Publications by authors named "Robert Nicholson"

140 Publications

Impact of galcanezumab on total pain burden: findings from phase 3 randomized, double-blind, placebo-controlled studies in patients with episodic or chronic migraine (EVOLVE-1, EVOLVE-2, and REGAIN trials).

J Headache Pain 2020 Oct 17;21(1):123. Epub 2020 Oct 17.

Eli Lilly and Company, Indianapolis, IN, USA.

Background: Focus on the frequency of migraine pain may undervalue the total burden of migraine as pain duration and severity may present unique, additive burden. A composite measure of total pain burden (TPB; frequency, severity, and duration) may provide a more comprehensive characterization of pain burden and treatment response in patients with episodic migraine (EM) or chronic migraine (CM). The impact of galcanezumab versus placebo on TPB among patients with EM or CM was analyzed.

Methods: Patients from randomized, double-blind, placebo-controlled episodic (two 6-month studies pooled) and chronic migraine (3-month) studies received once-monthly subcutaneous injection of galcanezumab 120 mg or placebo. A post hoc analysis of TPB for a given month was calculated as severity-weighted duration by multiplying duration (hours) and maximum pain severity (0 = none, 1 = mild, 2 = moderate, 3 = severe) of migraine for each day and summing these over the days in a month. Least square mean change from baseline in monthly TPB across Months 1-6 (EM, N = 444 galcanezumab, N = 894 placebo) and Months 1-3 (CM, N = 278 galcanezumab, N = 558 placebo) were compared using a mixed-model repeated measures model. Correlation of the Migraine Specific Quality of Life Questionnaire (MSQ) and Migraine Disability Assessment Scale (MIDAS) to TPB at baseline was assessed.

Results: At baseline, the duration of migraine on a given migraine headache day accounted for the greatest unique proportion of variability (EM, 57.4% and CM, 61.1%) to TPB after adjusting for frequency of migraine headache days and maximum pain severity. The decrease from baseline in monthly TPB was greater with galcanezumab than placebo for patients with EM (68.6 versus 36.2) and CM (102.6 versus 44.4). The average percent reduction of TPB from baseline was significantly greater with galcanezumab compared with placebo in patients with EM (50.8% versus 17.2%) and CM (29.7% versus 11.0%). In patients with EM and CM, TPB correlated with MSQ total score (r = - 0.35 and r = - 0.37) and MIDAS (r = 0.34 and r = 0.32).

Conclusions: Greater reduction in TPB was seen in patients with EM and CM treated with galcanezumab 120 mg once-monthly injection relative to placebo. Discussing TPB supports patient-centric conversations regarding treatment expectations when clinicians are evaluating options for migraine prevention.

Trial Registration: ClinicalTrials.gov : # NCT02614183 (I5Q-MC-CGAG; EVOLVE-1), # NCT02614196 (I5Q-MC-CGAH; EVOLVE-2), and # NCT02614261 (I5Q-MC-CGAI; REGAIN) - all 3 trials were registered on 23 November 2015.
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http://dx.doi.org/10.1186/s10194-020-01190-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7568830PMC
October 2020

Assessing evidence-based medicine and opioid/barbiturate as first-line acute treatment of pediatric migraine and primary headache: A retrospective observational study of health systems data.

Cephalalgia 2019 Jul 20;39(8):1000-1009. Epub 2019 Feb 20.

5 Mercy Research, Chesterfield, MO, USA.

Objectives: To evaluate providers' use and predictors of evidence-based medicine or opioid/barbiturate as first-line acute treatment for children's initial presentation of acute migraine or primary headache.

Methods: This retrospective, observational study utilized patient (children ages 6-17) and provider/encounter characteristics extracted from the patient's Electronic Health Record from 2008-2014 during an initial encounter for migraine or primary headache. The primary outcome was provider evidence-based medicine utilization; overall prescriptions and opioid/barbiturate prescriptions were also evaluated. Hierarchical linear modeling examined whether Level 1 (patient: Demographic, insurance type) and Level 2 (provider/encounter: Treatment setting/location, encounter diagnoses) characteristics influenced outcomes.

Results: In all, 38,926 patients (56.7% female, mean age = 12.1) and 1617 providers were evaluated. Only 17.7% of patients were diagnosed with migraine; 16.1% received evidence-based medicine. Older children (OR = 1.07,  < 0.001), females (OR = 1.14,  < 0.001), and those diagnosed with migraine (OR = 4.71,  < 0.001) were more likely to receive evidence-based medicine. Among prescriptions, 15.8% were for opioids/barbiturates. Older children (OR = 1.14,  < 0.001) and those cared for in the emergency department/urgent care (OR = 2.02,  < 0.001) were at increased risk.

Conclusions: Demographics and migraine diagnosis are associated with evidence-based medicine and opioid/barbiturates. Primary care provides an opportunity to target provider interventions to enhance effective pediatric headache treatment.
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http://dx.doi.org/10.1177/0333102419833080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6933731PMC
July 2019

Co-Administration of Fish Oil With Signal Transduction Inhibitors Has Anti-Migration Effects in Breast Cancer Cell Lines, .

Open Biochem J 2018 31;12:130-148. Epub 2018 Aug 31.

School of Pharmacy & Pharmaceutical Sciences, Cardiff University, CF10 3NB, Cardiff, United Kingdom.

Background: There is an urgent need for new therapies to treat cancer metastasis. Fish oil, with high omega 3 fatty acid content, has shown anticancer activity and signal transduction inhibitors have shown anti-metastatic properties.

Objective: To provide preliminary data on the anti-migration potential of signal transduction inhibitors and co-administered fish oil.

Methods: MCF-7, TamR and FasR breast cancer cell lines were used to determine the effects of combinations of PD98059, LY294002 and fish oil in growth assays. Modulations of p-Src and COX-2, both mediators of motility and invasion, were then determined by Western blotting and IHC to ascertain effects on migration potential.

Results: Migration rates for the three cell lines examined were ranked: FasR>TamR>MCF-7 ( <0.05). Addition of fish oil reduced the number of TamR cells migrating after 48h ( <0.05), while the addition of PD98059 and LY294002 also decreased migratory potential of TamR cells ( <0.05). Addition of PD98059 and LY294002 to TamR cells did not result in a significant decrease in p-Src levels; as was the case when PD98059, LY294002 and 4-hydroxytamoxifen were added to MCF-7 cells. However, the co-administration of fish oil markedly reduced p-Src and COX-2 expression in both cell lines.

Conclusion: Co-administration of a commercial fish oil with signal transduction inhibitors results in decreased cell migration an unknown co-operative mechanism and could constitute a novel approach for the treatment of breast cancer metastasis.
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http://dx.doi.org/10.2174/1874091X01812010130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6142674PMC
August 2018

Correction to: Heregulin β1 drives gefitinib-resistant growth and invasion in tamoxifen-resistant MCF-7 breast cancer cells.

Breast Cancer Res 2018 08 30;20(1):98. Epub 2018 Aug 30.

Tenovus Centre for Cancer Research, Welsh School of Pharmacy, Cardiff University, Redwood Building, King Edward VII Avenue, Cardiff, CF10 3XF, UK.

After the publication of this work [1], an error was noticed in Fig. 2b and Fig. 4b as well as Fig. 4b. and Fig. 5d. Images of the ERK1/2 blots were accidentally duplicated. In Fig. 5a. and Fig. 5c., the last lane for p-ERK1/2 was mistakenly cropped out of the final image. The original blot for Fig. 4b., "total EGFR" (or lane 2) is shown below to avoid any misunderstanding of the data. We apologize for this error, which did not affect any of the interpretations or conclusions of the article.
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http://dx.doi.org/10.1186/s13058-018-0999-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6117898PMC
August 2018

Acute migraine medication adherence, migraine disability and patient satisfaction: A naturalistic daily diary study.

Cephalalgia 2017 Sep 3;37(10):955-964. Epub 2016 Aug 3.

4 Mercy Virtual, Chesterfield, MO, USA.

Objective To examine the influence of acute migraine medication adherence on migraine disability and acute medication satisfaction. Methods Adults with migraine completed three months of daily electronic diaries assessing headache symptoms, acute medication taken, acute medication satisfaction, and daily migraine disability. Repeated measures mixed-effects models examined the effect of initial medication type [migraine-specific medication (MSM) vs. over-the-counter analgesic (OTC) vs. an opiate/barbiturate], the severity of pain at dosing, and their interaction with daily migraine disability and satisfaction with acute medication. Results Participants (N = 337; 92.5% female; 91.1% Caucasian, non-Hispanic; 84.0% with episodic migraine) recorded 29,722 diary days. Participants took acute medication on 96.5% of 8090 migraine days. MSM was most frequently taken first (58%), followed by OTC (29.9%) and an opiate/barbiturate (12.1%). Acute medication was most frequently taken when pain was mild (41.2%), followed by moderate (37.7%) and severe pain (11.4%). Initially dosing with MSM while pain was mild was associated with the lowest daily disability [medication × pain at dosing F (4, 6336.12) = 58.73, p < .001] and highest acute medication satisfaction [medication × pain at dosing F (4, 3867.36) = 24.00, p < .001]. Conclusion Using an MSM (triptan or ergot) first was associated with the lowest migraine disability and highest acute medication satisfaction.
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http://dx.doi.org/10.1177/0333102416663459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5329165PMC
September 2017

Restricted activity and persistent pain following motor vehicle collision among older adults: a multicenter prospective cohort study.

BMC Geriatr 2016 Apr 19;16:86. Epub 2016 Apr 19.

Department of Anesthesiology, University of North Carolina, 170 Manning Dr, Chapel Hill, NC, USA.

Background: Restricted physical activity commonly occurs following acute musculoskeletal pain in older adults and may influence long-term outcomes. We sought to examine the relationship between restricted physical activity after motor vehicle collision (MVC) and the development of persistent pain.

Methods: We examined data from a prospective study of adults ≥65 years of age presenting to the emergency department (ED) after MVC without life-threatening injuries. Restricted physical activity 6 weeks after MVC was defined in three different ways: 1) by a ≥25 point decrease in Physical Activity Scale in the Elderly (PASE) score, 2) by the answer "yes" to the question, "during the past two weeks, have you stayed in bed for at least half a day?", and 3) by the answer "yes" to the question, "during the past two weeks, have you cut down on your usual activities as compared to before the accident?" We examined relationships between each definition of restricted activity and pain severity, pain interference, and functional capacity at 6 months with adjustment for confounders.

Results: Within the study sample (N = 164), adjusted average pain severity scores at 6 months did not differ between patients with and without restricted physical activity based on decreased PASE score (2.54 vs. 2.07, p = 0.32). In contrast, clinically and statistically important differences in adjusted average pain severity at 6 months were observed for patients who reported spending half a day in bed vs. those who did not (3.56 vs. 1.91, p < 0.01). In adjusted analyses, both decreased PASE score and cutting down on activity were associated with functional capacity at 6 months, but only decreased PASE score was associated with increased ADL difficulty at 6 months (0.70 vs. -0.01, p = 0.02).

Conclusions: Among older adults experiencing MVC, those reporting bed rest or reduced activity 6 weeks after the collision reported higher pain and pain interference scores at 6 months. More research is needed to determine if interventions to promote activity can improve outcomes after MVC in older adults.
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http://dx.doi.org/10.1186/s12877-016-0260-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4837524PMC
April 2016

Estrogen receptor-α directly regulates the hypoxia-inducible factor 1 pathway associated with antiestrogen response in breast cancer.

Proc Natl Acad Sci U S A 2015 Dec 23;112(49):15172-7. Epub 2015 Nov 23.

Growth Factor Group, Cancer Research UK, Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DS, United Kingdom;

A majority of breast cancers are driven by estrogen via estrogen receptor-α (ERα). Our previous studies indicate that hypoxia-inducible factor 1α (HIF-1α) cooperates with ERα in breast cancer cells. However, whether ERα is implicated in the direct regulation of HIF-1α and the role of HIF-1α in endocrine therapy response are unknown. In this study we found that a subpopulation of HIF-1α targets, many of them bearing both hypoxia response elements and estrogen response elements, are regulated by ERα in normoxia and hypoxia. Interestingly, the HIF-1α gene itself also bears an estrogen response element, and its expression is directly regulated by ERα. Clinical data revealed that expression of the HIF-1α gene or a hypoxia metagene signature is associated with a poor outcome to endocrine treatment in ERα(+) breast cancer. HIF-1α was able to confer endocrine therapy resistance to ERα(+) breast cancer cells. Our findings define, for the first time to our knowledge, a direct regulatory pathway between ERα and HIF-1α, which might modulate hormone response in treatment.
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http://dx.doi.org/10.1073/pnas.1422015112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4679044PMC
December 2015

Development of a measure of self-efficacy for acute headache medication adherence.

J Behav Med 2016 Dec 24;39(6):1033-1042. Epub 2015 Sep 24.

Ohio University, Athens, OH, USA.

Acute medication adherence is essential to manage chronic, episodic disorders, including headache. This paper describes the development of a measure of acute medication self-efficacy for headache (AMSE-H). Phase 1: 14 AMSE-H items were generated through qualitative interviews with 21 patients and 15 clinical headache experts. Phase 2: Researchers selected 7 AMSE-H items by examining item performance in 35 headache patients. Phase 3: Migraine patients (n = 161) completed the AMSE-H, and measures of outcome expectancies, perceived access to medication, headache management self-efficacy (n = 58) and a 1-week AMSE-H re-test (n = 103). Content validity was established through input of multiple stakeholder groups during item generation. PCA identified two components: cross-episode self-efficacy (eigenvalue = 3.4) and Episode-Specific Self-Efficacy (eigenvalue = 1.0). These subscales are internally consistent (.73-.80), have low 1-week test-retest reliability (rs = .52-.66), and demonstrated solid construct and discriminant validity. The AMSE-H is brief, theory-driven, focused, socially valid measure acceptable to both patients and providers.
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http://dx.doi.org/10.1007/s10865-015-9683-9DOI Listing
December 2016

Biological effects of fulvestrant on estrogen receptor positive human breast cancer: short, medium and long-term effects based on sequential biopsies.

Int J Cancer 2016 Jan 30;138(1):146-59. Epub 2015 Jul 30.

Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, CF10 3NB, United Kingdom.

We report the first study of the biological effect of fulvestrant on ER positive clinical breast cancer using sequential biopsies through to progression. Thirty-two locally/systemically advanced breast cancers treated with first-line fulvestrant (250 mg/month) were biopsied at therapy initiation, 6 weeks, 6 months and progression and immunohistochemically-analyzed for Ki67, ER, EGFR and HER2 expression/signaling activity. This series showed good fulvestrant responses (duration of response [DoR] = 25.8 months; clinical benefit = 81%). Ki67 fell (p < 0.001) in 79% of tumours by 6 months and lower Ki67 at all preprogression time-points predicted for longer DoR. ER and PR significantly decreased in all tumours by 6 months (p < 0.001), with some declines in ER (serine 118) phosphorylation and Bcl-2 (p = 0.007). There were modest HER2 increases (p = 0.034, 29% tumours) and loss of any detectable EGFR phosphorylation (p = 0.024, 50% tumours) and MAP kinase (ERK1/2) phosphorylation (p = 0.019, 65% tumours) by 6 months. While ER remained low, there was some recovery of Ki67, Bcl-2 and (weakly) EGFR/MAPK activity in 45-67% patients at progression. Fulvestrant's anti-proliferative impact is related to DoR, but while commonly downregulating ER and indicators of its signaling and depleting EGFR/MAPK signaling in some patients, additional elements must determine response duration. Residual ER at fulvestrant relapse explains reported sensitivity to further endocrine therapies. Occasional modest treatment-induced HER2 and weakly detectable EGFR/HER2/MAPK signaling at relapse suggests targeting of such activity might have value alongside fulvestrant in some patients. However, unknown pathways must drive relapse in most. Ki67 has biomarker potential to predict fulvestrant outcome and as a quantitative measure of response.
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http://dx.doi.org/10.1002/ijc.29682DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4879515PMC
January 2016

DNA methylation of oestrogen-regulated enhancers defines endocrine sensitivity in breast cancer.

Nat Commun 2015 Jul 14;6:7758. Epub 2015 Jul 14.

1] Epigenetics Research Program, Genomics and Epigenetics Division, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia [2] Faculty of Medicine, St Vincent's Clinical School, UNSW, NSW 2052 &St Vincent's Hospital, Sydney, New South Wales 2010, Australia.

Expression of oestrogen receptor (ESR1) determines whether a breast cancer patient receives endocrine therapy, but does not guarantee patient response. The molecular factors that define endocrine response in ESR1-positive breast cancer patients remain poorly understood. Here we characterize the DNA methylome of endocrine sensitivity and demonstrate the potential impact of differential DNA methylation on endocrine response in breast cancer. We show that DNA hypermethylation occurs predominantly at oestrogen-responsive enhancers and is associated with reduced ESR1 binding and decreased gene expression of key regulators of ESR1 activity, thus providing a novel mechanism by which endocrine response is abated in ESR1-positive breast cancers. Conversely, we delineate that ESR1-responsive enhancer hypomethylation is critical in transition from normal mammary epithelial cells to endocrine-responsive ESR1-positive cancer. Cumulatively, these novel insights highlight the potential of ESR1-responsive enhancer methylation to both predict ESR1-positive disease and stratify ESR1-positive breast cancer patients as responders to endocrine therapy.
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http://dx.doi.org/10.1038/ncomms8758DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4510968PMC
July 2015

Improving medication adherence in migraine treatment.

Curr Pain Headache Rep 2015 Jun;19(6):24

Ferkauf Graduate School of Psychology of Yeshiva University, 1165 Morris Park Ave, Bronx, NY, 10461, USA,

Medication adherence is integral to successful treatment of migraine and other headache. The existing literature examining medication adherence in migraine is small, and the methodologies used to assess adherence are limited. However, these studies broadly suggest poor adherence to both acute and preventive migraine medications, with studies using more objective monitoring reporting lower adherence rates. Methods for improving medication adherence are described, including organizational strategies, provider-monitoring and self-monitoring of adherence, regimen strategies, patient education, self-management skills training (e.g., stimulus control, behavioral contracts), and cognitive-behavioral therapy techniques. The article concludes by discussing the future of research regarding adherence to medications for migraine and other headaches.
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http://dx.doi.org/10.1007/s11916-015-0498-8DOI Listing
June 2015

Reprogramming of the ERRα and ERα target gene landscape triggers tamoxifen resistance in breast cancer.

Cancer Res 2015 Feb 2;75(4):720-31. Epub 2015 Feb 2.

Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Endocrine treatment regimens for breast cancer that target the estrogen receptor-α (ERα) are effective, but acquired resistance remains a limiting drawback. One mechanism of acquired resistance that has been hypothesized is functional substitution of the orphan receptor estrogen-related receptor-α (ERRα) for ERα. To examine this hypothesis, we analyzed ERRα and ERα in recurrent tamoxifen-resistant breast tumors and conducted a genome-wide target gene profiling analysis of MCF-7 breast cancer cell populations that were sensitive or resistant to tamoxifen treatment. This analysis uncovered a global redirection in the target genes controlled by ERα, ERRα, and their coactivator AIB1, defining a novel set of target genes in tamoxifen-resistant cells. Beyond differences in the ERα and ERRα target gene repertoires, both factors were engaged in similar pathobiologic processes relevant to acquired resistance. Functional analyses confirmed a requirement for ERRα in tamoxifen- and fulvestrant-resistant MCF-7 cells, with pharmacologic inhibition of ERRα sufficient to partly restore sensitivity to antiestrogens. In clinical specimens (n = 1041), increased expression of ERRα was associated with enhanced proliferation and aggressive disease parameters, including increased levels of p53 in ERα-positive cases. In addition, increased ERRα expression was linked to reduced overall survival in independent tamoxifen-treated patient cohorts. Taken together, our results suggest that ERα and ERRα cooperate to promote endocrine resistance, and they provide a rationale for the exploration of ERRα as a candidate drug target to treat endocrine-resistant breast cancer.
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http://dx.doi.org/10.1158/0008-5472.CAN-14-0652DOI Listing
February 2015

Workshop report: Crystal City V--quantitative bioanalytical method validation and implementation: the 2013 revised FDA guidance.

AAPS J 2015 Mar 31;17(2):277-88. Epub 2014 Dec 31.

U.S. Food and Drug Administration, Silver Spring, MD, USA.

In September 2013, the FDA released a draft revision of the Bioanalytical Method Validation (BMV) Guidance, which included a number of changes to the expectations for bioanalysis, most notably the inclusion of biomarker assays and data. To provide a forum for an open, inclusive discussion of the revised draft BMV Guidance, the AAPS and FDA once again collaborated to convene a two-and-a-half day workshop during early December 2013 in Baltimore, MD, USA. The resulting format embodied extensive open discussion and each thematic session included only brief, concise descriptions by Agency and industry representatives prior to opening the floor discussion. The Workshop was built around four thematic sessions (Common Topics, Chromatographic, Ligand-Binding Assays, and Biomarkers) and a final session with international regulators, concluding with a review of the outcomes and recommendations from the thematic sessions. This Workshop report summarizes the outcomes and includes topics of agreement, those where the FDA will consider the Industry's perspective, and those where the workshop provided a first open dialogue. This article will be available to the bioanalytical community at http://www.aaps.org/BMV13 .
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http://dx.doi.org/10.1208/s12248-014-9696-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4365089PMC
March 2015

8th GCC: consolidated feedback to US FDA on the 2013 draft FDA guidance on bioanalytical method validation.

Bioanalysis 2014 ;6(22):2957-63

Covance Laboratories, Chantilly, VA, USA.

The 8th GCC Closed Forum for Bioanalysis was held in Baltimore, MD, USA on 5 December 2013, immediately following the 2013 AAPS Workshop (Crystal City V): Quantitative Bioanalytical Methods Validation and Implementation--The 2013 Revised FDA Guidance. This GCC meeting was organized to discuss the contents of the draft revised FDA Guidance on bioanalytical method validation that was published in September 2013 and consolidate the feedback of the GCC members. In attendance were 63 senior-level participants, from seven countries, representing 46 bioanalytical CRO companies/sites. This event represented a unique opportunity for CRO bioanalytical experts to share their opinions and concerns regarding the draft FDA Guidance, and to build unified comments to be provided to the FDA.
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http://dx.doi.org/10.4155/bio.14.287DOI Listing
July 2015

A good drug made better: the fulvestrant dose-response story.

Clin Breast Cancer 2014 Dec 24;14(6):381-9. Epub 2014 Jun 24.

Breast Cancer Molecular Pharmacology Group, School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, UK.

Sequential use of endocrine therapies remains the cornerstone of treatment for hormone receptor-positive advanced breast cancer, before the use of cytotoxic chemotherapy for unresponsive disease. Fulvestrant is an estrogen receptor (ER) antagonist approved for the treatment of postmenopausal women with ER+ advanced breast cancer after failure of prior antiestrogen therapy. Initially approved at a monthly dose of 250 mg, the recommended fulvestrant dose was revised to 500 mg (500 mg/mo plus 500 mg on day 14 of month 1) after demonstration of improved progression-free survival versus fulvestrant 250 mg. We have reviewed the dose-dependent effects of fulvestrant, both from a retrospective combined analysis of dose-dependent reduction of tumor biomarkers in the presurgical setting (3 previously reported studies: Study 18, Neoadjuvant Endocrine Therapy for Women with Estrogen-Sensitive Tumors, and Trial 57) and from a review of clinical studies for advanced breast cancer in postmenopausal women. Analysis of presurgical data revealed a consistent dose-dependent effect for fulvestrant on tumor biomarkers, with increasing fulvestrant dose resulting in greater reductions in ER, progesterone receptor, and Ki67 labeling index. The dose-dependent biological effect corresponds with the dose-dependent clinical efficacy observed in the treatment of advanced breast cancer after failure of prior antiestrogen therapy. Although it remains to be determined in a phase III trial, cross-trial comparisons suggest a dose-dependent relationship for fulvestrant as first-line treatment for advanced breast cancer. Overall, biological and clinical data demonstrate a strong dose-dependent relationship for fulvestrant, supporting the efficacy benefit seen with fulvestrant 500 mg over the 250 mg dose.
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http://dx.doi.org/10.1016/j.clbc.2014.06.005DOI Listing
December 2014

Recommendations on incurred sample stability (ISS) by GCC.

Bioanalysis 2014 Sep;6(18):2385-90

Quintiles Bioanalytical & ADME Labs, Ithaca, NY, USA.

The topic of incurred sample stability (ISS) has generated considerable discussion within the bioanalytical community in recent years. The subject was an integral part of the seventh annual Workshop on Recent Issues in Bioanalysis (WRIB) held in Long Beach, CA, USA, in April 2013, and at the Global CRO Council for Bioanalysis (GCC) meeting preceding it. Discussion at both events focused on the use of incurred samples for ISS purposes in light of results from a recent GCC survey completed by member companies. This paper reports the consensus resulting from these discussions and serves as a useful reference for depicting ISS issues and concerns, summarizing the GCC survey results and providing helpful recommendations on ISS in the context of bioanalytical method development and application.
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http://dx.doi.org/10.4155/bio.14.155DOI Listing
September 2014

Quantification of pancreatic cancer proteome and phosphorylome: indicates molecular events likely contributing to cancer and activity of drug targets.

PLoS One 2014 26;9(3):e90948. Epub 2014 Mar 26.

Proteome Sciences plc, Cobham, United Kingdom.

Objective: LC-MS/MS phospho-proteomics is an essential technology to help unravel the complex molecular events that lead to and propagate cancer. We have developed a global phospho-proteomic workflow to determine activity of signaling pathways and drug targets in pancreatic cancer tissue for clinical application.

Methods: Peptides resulting from tryptic digestion of proteins extracted from frozen tissue of pancreatic ductal adenocarcinoma and background pancreas (n = 12), were labelled with tandem mass tags (TMT 8-plex), separated by strong cation exchange chromatography, then were analysed by LC-MS/MS directly or first enriched for phosphopeptides using IMAC and TiO2, prior to analysis. In-house, commercial and freeware bioinformatic platforms were used to identify relevant biological events from the complex dataset.

Results: Of 2,101 proteins identified, 152 demonstrated significant difference in abundance between tumor and non-tumor tissue. They included proteins that are known to be up-regulated in pancreatic cancer (e.g. Mucin-1), but the majority were new candidate markers such as HIPK1 & MLCK. Of the 6,543 unique phosphopeptides identified (6,284 unique phosphorylation sites), 635 showed significant regulation, particularly those from proteins involved in cell migration (Rho guanine nucleotide exchange factors & MRCKα) and formation of focal adhesions. Activator phosphorylation sites on FYN, AKT1, ERK2, HDAC1 and other drug targets were found to be highly modulated (≥2 fold) in different cases highlighting their predictive power.

Conclusion: Here we provided critical information enabling us to identify the common and unique molecular events likely contributing to cancer in each case. Such information may be used to help predict more bespoke therapy suitable for an individual case.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0090948PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3966770PMC
December 2015

Impact of dual mTORC1/2 mTOR kinase inhibitor AZD8055 on acquired endocrine resistance in breast cancer in vitro.

Breast Cancer Res 2014 Jan 23;16(1):R12. Epub 2014 Jan 23.

Introduction: Upregulation of PI3K/Akt/mTOR signalling in endocrine-resistant breast cancer (BC) has identified mTOR as an attractive target alongside anti-hormones to control resistance. RAD001 (everolimus/Afinitor®), an allosteric mTOR inhibitor, is proving valuable in this setting; however, some patients are inherently refractory or relapse during treatment requiring alternative strategies. Here we evaluate the potential for novel dual mTORC1/2 mTOR kinase inhibitors, exemplified by AZD8055, by comparison with RAD001 in ER + endocrine resistant BC cells.

Methods: In vitro models of tamoxifen (TamR) or oestrogen deprivation resistance (MCF7-X) were treated with RAD001 or AZD8055 alone or combined with anti-hormone fulvestrant. Endpoints included growth, cell proliferation (Ki67), viability and migration, with PI3K/AKT/mTOR signalling impact monitored by Western blotting. Potential ER cross-talk was investigated by immunocytochemistry and RT-PCR.

Results: RAD001 was a poor growth inhibitor of MCF7-derived TamR and MCF7-X cells (IC50 ≥1 μM), rapidly inhibiting mTORC1 but not mTORC2/AKT signalling. In contrast AZD8055, which rapidly inhibited both mTORC1 and mTORC2/AKT activity, was a highly effective (P <0.001) growth inhibitor of TamR (IC50 18 nM) and MCF7-X (IC50 24 nM), and of a further T47D-derived tamoxifen resistant model T47D-tamR (IC50 19 nM). AZD8055 significantly (P <0.05) inhibited resistant cell proliferation, increased cell death and reduced migration. Furthermore, dual treatment of TamR or MCF7-X cells with AZD8055 plus fulvestrant provided superior control of resistant growth versus either agent alone (P <0.05). Co-treating with AZD8055 alongside tamoxifen (P <0.01) or oestrogen deprivation (P <0.05) also effectively inhibited endocrine responsive MCF-7 cells. Although AZD8055 inhibited oestrogen receptor (ER) ser167 phosphorylation in TamR and MCF7-X, it had no effect on ER ser118 activity or expression of several ER-regulated genes, suggesting the mTOR kinase inhibitor impact was largely ER-independent. The capacity of AZD8055 for ER-independent activity was further evidenced by growth inhibition (IC5018 and 20 nM) of two acquired fulvestrant resistant models lacking ER.

Conclusions: This is the first report demonstrating dual mTORC1/2 mTOR kinase inhibitors have potential to control acquired endocrine resistant BC, even under conditions where everolimus fails. Such inhibitors may prove of particular benefit when used alongside anti-hormonal treatment as second-line therapy in endocrine resistant disease, and also potentially alongside anti-hormones during the earlier endocrine responsive phase to hinder development of resistance.
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http://dx.doi.org/10.1186/bcr3604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3978713PMC
January 2014

Medication class effects on visit-to-visit variability of blood pressure measurements: analysis of electronic health record data in the "real world".

J Clin Hypertens (Greenwich) 2013 Sep 12;15(9):655-62. Epub 2013 Jul 12.

Center for Innovative Care, Mercy Health, Chesterfield, MO.

Blood pressure (BP) visit-to-visit variability (VVV) influences the risk of vascular events and mortality. Research has suggested that antihypertensive medication classes may differentially impact VVV. This study evaluated whether antihypertensive medication class differentially impacted BP VVV among hypertensive individuals in a clinical, "real-world" setting as well as the association between VVV and patient characteristics. Clinical observational data were extracted for adults (mean age, 63; 56% female, 86% Caucasian) with hypertension from the Mercy EpicCare EHR-Derived Database (MEDD) (n=183,374) who had at least 4 outpatient visits with BP readings. A multilevel mixed model for change over time estimated between- and within-subject effects on the absolute real VVV of systolic BP. Diuretics significantly lowered VVV (β=-0.32[-0.39 to-0.25]) and α-/β-blockers resulted in the highest VVV (β=0.89 [0.77-1.00]). Being older, female, and having a higher systolic BP and certain comorbid conditions significantly raised VVV (P<.001). The findings from the MEDD were consistent in general with other research on BP VVV. However, the magnitude of effect of antihypertensive medication class and patient characteristics was relatively low (<10% of the BP VVV variance for any one variable). More research is needed to evaluate the extent to which the class of antihypertensive medication class impacts BP VVV in the outpatient setting.
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http://dx.doi.org/10.1111/jch.12165DOI Listing
September 2013

Impact of NSAID and Triptan use on developing chronic migraine: results from the American Migraine Prevalence and Prevention (AMPP) study.

Headache 2013 Nov-Dec;53(10):1548-63. Epub 2013 Aug 28.

Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA.

Objectives: To assess the influence of triptan or nonsteroidal anti-inflammatory drug (NSAID) use on the likelihood of developing chronic migraine (CM) among persons with episodic migraine (EM).

Background: CM is common in tertiary headache care, and relative to EM, CM is associated with a number of deleterious outcomes, including higher headache-related disability, reduced health-related quality of life, and increased direct and indirect costs. Symptomatic medication use has emerged as an important risk factor for the development of CM. Limited evidence based on a single year of follow up suggests that the association between NSAID and triptan use with the onset of CM varies in a dose-dependent manner that interacts with headache frequency. However, this interaction has never been explicitly studied. Herein, we evaluate results from a large-scale, 5-year, population-based observational study to characterize these relationships and test the hypothesis that NSAID use may modify the effect of triptan use on CM onset.

Methods: In the American Migraine Prevalence and Prevention (AMPP) study, 11,249 participants had EM in 2005 and provided up to 5 years of annual follow-up data. We analyzed the characteristics of persons with EM 1 year that predicted new onset CM in the subsequent year, focusing on treatment with NSAIDs and triptans as exposures. These adjacent years of data provide the basis for analysis and are termed "couplets." Repeated measures logistic regression with a subject-specific random intercept was used to model the likelihood of transition from EM to CM as a function of NSAID or triptan dose while controlling for a number of covariates including headache features, use of other medications, and the number of couplets per individual.

Results: The analysis included 9031 individuals with EM contributing up to 5 years of data and up to 4 couplets each. Results indicated that on average, 55% of the participants used NSAIDs in any given year and 2% transitioned to CM over subsequent years. Among the 20% using triptans, 3% per year transitioned to CM. Among persons with less than 10 headache days per month, frequency of NSAID use was associated with dose-dependent reductions in risk of CM onset. Among those with 10-14 headache days per month, increasing days per month of NSAID use was associated with increasing risk of CM onset. Increasing days per month of triptan use was associated with increased risk of transitioning to CM. Combination use of NSAIDs and triptans was not protective against transition to CM, but was also not statistically significantly associated with increased risk of CM onset.

Conclusion: Triptan use in EM is associated with an increased risk of CM onset that increases with days of medication use. For NSAIDs, effects depend on headache days per month. NSAIDs are protective in individuals with less than 10 headache days per month but associated with increased risk with 10 or more headache days per month. Combining a triptan and NSAID was not associated with a statistically significant increased risk of CM onset, whereas increased risk of CM onset was significantly associated with triptan monotherapy.
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http://dx.doi.org/10.1111/head.12201DOI Listing
July 2014

Targeting focal adhesion kinase in ER+/HER2+ breast cancer improves trastuzumab response.

Endocr Relat Cancer 2013 Oct 28;20(5):691-704. Epub 2013 Aug 28.

School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Wales, UK.

The HER2 transmembrane receptor is a well-characterised predictive marker for trastuzumab benefit and may be associated with decreased benefit from endocrine therapy use. Despite the clinical effectiveness of anti-HER2 agents in such cases, resistance represents a significant limiting factor. Focal adhesion kinase (FAK) plays an important role in HER2 signalling, mediating downstream Akt activation in addition to HER2 cross talk with other growth factor receptors. In this study, we investigated the therapeutic potential of FAK in oestrogen receptor-positive (ER+)/HER2+ breast cancer using the novel FAK-specific inhibitor PF4554878 ('PF878'). The activation of the FAK/HER2 signalling pathway was assessed in ER+/HER2- (MCF7 and T47D) and ER+/HER2+ (BT-474 and MDAMB361) breast cancer cells in the presence or absence of PF878 and PF878±trastuzumab. The effects of PF878 on cell growth as a monotherapy and in combination with trastuzumab were assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and Coulter counting with isobologram analysis to determine synergy/additive effects. FAK activation (at Y861 but not at Y397) was highest in ER+/HER2+ cells, which also demonstrated the greatest sensitivity to PF878. As a monotherapy, PF878 prevented heregulin-induced MDA361 cell migration, but had no significant effect on cell growth. The treatment of ER+/HER2+ cells with PF878 and trastuzumab in combination resulted in the synergistic inhibition of cell proliferation. Underlying this was an abrogation of Akt activity and increased poly(ADP-ribose) polymerase cleavage, effects that were greatest in trastuzumab-refractory MDA361 cells. Collectively, these data support a role for FAK in ER+/HER2+ breast cancer, where its targeting has the potential to improve trastuzumab response. This is particularly important in the context of ER+/HER2+, trastuzumab-refractory disease, where FAK inhibition may present an important strategy to restore trastuzumab sensitivity.
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http://dx.doi.org/10.1530/ERC-13-0019DOI Listing
October 2013

Global characterization of signalling networks associated with tamoxifen resistance in breast cancer.

FEBS J 2013 Nov 19;280(21):5237-57. Epub 2013 Aug 19.

Cancer Research Program, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales, Australia.

Acquired resistance to the anti-estrogen tamoxifen remains a significant challenge in breast cancer management. In this study, we used an integrative approach to characterize global protein expression and tyrosine phosphorylation events in tamoxifen-resistant MCF7 breast cancer cells (TamR) compared with parental controls. Quantitative mass spectrometry and computational approaches were combined to identify perturbed signalling networks, and candidate regulatory proteins were functionally interrogated by siRNA-mediated knockdown. Network analysis revealed that cellular metabolism was perturbed in TamR cells, together with pathways enriched for proteins associated with growth factor, cell-cell and cell matrix-initiated signalling. Consistent with known roles for Ras/MAPK and PI3-kinase signalling in tamoxifen resistance, tyrosine-phosphorylated MAPK1, SHC1 and PIK3R2 were elevated in TamR cells. Phosphorylation of the tyrosine kinase Yes and expression of the actin-binding protein myristoylated alanine-rich C-kinase substrate (MARCKS) were increased two- and eightfold in TamR cells respectively, and these proteins were selected for further analysis. Knockdown of either protein in TamR cells had no effect on anti-estrogen sensitivity, but significantly decreased cell motility. MARCKS expression was significantly higher in breast cancer cell lines than normal mammary epithelial cells and in ER-negative versus ER-positive breast cancer cell lines. In primary breast cancers, cytoplasmic MARCKS staining was significantly higher in basal-like and HER2 cancers than in luminal cancers, and was independently predictive of poor survival in multivariate analyses of the whole cohort (P < 0.0001) and in ER-positive patients (P = 0.0005). These findings provide network-level insights into the molecular alterations associated with the tamoxifen-resistant phenotype, and identify MARCKS as a potential biomarker of therapeutic responsiveness that may assist in stratification of patients for optimal therapy.
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http://dx.doi.org/10.1111/febs.12441DOI Listing
November 2013

BCL-2 hypermethylation is a potential biomarker of sensitivity to antimitotic chemotherapy in endocrine-resistant breast cancer.

Mol Cancer Ther 2013 Sep 16;12(9):1874-85. Epub 2013 Jul 16.

Corresponding Author: Andrew Stone, Garvan Institute of Medical Research, L9 TKCC, 370 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia.

Overexpression of the antiapoptotic factor BCL-2 is a frequent feature of malignant disease and is commonly associated with poor prognosis and resistance to conventional chemotherapy. In breast cancer, however, high BCL-2 expression is associated with favorable prognosis, estrogen receptor (ER) positivity, and low tumor grade, whereas low expression is included in several molecular signatures associated with resistance to endocrine therapy. In the present study, we correlate BCL-2 expression and DNA methylation profiles in human breast cancer and in multiple cell models of acquired endocrine resistance to determine whether BCL-2 hypermethylation could provide a useful biomarker of response to cytotoxic therapy. In human disease, diminished expression of BCL-2 was associated with hypermethylation of the second exon, in a region that overlapped a CpG island and an ER-binding site. Hypermethylation of this region, which occurred in 10% of primary tumors, provided a stronger predictor of patient survival (P = 0.019) when compared with gene expression (n = 522). In multiple cell models of acquired endocrine resistance, BCL-2 expression was significantly reduced in parallel with increased DNA methylation of the exon 2 region. The reduction of BCL-2 expression in endocrine-resistant cells lowered their apoptotic threshold to antimitotic agents: nocodazole, paclitaxel, and the PLK1 inhibitor BI2536. This phenomenon could be reversed with ectopic expression of BCL-2, and rescued with the BCL-2 inhibitor ABT-737. Collectively, these data imply that BCL-2 hypermethylation provides a robust biomarker of response to current and next-generation cytotoxic agents in endocrine-resistant breast cancer, which may prove beneficial in directing therapeutic strategy for patients with nonresectable, metastatic disease.
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http://dx.doi.org/10.1158/1535-7163.MCT-13-0012DOI Listing
September 2013

A randomized trial to assess the biological activity of short-term (pre-surgical) fulvestrant 500 mg plus anastrozole versus fulvestrant 500 mg alone or anastrozole alone on primary breast cancer.

Breast Cancer Res 2013 Mar 5;15(2):R18. Epub 2013 Mar 5.

Introduction: Fulvestrant shows dose-dependent biological activity. Greater estrogen-receptor (ER) blockade may feasibly be achieved by combining fulvestrant with anastrozole. This pre-surgical study compared fulvestrant plus anastrozole versus either agent alone in patients with ER-positive breast cancer.

Methods: In this double-blind, multicenter trial, 121 patients received fulvestrant 500 mg on Day 1 plus anastrozole 1 mg/day for 14 to 21 days (F + A); fulvestrant plus anastrozole placebo (F); or fulvestrant placebo plus anastrozole (A), 2 to 3 weeks before surgery. ER, progesterone-receptor (PgR) and Ki67 expression were determined from tumor biopsies before treatment and at surgery.

Results: A total of 103 paired samples were available (F, n = 35; F+A, n = 31; A, n = 37). All treatments significantly reduced mean ER expression from baseline (F: -41%, P = 0.0001; F + A: -39%, P = 0.0001; A: -13%, P = 0.0034). F and F + A led to greater reductions in ER versus A (both P = 0.0001); F + A did not lead to additional reductions versus F. PgR and Ki67 expression were significantly reduced with all treatments (means were -34% to -45%, and -75% to -85%, respectively; all P = 0.0001), with no differences between groups.

Conclusions: In this short-term study, all treatments reduced ER expression, although F and F + A showed greater reductions than A. No significant differences were detected between the treatment groups in terms of PgR and Ki67 expression. No additional reduction in tumor biomarkers with combination treatment was observed, suggesting that F + A is unlikely to have further clinical benefit over F alone.

Trial Registration: Clinicaltrials.gov NCT00259090.
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http://dx.doi.org/10.1186/bcr3393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3672778PMC
March 2013

Lightning and its association with the frequency of headache in migraineurs: an observational cohort study.

Cephalalgia 2013 Apr 24;33(6):375-83. Epub 2013 Jan 24.

Department of Internal Medicine, University of Cincinnati College of Medicine, OH, USA.

Aim: The aim of this article is to determine if lightning is associated with the frequency of headache in migraineurs.

Methods: Participants fulfilling diagnostic criteria for International Headache Society-defined migraine were recruited from sites located in Ohio ( N  = 23) and Missouri ( N  = 67). They recorded headache activity in a daily diary for three to six months. A generalized estimating equations (GEE) logistic regression determined the odds ratio (OR) of headache on lightning days compared to non-lightning days. Other weather factors associated with thunderstorms were also added as covariates to the GEE model to see how they would attenuate the effect of lightning on headache.

Results: The mean age of the study population was 44 and 91% were female. The OR for headache was 1.31 (95% confidence limits (CL); 1.07, 1.66) during lighting days as compared to non-lightning days. The addition of thunderstorm-associated weather variables as covariates were only able to reduce the OR for headache on lightning days to 1.18 (95% CL; 1.02, 1.37). The probability of having a headache on lightning days was also further increased when the average current of lightning strikes for the day was more negative.

Conclusion: This study suggests that lightning represents a trigger for headache in migraineurs that cannot be completely explained by other meteorological factors. It is unknown if lightning directly triggers headaches through electromagnetic waves or indirectly through production of bioaerosols (e.g. ozone), induction of fungal spores or other mechanisms. These results should be interpreted cautiously until replicated in a second dataset.
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http://dx.doi.org/10.1177/0333102412474502DOI Listing
April 2013

ELF5 suppresses estrogen sensitivity and underpins the acquisition of antiestrogen resistance in luminal breast cancer.

PLoS Biol 2012 27;10(12):e1001461. Epub 2012 Dec 27.

Cancer Research Program and The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.

We have previously shown that during pregnancy the E-twenty-six (ETS) transcription factor ELF5 directs the differentiation of mammary progenitor cells toward the estrogen receptor (ER)-negative and milk producing cell lineage, raising the possibility that ELF5 may suppress the estrogen sensitivity of breast cancers. To test this we constructed inducible models of ELF5 expression in ER positive luminal breast cancer cells and interrogated them using transcript profiling and chromatin immunoprecipitation of DNA followed by DNA sequencing (ChIP-Seq). ELF5 suppressed ER and FOXA1 expression and broadly suppressed ER-driven patterns of gene expression including sets of genes distinguishing the luminal molecular subtype. Direct transcriptional targets of ELF5, which included FOXA1, EGFR, and MYC, accurately classified a large cohort of breast cancers into their intrinsic molecular subtypes, predicted ER status with high precision, and defined groups with differential prognosis. Knockdown of ELF5 in basal breast cancer cell lines suppressed basal patterns of gene expression and produced a shift in molecular subtype toward the claudin-low and normal-like groups. Luminal breast cancer cells that acquired resistance to the antiestrogen Tamoxifen showed greatly elevated levels of ELF5 and its transcriptional signature, and became dependent on ELF5 for proliferation, compared to the parental cells. Thus ELF5 provides a key transcriptional determinant of breast cancer molecular subtype by suppression of estrogen sensitivity in luminal breast cancer cells and promotion of basal characteristics in basal breast cancer cells, an action that may be utilised to acquire antiestrogen resistance.
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http://dx.doi.org/10.1371/journal.pbio.1001461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3531499PMC
May 2013

Recommendations on biomarker bioanalytical method validation by GCC.

Bioanalysis 2012 Oct;4(20):2439-46

Quotient Bioresearch, Fordham, UK.

The 5th GCC in Barcelona (Spain) and 6th GCC in San Antonio (TX, USA) events provided a unique opportunity for CRO leaders to openly share opinions and perspectives, and to agree upon recommendations on biomarker bioanalytical method validation.
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http://dx.doi.org/10.4155/bio.12.197DOI Listing
October 2012

Pro-metastatic tumor-stroma interactions in breast cancer.

Future Oncol 2012 Nov;8(11):1427-42

School of Pharmacy & Pharmaceutical Sciences, Redwood Building, Cardiff University, UK.

The vast majority of breast cancer-related deaths are due to metastatic disease. Reciprocal and complex interactions between epithelial tumor cells and the various components of the tumor microenvironment influence tumor progression and metastases although the molecular mechanisms underlying these metastasis-promoting effects are not fully characterized. Identifying and understanding pathways of tumor-stroma cross-talk are likely to lead to the development of novel prognostic biomarkers for metastasis and strategies to prevent metastasis at its earliest stages, resulting in improved patient outcomes.
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http://dx.doi.org/10.2217/fon.12.134DOI Listing
November 2012