Publications
818 results found
Carter P, Alifrangis CC, Cereser B, et al., 2018, Does molecular profiling of tumors using the Caris molecular intelligence platform improve outcomes for cancer patients?, Oncotarget, Vol: 9, Pages: 9456-9467, ISSN: 1949-2553
We evaluated the effect of tailoring treatments based on predictions informed by tumor molecular profiles across a range of cancers, using data from Caris Life Sciences. These included breast carcinoma, colorectal adenocarcinoma, female genital tract malignancy, lung non-small cell lung cancer, neuroendocrine tumors, ovarian surface epithelial carcinomas, and urinary tract cancers.Molecular profiles using mostly immunohistochemistry (IHC) and DNA sequencing for tumors from 841 patients had been previously used to recommend treatments; some physicians followed the suggestions completely while some did not. This information was assessed to find out if the outcome was better for the patients where their received drugs matched recommendations.The IHC biomarker for the progesterone receptor and for the androgen receptor were found to be most prognostic for survival overall. The IHC biomarkers for P-glycoprotein (PGP), tyrosine-protein kinase Met (cMET) and the DNA excision repair protein ERCC1 were also shown to be significant predictors of outcome. Patients whose treatments matched those predicted to be of benefit survived for an average of 512 days, compared to 468 days for those that did not (P = 0.0684). In the matched treatment group, 34% of patients were deceased at the completion of monitoring, whereas this was 47% in the unmatched group (P = 0.0001).
Esteva FJ, Stebbing J, Wood-Horrall RN, et al., 2018, A randomised trial comparing the pharmacokinetics and safety of the biosimilar CT-P6 with reference trastuzumab, Cancer Chemotherapy and Pharmacology, Vol: 81, Pages: 505-514, ISSN: 0344-5704
PURPOSE: Access to trastuzumab, a valuable anti-cancer treatment, can be limited by cost. The primary aim of this study was to evaluate and compare the PK profiles of CT-P6, a biosimilar of trastuzumab, and US-licensed reference trastuzumab (Herceptin®) in healthy subjects. Secondary study aims included comparison of the safety and immunogenicity of CT-P6 and reference trastuzumab in these subjects. METHODS: We performed a single-dose, randomised, double-blind, parallel group study (NCT02665637) comparing CT-P6 with reference trastuzumab (6 mg/kg, 90 min intravenous infusion) in 70 healthy adult males. Pharmacokinetics, safety and immunogenicity were evaluated up to 10 weeks post-dose. Primary endpoints were area under the serum concentration-time curve (AUC) from time 0 to infinity (AUCinf); AUC from time 0 to last quantifiable concentration (AUClast); and observed maximum serum concentration (Cmax). The pre-determined equivalence criterion was a 90% confidence interval of 80-125% for ratios of geometric least squares (LS) means. RESULTS: Equivalence of CT-P6 and reference trastuzumab was demonstrated. Ratios (CT-P6/reference trastuzumab) of geometric LS means (90% confidence interval) were: AUCinf 99.05 (93.00, 105.51); AUClast 99.30 (92.85, 106.20); Cmax 96.58 (90.93, 102.59). Safety profiles were similar; treatment-emergent adverse events occurred in ten subjects (28.6%) in the CT-P6 group and 11 (31.4%) in the reference trastuzumab group. No serious adverse events or deaths occurred. No subjects tested positive for anti-drug antibodies. CONCLUSIONS: These data add to the totality of evidence required to demonstrate biosimilarity. A phase III study of CT-P6-in which equivalent neoadjuvant efficacy to reference trastuzumab has been demonstrated-is ongoing.
Savage P, Horlock C, Stott B, et al., 2018, Enhanced sensitivity of lymphoid cells to ethanol adh acetaldehyde toxicity; implications for gdept and adoptive t cell therapy, Current Pharmacogenomics and Personalized Medicine, Vol: 16, Pages: 118-123, ISSN: 1875-6921
© 2018, Bentham Science Publishers. Background: The ability to kill lymphoid cells with a non-toxic prodrug/gene/ toxin system would be of value in the treatment of lymphoid malignancies and in the regulation of T cells used in adoptive immunotherapy. Objective: In this in vitro study we examined the ability of a novel prodrug/gene/toxin system to produce cytotoxicity in lymphoid cells. The system uses a non-toxic prodrug ethanol, human alcohol dehydrogenase and exerts the toxic action via the prolonged production of acetaldehyde produced within targeted cells. Methods: Raji B cells were transduced with an alcohol dehydrogenase containing lentivi-rus and then exposed to differing durations of daily ethanol exposure. Cell numbers and viability were assessed by trypan blue exclusion. Results: Individually, ethanol and the ADH gene were non-toxic to Raji B cells. Exposure of ADH transduced cells to ethanol produced prompt growth inhibition and later cell killing that could be negated by the presence of 4-MP the alcohol dehydrogenase inhibitor. At 96 hours exposure to ethanol the number of ADH transduced cells had declined by up to 66% and their total number comprised only 2% of the proliferating untreated control cells. Conclusion: The ethanol ADH acetaldehyde system offers a simple, safe, non-toxic approach to cancer therapy prodrug toxin technology. It may also offer a safe and non-toxic system to control the number and action of T cells used in adoptive immunotherapy.
Stebbing J, Baranau Y, Manikhas A, et al., 2018, Total pathological complete response versus breast pathological complete response in clinical trials of reference and biosimilar trastuzumab in the neoadjuvant treatment of breast cancer, EXPERT REVIEW OF ANTICANCER THERAPY, Vol: 18, Pages: 531-541, ISSN: 1473-7140
Carter P, Alifrangis C, Cereser B, et al., 2017, Assessing tumor molecular profiling to guide treatments for patients with advanced female genital tract malignancy, Oncotarget, Vol: 9, Pages: 6007-6014, ISSN: 1949-2553
Tumor molecular profiling has enabled selection of targeted therapies in a host of solid tumors. Here we used a retrospective clinical cohort, to evaluate the benefit of tailoring treatments for female genital tract malignancy, using tumor molecular profiles. Clinical outcome data for 112 patients was retrospectively separated into two groups. These either followed a matched treatment plan that incorporated at least one drug recommended according to their tumor profile and none that were expected to have no benefit (64 patients), or was unmatched with suggested treatments and received at least one drug that was anticipated to lack benefit for that tumor (48 patients).In the group of patients whose drugs matched those recommended by molecular profiling of their tumor, their overall survival was 593 days on average, compared to 449 days for patients that did not; removing drugs predicted to have no benefit from treatment regimens received after profiling increased survival by 144 days on average (P = 0.0265). In the matched treatment group, 30% of patients had died by the last time of monitoring, whereas this was 40% in the unmatched group (P = 0.2778). The IHC biomarker for the progesterone receptor was demonstrated to be prognostic for survival.
Soraas L, Stebbing J, 2017, Brief report: geographic variation in EGFR mutation frequency in lung adenocarcinoma may be explained by interethnic genetic variation, Journal of Thoracic Oncology, Vol: 13, Pages: 454-458, ISSN: 1556-0864
Our understanding of the etiology of EGFR mutant lung cancer remains incomplete. One persistent finding in the literature is the geographic variation in the frequency of EGFR mutations in lung adenocarcinoma. We investigated the association between two biomarkers of East Asian ancestry, the genetic polymorphisms EDAR V370A and ABCC11 G180A, and the frequency of EGFR mutations in lung adenocarcinoma patients in a range of countries. The Pearson's linear correlation between the frequency of EGFR mutations and the EDAR polymorphism was 0.92 (P < 2.2 x 10-10) and for the ABCC11 polymorphism it was 0.72 (P < 1.6 x 10-4). These results suggest that the variation in the measured frequency of EGFR mutations in lung adenocarcinoma can be explained, at least in part, by interethnic genetic variation. To improve our understanding of this disease, studies exploring the genetic polymorphism(s) that cause these interethnic differences, as well as the mechanisms of actions through which they work, are warranted.
Martin M, Holmes FA, Ejlertsen B, et al., 2017, Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial., Lancet Oncology, Vol: 18, Pages: 1688-1700, ISSN: 1470-2045
BACKGROUND: ExteNET showed that 1 year of neratinib, an irreversible pan-HER tyrosine kinase inhibitor, significantly improves 2-year invasive disease-free survival after trastuzumab-based adjuvant therapy in women with HER2-positive breast cancer. We report updated efficacy outcomes from a protocol-defined 5-year follow-up sensitivity analysis and long-term toxicity findings. METHODS: In this ongoing randomised, double-blind, placebo-controlled, phase 3 trial, eligible women aged 18 years or older (≥20 years in Japan) with stage 1-3c (modified to stage 2-3c in February, 2010) operable breast cancer, who had completed neoadjuvant and adjuvant chemotherapy plus trastuzumab with no evidence of disease recurrence or metastatic disease at study entry. Patients who were eligible patients were randomly assigned (1:1) via permuted blocks stratified according to hormone receptor status (hormone receptor-positive vs hormone receptor-negative), nodal status (0 vs 1-3 vs or ≥4 positive nodes), and trastuzumab adjuvant regimen (given sequentially vs concurrently with chemotherapy), then implemented centrally via an interactive voice and web-response system, to receive 1 year of oral neratinib 240 mg/day or matching placebo. Treatment was given continuously for 1 year, unless disease recurrence or new breast cancer, intolerable adverse events, or consent withdrawal occurred. Patients, investigators, and trial funder were masked to treatment allocation. The predefined endpoint of the 5-year analysis was invasive disease-free survival, analysed by intention to treat. ExteNET is registered with ClinicalTrials.gov, number NCT00878709, and is closed to new participants. FINDINGS: Between July 9, 2009, and Oct 24, 2011, 2840 eligible women with early HER2-positive breast cancer were recruited from community-based and academic institutions in 40 countries and randomly assigned to receive neratinib (n=1420) or placebo (n=1420). After a median follow-up of 5·2 years (IQR 2&m
Miller G, Stebbing J, 2017, Thirty years of Oncogene, Oncogene, Vol: 37, Pages: 553-554, ISSN: 0950-9232
Stebbing J, Sanders DA, 2017, The importance of being earnest in post-publication review: scientific fraud and the scourges of anonymity and excuses., Oncogene, Vol: 37, Pages: 695-696, ISSN: 0950-9232
Frampton AE, Miller HC, Malczewska A, et al., 2017, MicroRNAs Associated with Small Bowel Neuroendocrine Tumours and Their Metastases, 14th Annual ENETS Conference for the Diagnosis and Treatment of Neuroendocrine Tumor Disease, Publisher: Karger Publishers, Pages: 22-22, ISSN: 0028-3835
Chandrasinghe P, Cereser B, Moorghen M, et al., 2017, Role of SMAD proteins in colitis-associated cancer: from known to the unknown., Oncogene, Vol: 37, Pages: 1-7, ISSN: 0950-9232
Small mothers against decapentaplegic (SMAD) proteins are a family of signal transduction molecules in transforming growth factor β (TGFβ) ligand pathways that have been found to have a key role in the pathogenesis of inflammatory bowel disease (IBD). Long standing IBD predisposes individuals to colitis-associated colorectal cancer (CAC), an entity that possess unique characteristics compared to hereditary and sporadic cancer. The ligands of the TGFβ super family along with SMADs have also been implicated in several aspects of colorectal cancer formation. SMAD proteins are shown to be involved in a number of potentially carcinogenic mechanisms such as altering gene transcription, controlling stem cell differentiation to causing epigenetic changes. Modulation of these proteins has emerged as a novel therapeutic intervention for IBD although its effect on carcinogenesis remains elusive. This account reviews available evidence linking SMAD proteins to CAC and explores the potential areas for future research in this area.Oncogene advance online publication, 4 September 2017; doi:10.1038/onc.2017.300.
Stebbing J, Baranau Y, Baryash V, 2017, CT-P6 compared with reference trastuzumab for HER2-positive breast cancer: a randomised, double-blind, active-controlled, phase 3 equivalence trial (vol 18, pg 917, 2017), LANCET ONCOLOGY, Vol: 18, Pages: E510-E510, ISSN: 1470-2045
Frampton AE, Funel N, Giovannetti E, et al., 2017, y Dicing and slicing pancreatic cancer, 20th Annual Scientific Meeting of the Association-of-Upper-Gastrointestinal-Surgeons-of-Great-Britain-and-Ireland (AUGIS), Publisher: WILEY, Pages: 13-13, ISSN: 0007-1323
Harding V, Stebbing J, 2017, Liquorice: a treatment for all sorts?, Lancet Oncology, Vol: 18, Pages: 1155-1155, ISSN: 1470-2045
Esteva FJ, Baranau Y, Baryash V, et al., 2017, Double-blind, randomized phase III study to compare the efficacy and safety of trastuzumab and its biosimilar candidate CT-P6 in HER2 positive early breast cancer (EBC), 42nd European-Society-for-Medical-Oncology Congress (ESMO), Publisher: OXFORD UNIV PRESS, ISSN: 0923-7534
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Izumchenko E, Paz K, Ciznadija D, et al., 2017, Patient-derived xenografts effectively capture responses to oncology therapy in a heterogeneous cohort of patients with solid tumors, Annals of Oncology, Vol: 28, Pages: 2595-2605, ISSN: 0923-7534
BackgroundWhile patient-derived xenografts (PDXs) offer a powerful modality for translational cancer research, a precise evaluation of how accurately patient responses correlate with matching PDXs in a large, heterogeneous population is needed for assessing the utility of this platform for preclinical drug-testing and personalized patient cancer treatment.Patients and methodsTumors obtained from surgical or biopsy procedures from 237 cancer patients with a variety of solid tumors were implanted into immunodeficient mice and whole-exome sequencing was carried out. For 92 patients, responses to anticancer therapies were compared with that of their corresponding PDX models.ResultsWe compared whole-exome sequencing of 237 PDX models with equivalent information in The Cancer Genome Atlas database, demonstrating that tumorgrafts faithfully conserve genetic patterns of the primary tumors. We next screened PDXs established for 92 patients with various solid cancers against the same 129 treatments that were administered clinically and correlated patient outcomes with the responses in corresponding models. Our analysis demonstrates that PDXs accurately replicate patients’ clinical outcomes, even as patients undergo several additional cycles of therapy over time, indicating the capacity of these models to correctly guide an oncologist to treatments that are most likely to be of clinical benefit.ConclusionsIntegration of PDX models as a preclinical platform for assessment of drug efficacy may allow a higher success-rate in critical end points of clinical benefit.
Wendler F, Favicchio R, Simon T, et al., 2017, Extracellular vesicles swarm the cancer microenvironment: from tumor-stroma communication to drug intervention, ONCOGENE, Vol: 36, Pages: 877-884, ISSN: 0950-9232
Zanini E, Louis LS, Antony J, et al., 2017, The tumor suppressor protein OPCML potentiates anti-EGFR and anti-HER2 targeted therapy in HER2-positive ovarian and breast cancer., Molecular Cancer Therapeutics, Vol: 16, Pages: 2246-2256, ISSN: 1535-7163
OPCML is a tumor suppressor gene that is frequently inactivated in ovarian cancer and many other cancers by somatic methylation. We have previously shown that OPCML exerts its suppressor function by negatively regulating a spectrum of receptor tyrosine kinases (RTKs), such as ErbB2/HER2, FGFR1 and EphA2, thus attenuating their related downstream signaling. The physical interaction of OPCML with this defined group of RTKs is a prerequisite for their downregulation. Overexpression/gene amplification of EGFR and HER2 is a frequent event in multiple cancers including ovarian and breast cancers. Molecular therapeutics against EGFR/HER2 or EGFR only, such as lapatinib and erlotinib respectively, were developed to target these receptors but resistance often occurs in relapsing cancers. Here we show that, though OPCML interacts only with HER2 and not with EGFR, the interaction of OPCML with HER2 disrupts the formation of the HER2-EGFR heterodimer and this translates into a better response to both lapatinib and erlotinib in HER2-expressing ovarian and breast cancer cell lines. Also, we show that high OPCML expression is associated with better response to lapatinib therapy in breast cancer patients and better survival in HER2-overexpressing ovarian cancer patients, suggesting that OPCML co-therapy could be a valuable sensitizing approach to RTK inhibitors.
Stebbing J, Baranau Y, Baryash V, 2017, CT-P6 compared with reference trastuzumab for HER2-positive breast cancer: a randomised, double-blind, active-controlled, phase 3 equivalence trial (vol 18, pg 917, 2017), Lancet Oncology, Vol: 18, Pages: E433-E433, ISSN: 1470-2045
Craddock C, Cathcart P, Stebbing J, 2017, Chilli-too hot to handle?, Lancet Oncology, Vol: 18, Pages: 1005-1005, ISSN: 1470-2045
Stebbing J, Baranau Y, Baryash V, et al., 2017, CT-P6 compared with reference trastuzumab for HER2-positive breast cancer: a randomised, double-blind, active-controlled, phase 3 equivalence trial, Lancet Oncology, Vol: 18, Pages: 917-928, ISSN: 1470-2045
BackgroundCT-P6 is a proposed biosimilar to reference trastuzumab. In this study, we aimed to establish equivalence of CT-P6 to reference trastuzumab in neoadjuvant treatment of HER2-positive early-stage breast cancer.MethodsIn this randomised, double-blind, active-controlled, phase 3 equivalence trial, we recruited women aged 18 years or older with stage I–IIIa operable HER2-positive breast cancer from 112 centres in 23 countries. Inclusion criteria were an Eastern Cooperative Oncology Group performance status score of 0 or 1; a normal left ventricular ejection fraction of at least 55%; adequate bone marrow, hepatic, and renal function; at least one measureable lesion; and known oestrogen and progesterone receptor status. Exclusion criteria included bilateral breast cancer, previous breast cancer treatment, previous anthracycline treatment, and pregnancy or lactation. We randomly allocated patients 1:1 to receive neoadjuvant CT-P6 or reference trastuzumab intravenously (eight cycles, each lasting 3 weeks, for 24 weeks; 8 mg/kg on day 1 of cycle 1 and 6 mg/kg on day 1 of cycles 2–8) in conjunction with neoadjuvant docetaxel (75 mg/m2 on day 1 of cycles 1–4) and FEC (fluorouracil [500 mg/m2], epirubicin [75 mg/m2], and cyclophosphamide [500 mg/m2]; day 1 of cycles 5–8) therapy. We stratified randomisation by clinical stage, receptor status, and country and used permuted blocks. We did surgery within 3–6 weeks of the final neoadjuvant study drug dose, followed by an adjuvant treatment period of up to 1 year. We monitored long-term safety and efficacy for 3 years after the last patient was enrolled. Participants and investigators were masked to treatment until study completion. The primary efficacy endpoint, analysed in the per-protocol population, was pathological complete response, assessed via specimens obtained during surgery, analysed by masked central review of local histopathology reports. The equivalence margin was −0·
Frampton AE, Ottaviani S, Stebbing J, et al., 2017, TGF-Beta Induces miR-100 and miR-125b Promoting EMT and Stemness in Pancreatic Cancer, International Congress of the Association-of-Surgeons-of-Great-Britain-and-Ireland, Publisher: WILEY, Pages: 6-6, ISSN: 0007-1323
Frampton AE, Ottaviani S, Stebbing J, et al., 2017, TGF-Beta Induces miR-100 and miR-125b Promoting EMT and Stemness in Pancreatic Cancer, International Congress of the Association-of-Surgeons-of-Great-Britain-and-Ireland, Publisher: WILEY, Pages: 21-21, ISSN: 0007-1323
Melaiu O, Stebbing J, Lombardo Y, et al., 2017, MSLN gene silencing has an anti-malignant effect on cell lines overexpressing mesothelin deriving from malignant pleural mesothelioma (vol 9, e85935, 2014), PLoS ONE, Vol: 12, ISSN: 1932-6203
Stebbing J, Valerievich Y, Baryash BV, et al., 2017, Double-blind, randomized phase III study to compare the efficacy and safety of CT-P6, trastuzumab biosimilar candidate versus trastuzumab as neoadjuvant treatment in HER2 positive early breast cancer (EBC), 53rd Annual Clinical Science Meeting of the American-Society-of-Clinical-Oncology (ASCO) / Symposium on Old Targets, New Drugs - Her2 and MET, Publisher: AMER SOC CLINICAL ONCOLOGY, ISSN: 0732-183X
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Frilling A, Kaemmerer D, Kidd MS, et al., 2017, Surgery in combination with peptide receptor radionuclide therapy is effective in metastatic neuroendocrine tumors and is definable by blood gene transcript analysis., 53rd Annual Clinical Science Meeting of the American-Society-of-Clinical-Oncology (ASCO) / Symposium on Old Targets, New Drugs - Her2 and MET, Publisher: AMER SOC CLINICAL ONCOLOGY, ISSN: 0732-183X
Cathcart P, Craddock C, Stebbing J, 2017, Fasting: starving cancer., Lancet Oncology, Vol: 18, Pages: 431-431, ISSN: 1474-5488
Esteva FJ, Lee SJ, Stebbing J, et al., 2017, Phase I clinical trial comparing PK and safety of trastuzumab and its biosimilar candidate CT-P6, BREAST, Vol: 32, Pages: S68-S69, ISSN: 0960-9776
Meijer LL, Frampton AE, Garajova I, et al., 2017, Circulating microRNAs as dynamic biomarkers of response to treatment with FOLFIRINOX combination therapy in advanced pancreatic ductal adenocarcinoma, LANCET, Vol: 389, Pages: 68-68, ISSN: 0140-6736
Boulianne B, Robinson ME, May PC, et al., 2017, Lineage-specific genes are prominent DNA damage hotspots during leukemic transformation of B-cell precursors, Cell Reports, Vol: 18, Pages: 1687-1698, ISSN: 2211-1247
In human leukemia, lineage-specific genes represent predominant targets of deletion, with lymphoid-specific genes frequently affected in lymphoid leukemia and myeloid-specific genes in myeloid leukemia. To investigate the basis of lineage-specific alterations, we analyzed global DNA damage in primary B-cell precursors expressing leukemia-inducing oncogenes by ChIP-Seq. We identified >1000 sensitive regions, of which B-lineage-specific genes constitute the most prominent targets. Identified hotspots at B-lineage genes relate to DNA-DSBs, affect genes that harbor genomic lesions in human leukemia, and associate with ectopic deletionin successfully transformed cells. We further show that mostidentified regions overlap with gene bodies of highly expressed genes, and that induction of a myeloidlineage phenotype in transformed B-cell precursors promotes de novoDNA damage atmyeloid loci. Hence, we demonstrate thatlineage-specific transcriptionpredisposeslineage-specificgenes in transformed B-cell precursorsto DNA damage, whichis likely to promote the frequent alteration oflineage-specific genes in human leukemia.
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