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Thread: PARP Inhibitiors in Breast and Other Cancers

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    Distinguished Community Member gpawelski's Avatar
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    Default PARP Inhibitiors in Breast and Other Cancers

    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 Iniparib, 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.
    Gregory D. Pawelski

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    Distinguished Community Member gpawelski's Avatar
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    Default Ex vivo analysis of the mTOR/PI3K & MEK/ERK inhibitors

    Presentation Abstract Number: 650

    Presentation Title: Ex vivo analysis of the mTOR/PI3K & MEK/ERK inhibitors, BEZ235 & AZD6244, alone and in combination in human tumor primary culture micro-spheroids: Exploration of horizontal pathway targeting

    Presentation Time: Sunday, Apr 03, 2011, 1:00 PM - 5:00 PM

    Location: Exhibit Hall A4-C, Poster Section 27

    Poster Section: 27

    Poster Board Number: 24

    Author Block: Robert Alan Nagourney, Paula J. Bernard, Federico R. Francisco, Ryan Wexler, Steven S. Evans. Rational Therapeutics, Inc., Long Beach, CA

    Abstract Body:

    Therapeutic targeting of signal transduction pathways offers fertile ground for the discovery of small molecule kinase inhibitors and novel combinations. The success of Imatinib in CML, the first clinically approved oral TKI, reflects in part, the linear association between the malignant phenotype and c-Abl activation. However, most solid tumors reveal complex interactions between signal pathways that cross talk at points of commonality, the subject of prior report (Nagourney, RA Proc. AACR, 2010). To examine the clinical potential of BEZ235 and AZD6244, inhibitors of the PI3K & MEK/ERK pathways, we applied Ex Vivo Analysis of Programmed Cell Death (EVA/PCD™) (Nagourney RA, Curr. Treat Options in Oncology, 2006) to tumor micro-spheroids isolated from 24 patients. Drugs were tested alone and in combination. Five point dose response curves were interpolated to provide LC50 values. Synergy was assessed by median effect. Activity comparisons were conducted by modified Z-Score. LC50 values by Z-score for AZD revealed Melanoma > Breast > NSCLC > Myeloma >Ovarian > Uterine >Sarcoma > Renal, while BEZ revealed Breast > Renal > NSCLC > Ovarian > Myeloma > Sarcoma > Uterine. By combining BEZ with AZD, we then explored the simultaneous inhibition of the MEK/ERK and PI3K/mTOR pathways. Results in 5 of the first 6 analyses revealed activity & synergy for the dual pathway inhibitor combination. These results 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 developmental. Disease specific profiles and sequence dependence are being explored and will be reported.

    Supported in part by the Vanguard Cancer Foundation and The Nagourney Institute.

    American Association for Cancer Research
    Gregory D. Pawelski

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    Default 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.

    Horizontal and vertical signal pathway inhibition in human tumor primary culture micro-spheroids

    Robert Alan Nagourney, Paula J. Bernard, Federico R. Francisco, and Steven S. Evans
    Rational Therapeutics, Long Beach, CA.

    Introduction:

    Signal transduction pathways are targets for small molecule tyrosine and serine-threonine kinase inhibitors. Redundancy and cross talk between pathways can complicate the application of genomic signatures but proteomic and functional platforms may more closely approximate tumor phenotypes. We used EVA/PCD (ex vivo analysis of programmed cell death), a functional platform measuring both apoptotic & non-apoptotic events to examine the PI3K and EGFr pathways in human 1° culture micro-spheroids.

    Methods:

    337 tumor specimens provided from the OR were mechanically and enzymatically disaggregated and exposed to EGFr (Gefitinib), AKT (B-15), PI3K (LY294002) & mTOR (Rapamycin) inhibitors with LC50 values interpolated from 5-point dose response curves. Synergy was assessed by median effect and correlation coefficients by Pearson Moment.

    Results:

    Parallel Pearson Moment analyses in 51 specimens by 2-tailed T, revealed LY vs. B15 (NS); LY vs. Rapa (P<0.02); B15 vs. Rapa (P<0.0025); Rapa vs. Gefitinib (P <0.001). Synergy analyses for Rapa & Gefitinib revealed synergy in 29%, additivity in 41%, sub-additivity in 13% and antagonism in 17%. Exploratory synergy analyses that combined Gefitinib & LY and Gefitinib & B-15, favored the Gefitinib& B-15 combination with 100% synergy in this small series.

    Conclusions:

    EVA/PCD analyses provide insights into cellular response to targeted therapies, alone and in combination. Correlative analyses identify points of commonality and/or disparity in downstream signaling that can be exploited in drug development and therapy. Synergy analyses reveal potentially important drug combinations. The EVA/PCD human tumor micro-spheroid platform provides a functional tool capable of streamlining drug development and cancer therapy.

    Supported by The Vanguard Cancer Foundation and the Nagourney Institute.

    Citation: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1764.
    Gregory D. Pawelski

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    Default Can the PARP Inhibitors be tested with the Functional Cytometric 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.
    Gregory D. Pawelski

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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.
    Gregory D. Pawelski

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    Default BRCA 1 or BRCA2 Breast & Ovarian Cancer Drug in Tablet Form

    Cancer Research UK's Drug Development Office has re-launched a trial of a promising drug to treat inherited breast and ovarian cancer - but this time taken as a tablet by outpatients.

    The Phase II clinical trial is led by The Sir Bobby Robson Cancer Trials Research Centre, Newcastle University and The Newcastle upon Tyne Hospitals NHS Foundation, and also runs across The Beatson West of Scotland Cancer Centre, UCL, PlymouthOncology Centre, University of Birmingham Hospital, Christie Hospital, Manchester; and St James' University Hospital, Leeds.

    Women with advanced breast or ovarian cancer with faults in the known high-riskBRCA1 or BRCA2 genes will receive the drug called AG-014699 (Rucaparib) - which belongs to a promising class of drugs called PARP inhibitors. The trial is also open to women with advanced serous ovarian cancer but unknown BRCA status.

    When both copies of the BRCA1 or BRCA2 genes are faulty, the cells rely on the alternative PARP pathway to repair damaged DNA - preventing cancer-causing mistakes being passed on to daughter cells. By also blocking PARP with drugs, cancer cells which have lost BRCA1 or BRCA2 can no longer repair DNA damage at all, causing these cancer cells to die. Serous ovarian cancer patients are also included in the study as they may have DNA repair deficits that could make them sensitive to treatment with a PARP inhibitor.

    Patients take the drug as a daily tablet at home over 21 days, only coming to hospital for check-ups and tests. This treatment plan replaces an earlier version of the trial of the drug where it was delivered intra-venously to patients on five days over the same period.

    The trial will initially establish the dosing schedule for the drug and evaluate whether it is effective for these patients.

    Professor Ruth Plummer, the trial's chief investigator, at the Northern Institute for Cancer Research, at Newcastle University, said: "We're seeing encouraging results in women with breast or ovarian cancer treated with PARP inhibitors. It's great news that we're able to run a trial of this exciting drug as a tablet which will be a much more convenient and comfortable way to receive the treatment.

    "Patients will be able to take a tablet at home - which will mean they can go to work or stay at home with their families, instead of spending long periods of time at hospital with the discomfort of receiving the drug through a drip."

    Faults in the BRCA1 or BRCA2 genes account for around five per cent of the 44,000 women in the UK with breast cancer and for more than five percent of the 6,600 women with ovarian cancer.

    PARP inhibitors are being used alone in clinical trials to treat patients with specific types of breast, ovarian and prostate cancers. They can also be combined with existingcancer treatments - including chemotherapy and radiotherapy.

    This latest trial is being funded and managed by the charity's Drug Development Office (DDO).

    Dr Nigel Blackburn, director of drug development at Cancer Research UK's Drug Development Office, said: "It's incredibly encouraging to launch a trial of this promising drug which is personalised to target the different genetic make-up of patients with breast and ovarian cancer. Providing the drug as a tablet will give patients a much improved quality of life.

    "This drug was developed through work led by Cancer Research UK scientists and we're continuing to invest further in targeted drugs like this. We hope that this new treatment approach will help extend the lives of women with breast and ovarian cancer. We look forward to the results with great interest."

    Source: Cancer Research UK
    Gregory D. Pawelski

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