP-1 clinical trials were done in large part through member practices of US Oncology, not through a major university or university consortium. And since most independent private practice oncologists are not with a 1,200 doctor practice like US Oncology, they do not get the discounts or rebates that US Oncology receives from drugmakers.

According to Forbes, US Oncology has become the nation's single largest purchaser of chemotherapy drugs, spending a projected $2 billion last year. The company has attracted a swarm of critics, often nonprofit or community hospitals, alleging that US Oncology destroys the fragile local economics of the U.S. health care system.

Congress had intensified its scrutiny of Medicare spending on pharmaceutical EPO, which represented the single largest drug expense for the program. When the reality of pharmaceutical EPO was exposed, US Oncology banked $8-10 million a year less than expected in their SEC Form 10-K report. They obused giving the drug so much that they couldn't convince Medicare otherwise.

In 2005, the company was subpoenaed by the U.S. Department of Justice about contracts and relationships with pharmaceutical companies.

Cancer Capitalists: [url]http://www.forbes.com/forbes/2006/1127/178.html
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Old 11-11-2012, 10:23 AM
gdpawel gdpawel is offline
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Default New mechanism of action for PARP

NIH researchers discover new mechanism of action for class of chemotherapy drugs

Bethesda, Maryland

Monday, November 05, 2012

The National Institutes of Health (NIH) researchers have discovered a significant new mechanism of action for a class of chemotherapy drugs known as poly (ADP-ribose) polymerase inhibitors, or PARP inhibitors. They have also identified differences in the toxic capabilities of three drugs in this class which are currently being tested in clinical trials. The study was conducted at the National Cancer Institute (NCI), part of NIH.

In recent years, drugs classified as PARP inhibitors have been shown to be promising anticancer agents for breast and ovarian cancer. Members of the PARP family of proteins are involved in a number of critical cellular processes, including DNA damage repair and programmed cell death. Prior to this study, PARP inhibitors were thought to work primarily by blocking PARP enzyme activity, thus preventing the repair of DNA damage and ultimately causing cell death.

In this study, scientists established that PARP inhibitors have an additional mode of action: localizing PARP proteins at sites of DNA damage, which has relevance to their anti-tumour activity. The trapped PARP protein–DNA complexes are highly toxic to cells because they block DNA replication. When the researchers tested three PARP inhibitors for their differential ability to trap PARP proteins on damaged DNA, they found that the trapping potency of the inhibitors varied widely.

"Critical to our research is that, while PARP inhibitors had been assumed to be of equivalent potency based on the degree to which they elicit PARP inhibition, we now know that they are not equivalent with respect to their potency to trap PARP," said Yves Pommier, MD, PhD., NCI Centre for Cancer Research. "Our findings suggest that PARP inhibitors should be categorized according to their potency to trap PARP, in addition to their enzyme inhibition abilities."

The PARP family of proteins in humans includes PARP1 and PARP2, which are DNA binding and repair proteins. When activated by DNA damage, these proteins recruit other proteins that do the actual work of repairing DNA. Under normal conditions, PARP1 and PARP2 are released from DNA once the repair process is underway. However, as this study shows, when they are bound to PARP inhibitors, PARP1 and PARP2 become trapped on DNA. The researchers showed that trapped PARP–DNA complexes are more toxic to cells than the unrepaired single-strand DNA breaks that accumulate in the absence of PARP activity, indicating that PARP inhibitors act as PARP poisons.

In collaboration with James Doroshow, MD, deputy director for clinical and translational research at NCI, the investigators used PARP assays (ways of measuring PARP activity in cells and tissues) to compare three PARP inhibitor compounds that are currently in clinical testing: MK-4827, olaparib, and veliparib.

The scientists found that the three PARP inhibitors differed in their ability to inhibit PARP enzyme activity, with olaparib being the most potent inhibitor, followed by veliparib and then MK-4827. However, in terms of toxicity, MK-4827 was the most potent, followed by olaparib and then veliparib. Moreover, PARP1 complexes with MK-4827 and olaparib were shown to be more tightly bound to DNA than complexes with veliparib.

These findings suggest that there may be two classes of PARP inhibitors, catalytic inhibitors that act mainly to inhibit PARP enzyme activity and do not trap PARP proteins on DNA, and dual inhibitors that both block PARP enzyme activity and act as PARP poison.

"Our findings suggest that clinicians who use PARP inhibitors in clinical trials should carefully choose their drug, because we now suspect results may differ, depending upon the PARP inhibitor used," said Junko Murai, MD, PhD., NCI Centre for Cancer Research. "As a next step, we are working to categorize other leading PARP inhibitors based upon both PARP trapping and PARP inhibition."

This work was supported by the Intramural Programme of NCI and by the Japan Society for the Promotion of Science (JSPS) Core-to-Core Programme. First author Junko Murai is a JSPS fellow working at NCI Centre for Cancer Research. Funding was provided by NCI grant Z01 BC 006150-19LMP.

The National Cancer Institute (NCI) leads the National Cancer Programme and the NIH effort to dramatically reduce the burden of cancer and improve the lives of cancer patients and their families, through research into prevention and cancer biology, the development of new interventions, and the training and mentoring of new researchers.

NIH, the nation's medical research agency, and is a component of the US Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases.
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Old 11-11-2012, 10:24 AM
gdpawel gdpawel is offline
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Default NIH researchers discover new mechanism of action for PARP

This new "NIH research discovery" brings up an interesting subject. While apoptosis represents an important mechanism of programmed cell death, it is only one of several cell death pathways.

Apoptotic cell death occurs with certain mutational events, DNA damage, oxidative stress and withdrawal of some growth factors particularly within the immune system.

Non-apoptotic programmed cell death includes: programmed necrosis, para-apoptosis, autophagic cell death, nutrient withdrawal, and subtypes associated with mis-folded protein response, and PARP mediated cell death.

While apoptotic cell death follows a recognized cascade of caspase mediated enzymatic events, non-apoptotic cell death occurs in the absence of caspase activation.

While caspase activation is of interest, comparably easy to measure and useful in many leukemias and lymphomas, it does not represent cancer cell death in all circumstances and can be an unreliable parameter in many solid tumors.

Labs that focus on measurements of caspase activation can only measure apoptotic cell death. While apoptotic cell death is of importance in hematologic cancers and some solid tumors, it does not represent the mechanism of cell death in all tumors.

This is why functional profiling measures all cell death events by characterizing metabolic viability at the level of cell membrane integrity, ATP content, or mitochondrial function.
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