Recent Submissions

  • Randomised phase II study of amrubicin as single agent or in combination with cisplatin versus cisplatin etoposide as first-line treatment in patients with extensive stage small cell lung cancer - EORTC 08062.

    O'Brien, M E R; Konopa, K; Lorigan, Paul C; Bosquee, L; Marshall, E; Bustin, F; Margerit, S; Fink, C; Stigt, J A; Dingemans, A; et al. (2011-10)
    The EORTC 08062 phase II randomised trial investigated the activity and safety of single agent amrubicin, cisplatin combined with amrubicin, and cisplatin combined with etoposide as first line treatment in extensive disease (ED) small cell lung cancer (SCLC).
  • Second cancer risk after chemotherapy for Hodgkin's lymphoma: a collaborative British cohort study.

    Swerdlow, A J; Higgins, C D; Smith, P; Cunningham, D; Hancock, B W; Horwich, A; Hoskin, P J; Lister, T A; Radford, John A; Rohatiner, A Z S; et al. (2011-11-01)
    We investigated the long-term risk of second primary malignancy after chemotherapy for Hodgkin's lymphoma (HL) in a much larger cohort than any yet published, to our knowledge.
  • A phase I study to determine the safety, pharmacokinetics and pharmacodynamics of a dual VEGFR and FGFR inhibitor, brivanib, in patients with advanced or metastatic solid tumors.

    Jonker, D J; Rosen, L S; Sawyer, M B; de Braud, F; Wilding, G; Sweeney, C J; Jayson, Gordon C; McArthur, G A; Rustin, G; Goss, G; et al. (2011-06)
    This study was designed to determine the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of brivanib in patients with advanced/metastatic solid tumors.
  • Cancer cells metabolically "fertilize" the tumor microenvironment with hydrogen peroxide, driving the Warburg effect: implications for PET imaging of human tumors.

    Martinez-Outschoorn, U E; Lin, Z; Trimmer, C; Flomenberg, N; Wang, C; Pavlides, S; Pestell, R G; Howell, Anthony; Sotgia, F; Lisanti, M P; et al. (2011-08-01)
    Previously, we proposed that cancer cells behave as metabolic parasites, as they use targeted oxidative stress as a "weapon" to extract recycled nutrients from adjacent stromal cells. Oxidative stress in cancer-associated fibroblasts triggers autophagy and  mitophagy, resulting in compartmentalized cellular catabolism, loss of mitochondrial function, and the onset of aerobic glycolysis, in the tumor stroma. As such, cancer-associated fibroblasts produce high-energy nutrients (such as lactate and ketones) that fuel mitochondrial biogenesis, and oxidative metabolism in cancer cells. We have termed this new energy-transfer mechanism the "reverse Warburg effect." To further test the validity of this hypothesis, here we used an in vitro MCF7-fibroblast co-culture system, and quantitatively measured a variety of metabolic parameters by FACS analysis (analogous to laser-capture micro-dissection).  Mitochondrial activity, glucose uptake, and ROS production were measured with highly-sensitive fluorescent probes (MitoTracker, NBD-2-deoxy-glucose, and DCF-DA). Interestingly, using this approach, we directly show that cancer cells initially secrete hydrogen peroxide that then triggers oxidative stress in neighboring fibroblasts. Thus, oxidative stress is contagious (spreads like a virus) and is propagated laterally and vectorially from cancer cells to adjacent fibroblasts. Experimentally, we show that oxidative stress in cancer-associated fibroblasts quantitatively reduces mitochondrial activity, and increases glucose uptake, as the fibroblasts become more dependent on aerobic glycolysis.  Conversely, co-cultured cancer cells show significant increases in mitochondrial activity, and corresponding reductions in both glucose uptake and GLUT1 expression. Pre-treatment of co-cultures with extracellular catalase (an anti-oxidant enzyme that detoxifies hydrogen peroxide) blocks the onset of oxidative stress, and potently induces the death of cancer cells, likely via starvation.  Given that cancer-associated fibroblasts show the largest increases in glucose uptake, we suggest that PET imaging of human tumors, with Fluoro-2-deoxy-D-glucose (F-2-DG), may be specifically detecting the tumor stroma, rather than epithelial cancer cells.
  • Hydrogen peroxide fuels aging, inflammation, cancer metabolism and metastasis: the seed and soil also needs "fertilizer".

    Lisanti, Michael P; Martinez-Outschoorn, U E; Lin, Z; Pavlides, S; Whitaker-Menezes, D; Pestell, R G; Howell, Anthony; Sotgia, F; The Jefferson Stem Cell Biology and Regenerative Medicine Center, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA. (2011-08-01)
    In 1889, Dr. Stephen Paget proposed the "seed and soil" hypothesis, which states that cancer cells (the seeds) need the proper microenvironment (the soil) for them to grow, spread and metastasize systemically. In this hypothesis, Dr. Paget rightfully recognized that the tumor microenvironment has an important role to play in cancer progression and metastasis. In this regard, a series of recent studies have elegantly shown that the production of hydrogen peroxide, by both cancer cells and cancer-associated fibroblasts, may provide the necessary "fertilizer," by driving accelerated aging, DNA damage, inflammation and cancer metabolism, in the tumor microenvironment. By secreting hydrogen peroxide, cancer cells and fibroblasts are mimicking the behavior of immune cells (macrophages/neutrophils), driving local and systemic inflammation, via the innate immune response (NFκB). Thus, we should consider using various therapeutic strategies (such as catalase and/or other anti-oxidants) to neutralize the production of cancer-associated hydrogen peroxide, thereby preventing tumor-stroma co-evolution and metastasis. The implications of these findings for overcoming chemo-resistance in cancer cells are also discussed in the context of hydrogen peroxide production and cancer metabolism.
  • Understanding the metabolic basis of drug resistance: therapeutic induction of the Warburg effect kills cancer cells.

    Martinez-Outschoorn, U E; Lin, Z; Ko, Y H; Goldberg, A F; Flomenberg, N; Wang, C; Pavlides, S; Pestell, R G; Howell, Anthony; Sotgia, F; et al. (2011-08-01)
    Previously, we identified a form of epithelial-stromal metabolic coupling, in which cancer cells induce aerobic glycolysis in adjacent stromal fibroblasts, via oxidative stress, driving autophagy and mitophagy. In turn, these cancer-associated fibroblasts provide recycled nutrients to epithelial cancer cells, "fueling" oxidative mitochondrial metabolism and anabolic growth. An additional consequence is that these glycolytic fibroblasts protect cancer cells against apoptosis, by providing a steady nutrient stream of to mitochondria in cancer cells. Here, we investigated whether these interactions might be the basis of tamoxifen-resistance in ER(+) breast cancer cells. We show that MCF7 cells alone are Tamoxifen-sensitive, but become resistant when co-cultured with hTERT-immortalized human fibroblasts. Next, we searched for a drug combination (Tamoxifen + Dasatinib) that could over-come fibroblast-induced Tamoxifen-resistance. Importantly, we show that this drug combination acutely induces the Warburg effect (aerobic glycolysis) in MCF7 cancer cells, abruptly cutting off their ability to use their fuel supply, effectively killing these cancer cells. Thus, we believe that the Warburg effect in tumor cells is not the "root cause" of cancer, but rather it may provide the necessary clues to preventing chemo-resistance in cancer cells. Finally, we observed that this drug combination (Tamoxifen + Dasatinib) also had a generalized anti-oxidant effect, on both co-cultured fibroblasts and cancer cells alike, potentially reducing tumor-stroma co-evolution. Our results are consistent with the idea that chemo-resistance may be both a metabolic and stromal phenomenon that can be overcome by targeting mitochondrial function in epithelial cancer cells. Thus, simultaneously targeting both (1) the tumor stroma and (2) the epithelial cancer cells, with combination therapies, may be the most successful approach to anti-cancer therapy. This general strategy of combination therapy for overcoming drug resistance could be applicable to many different types of cancer.
  • Prevalence of BRCA1 and BRCA2 mutations in triple negative breast cancer.

    Evans, D G; Howell, Anthony; Ward, D; Lalloo, F; Jones, J L; Eccles, D M; Genetic Medicine, St Mary's Hospital, Oxford Road, Manchester, UK. (2011-08)
  • Vaccines for the treatment of non-small cell lung cancer: investigational approaches and clinical experience.

    Mellstedt, H; Vansteenkiste, J; Thatcher, Nick; Cancer Centre Karolinska, Department of Oncology, Karolinska University Hospital, Solna, SE-171 76 Stockholm, Sweden. (2011-07)
    Globally, lung cancer remains the most common malignancy and the leading cause of cancer-related death. Whilst resection is a therapeutic option for patients with early stage non-small cell lung cancer (NSCLC), most patients have locally advanced or metastatic disease at diagnosis, the treatment of which still presents a considerable challenge for medical oncologists. Therapeutic cancer vaccines offer a novel approach for the treatment of patients with NSCLC in both the adjuvant and advanced disease settings. Although early attempts to use such technologies were of limited success, increased knowledge of the molecular pathology of tumors, of the immune system in general, and of tumor immunity in particular, has facilitated the production of more sophisticated anticancer vaccines. A number of promising vaccine candidates based on different types of antigenic stimulus have now been evaluated in clinical studies. These include belagenpumatucel-L, a vaccine derived from four genetically modified, irradiated NSCLC cell lines and target protein-specific vaccines designed to induce responses against epidermal growth factor (EGF), melanoma-associated antigen A3 (MAGE-A3) and mucin 1 (MUC1). The purpose of this review is to describe the mode of action of the vaccine candidates that are most advanced in their clinical development for the treatment of NSCLC, and to summarize the most recent data from clinical studies of these vaccines.
  • Molecular Imaging and Pharmacokinetic Analysis of Carbon-11 Labeled Antisense Oligonucleotide LY2181308 in Cancer Patients.

    Saleem, Azeem; Matthews, Julian C; Ranson, Malcolm R; Callies, S; André, V; Lahn, M; Dickinson, C; Prenant, Christian; Brown, Gavin; McMahon, Adam; et al. (2011)
    Antisense oligonucleotides (ASOs) have potential as anti-cancer agents by specifically modulating genes involved in tumorigenesis. However, little is known about ASO biodistribution and tissue pharmacokinetics (PKs) in humans, including whether sufficient delivery to target tumor tissue may be achieved. In this preliminary study in human subjects, we used combined positron emission and computed tomography (PET-CT) imaging and subsequent modeling analysis of acquired dynamic data, to examine the in vivo biodistribution and PK properties of LY2181308 - a second generation ASO which targets the apoptosis inhibitor protein survivin. Following radiolabeling of LY2181308 with methylated carbon-11 ([(11)C]methylated-LY2181308), micro-doses (<1mg) were administered to three patients with solid tumors enrolled in a phase I trial. Moderate uptake of [(11)C]methylated-LY2181308 was observed in tumors (mean=32.5ng*h /mL, per mg administered intravenously). Highest uptake was seen in kidney and liver and lowest uptake was seen in lung and muscle. One patient underwent repeat analysis on day 15 of multiple dose therapy, during administration of LY2181308 (750mg), when altered tissue PKs and a favorable change in biodistribution was seen. [(11)C]methylated-LY2181308 exposure increased in tumor, lung and muscle, whereas renal and hepatic exposure decreased. This suggests that biological barriers to ASO tumor uptake seen at micro-doses were overcome by therapeutic dosing. In addition, (18)F-labeled fluorodeoxyglucose (FDG) scans carried out in the same patient before and after treatment showed up to 40% decreased tumor metabolism. For the development of anti-cancer ASOs, the results provide evidence of LY2181308 tumor tissue delivery and add valuable in vivo pharmacological information. For the development of novel therapeutic agents in general, the study exemplifies the merits of applying PET imaging methodology early in clinical investigations.
  • Balancing the efficacy and toxicity of chemotherapy in colorectal cancer.

    Braun, Michael S; Seymour, M T; Consultant, Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Road, Withington, Manchester M20 4BX, UK. (2011-01)
    As the therapeutic options for the treatment of colorectal cancer have expanded over the past 20 years, so has the complexity of decision making. The goals of treatment in the palliative, adjuvant and neoadjuvant settings vary and it is not only the efficacy of drugs that influence treatment decisions. Age, performance status, the presence of significant comorbidities and the different treatment regimens and strategies provide medical oncologists with an array of options to attempt to maximize patients' quality of life and longevity.
  • Fulvestrant revisited: efficacy and safety of the 500-mg dose.

    Howell, Anthony; Sapunar, F; CRUK Department of Medical Oncology, University of Manchester, Christie Hospital NHS Trust, Wilmslow Road, Manchester, UK. (2011-08)
    Postmenopausal women with hormone receptor-positive advanced breast cancer are candidates for endocrine therapy. As the disease will eventually progress in most patients, it is important to investigate agents with novel modes of action to reduce the likelihood of treatment cross-resistance. Fulvestrant is an estrogen receptor antagonist with no known agonist effects that has been shown to be as effective as anastrozole following failure on tamoxifen, at the approved dose of 250 mg/mo. However, pharmacokinetic modelling and evidence of clinical efficacy in early trials, together with the favorable tolerability profile of fulvestrant 250 mg, led to suggestions that increasing the fulvestrant dose would lead to an improved benefit-risk profile. This review describes the rationale behind the development of a 500 mg/mo higher dose of fulvestrant and details relevant clinical trials, including the pivotal phase III COmparisoN of Faslodex In Recurrent or Metastatic breast cancer (CONFIRM) study. CONFIRM demonstrated a significant improvement in progression-free survival for fulvestrant 500 mg versus 250 mg in postmenopausal patients who had progressed on previous endocrine therapy. Here, we present and discuss a pooled safety analysis of CONFIRM and three further clinical studies demonstrating fulvestrant 500 mg to be well-tolerated with no evidence of dose-related adverse events. Overall, these data indicate an improved benefit-risk profile for fulvestrant 500 mg versus 250 mg following failure on prior endocrine therapy, and suggest that fulvestrant 500 mg may be considered in future as initial endocrine treatment for advanced breast cancer.
  • Development of an advanced database for clinical trials integrated with an electronic patient record system.

    Newsham, A C; Johnston, C; Hall, G; Leahy, Michael G; Smith, A B; Vikram, A; Donnelly, A M; Velikova, G; Selby, P J; Fisher, S E; et al. (2011-08)
    Secondary use of patient databases is essential in healthcare if clinical trials are to progress efficiently to planned time and target and imperative if the planned UK expansion of research and development (R&D) at point of care is to be achieved. Integration of effective databases primarily designed to facilitate patient care with R&D requirements is needed but represents a complex challenge. We present a system that achieves an integrated approach with online management of complex datasets for clinical trials within care records using a specific study as an example to show functionality in practice; illustrating how this system provides an ideal resource to meet the needs of both clinicians and researchers.
  • Randomized, phase III trial of sequential epirubicin and docetaxel versus epirubicin alone in postmenopausal patients with node-positive breast cancer.

    Coombes, R C; Bliss, J M; Espie, M; Erdkamp, F; Wals, J; Tres, A; Marty, M; Coleman, R E; Tubiana-Mathieu, N; den Boer, M O; et al. (2011-08-20)
    The Docetaxel Epirubicin Adjuvant (DEVA) trial evaluated the efficacy and toxicity of incorporating docetaxel after epirubicin to create a sequential anthracycline-taxane regimen in early breast cancer.
  • Is serum or plasma more appropriate for intersubject comparisons in metabolomic studies? An assessment in patients with small-cell lung cancer.

    Wedge, D C; Allwood, J W; Dunn, W; Vaughan, A A; Simpson, Kathryn L; Brown, M; Priest, Lynsey; Blackhall, Fiona H; Whetton, Anthony D; Dive, Caroline; et al. (2011-09-01)
    In clinical analyses, the most appropriate biofluid should be analyzed for optimal assay performance. For biological fluids, the most readily accessible is blood, and metabolomic analyses can be performed either on plasma or serum. To determine the optimal agent for analysis, metabolic profiles of matched human serum and plasma were assessed by gas chromatography/time-of-flight mass spectrometry and ultrahigh-performance liquid chromatography mass spectrometry (in positive and negative electrospray ionization modes). Comparison of the two metabolomes, in terms of reproducibility, discriminative ability and coverage, indicated that they offered similar analytical opportunities. An analysis of the variation between 29 small-cell lung cancer (SCLC) patients revealed that the differences between individuals are markedly similar for the two biofluids. However, significant differences between the levels of some specific metabolites were identified, as were differences in the intersubject variability of some metabolite levels. Glycerophosphocholines, erythritol, creatinine, hexadecanoic acid, and glutamine in plasma, but not in serum, were shown to correlate with life expectancy for SCLC patients, indicating the utility of metabolomic analyses in clinical prognosis and the particular utility of plasma in relation to the clinical management of SCLC.
  • A phase 2 study of SP1049C, doxorubicin in P-glycoprotein-targeting pluronics, in patients with advanced adenocarcinoma of the esophagus and gastroesophageal junction.

    Valle, Juan W; Armstrong, Anne C; Newman, C; Alakhov, V; Pietrzynski, G; Brewer, Julie; Campbell, S; Corrie, P; Rowinsky, E K; Ranson, Malcolm R; et al. (2011-10)
    To evaluate the antitumor activity of SP1049C, a novel P-glycoprotein targeting micellar formulation of doxorubicin, consisting of doxorubicin and two non-ionic block copolymers (pluronics), in patients with advanced adenocarcinoma of the esophagus and gastroesophageal junction (GEJ). Patients and
  • Long-term safety of growth hormone replacement after CNS irradiation.

    Mackenzie, S; Craven, T; Gattamaneni, Rao; Swindell, Ric; Shalet, Stephen M; Brabant, Georg E; Department of Endocrinology, The Christie, Manchester Academic Health Science Centre, Wilmslow Road, Manchester M20 4BX, United Kingdom. (2011-09)
    Radiotherapy is a central component in the treatment of many brain tumors, but long-term sequelae include GH deficiency and increased risk of secondary neoplasms. It is unclear whether replacement therapy with GH (GHRT) further increases this risk.
  • A two-part phase II study of cediranib in patients with advanced solid tumours: the effect of food on single-dose pharmacokinetics and an evaluation of safety, efficacy and imaging pharmacodynamics.

    Mitchell, Claire L; O'Connor, James P B; Roberts, C; Watson, Y; Jackson, A; Cheung, S; Evans, J; Spicer, J; Harris, A; Kelly, C; et al. (2011-09)
    Cediranib (RECENTIN™) is an oral, highly potent VEGF inhibitor. This study evaluated the effect of food on the pharmacokinetics of cediranib and compared the administration of continual cediranib via two dosing strategies using this as a platform to investigate pharmacodynamic imaging biomarkers.
  • 1st ESMO Consensus Conference in lung cancer; Lugano 2010: small-cell lung cancer.

    Stahel, R; Thatcher, Nick; Früh, M; Le Péchoux, C; Postmus, P E; Sorensen, J B; Felip, E; Faivre-Finn, Corinne; Blackhall, Fiona H; Department of Oncology, University Hospital Zurich, Zurich, Switzerland. (2011-09)
    The 1st ESMO Consensus Conference on lung cancer was held in Lugano, Switzerland on 21st and 22nd May 2010 with the participation of a multidisciplinary panel of leading professionals in pathology and molecular diagnostics and medical, surgical and radiation oncology. Before the conference, the expert panel prepared clinically relevant questions concerning five areas as follows: early and locally advanced non-small-cell lung cancer (NSCLC), first-line metastatic NSCLC, second-/third-line NSCLC, NSCLC pathology and molecular testing, and small-cell lung cancer (SCLC) to be addressed through discussion at the Consensus Conference. All relevant scientific literature for each question was reviewed in advance. During the Consensus Conference, the panel developed recommendations for each specific question. The consensus agreement in SCLC is reported in this article. The recommendations detailed here are based on an expert consensus after careful review of published data. All participants have approved this final update.
  • Phase II trial of combretastatin A4 phosphate, carboplatin, and paclitaxel in patients with platinum-resistant ovarian cancer.

    Zweifel, M; Jayson, Gordon C; Reed, N S; Osborne, R; Hassan, B; Ledermann, J; Shreeves, G; Poupard, L; Lu, S-P; Balkissoon, J; et al. (2011-09)
    A previous dose-escalation trial of the vascular disrupting agent combretastatin A4 phosphate (CA4P) given before carboplatin, paclitaxel, or both showed responses in 7 of 18 patients with relapsed ovarian cancer.
  • A multicentre study of capecitabine, oxaliplatin plus bevacizumab as perioperative treatment of patients with poor-risk colorectal liver-only metastases not selected for upfront resection.

    Wong, R; Cunningham, D; Barbachano, Y; Saffery, C; Valle, Juan W; Hickish, T; Mudan, S; Brown, G; Khan, A; Wotherspoon, A; et al. (2011-09)
    Perioperative chemotherapy improves outcome in resectable colorectal liver-only metastasis (CLM). This study aimed to evaluate perioperative CAPOX (capecitabine-oxaliplatin) plus bevacizumab in patients with poor-risk CLM not selected for upfront resection.

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