• AXL inhibition extinguishes primitive JAK2 mutated myeloproliferative neoplasm progenitor cells

      Pearson, S; Blance, R; Somervaille, Tim CP; Whetton, AD; Pierce, A; Stem Cell and Leukaemia Proteomics Laboratory, Manchester Academic Health Science Centre, The University of Manchester, UK (2019)
      Myeloproliferative neoplasms (MPN) are clonal stem cell associated disorders inclusive of chronic myeloid leukemia (CML), Polycythaemia vera (PV), myelofibrosis (MF), and essential thrombocythemia (ET). They are characterized by increased production of myeloid cells with minimal effects on terminal differentiation but can undergo transformation to acute leukemias. PV is the most common chronic myeloproliferative neoplasm and in the majority of cases is characterized by a V617F point mutation in JAK2. This JAK2 activating mutation is also found in about half the patients with MF and ET. Such aberrant proteins offer great potential for the treatment of these diseases however inhibitors to JAK2 have had limited success in the clinic in terms of curing the disease. We have previously used advanced proteomic techniques to identify drug targets and thus develop novel treatment strategies to distinguish the leukemic clone in both CML and PV. Here, we build on our proteomic data sets to characterize a new target, the receptor tyrosine kinase AXL. AXL is overexpressed in acute myeloid leukemia and importantly small molecule inhibitors have been developed which are currently in clinical trial hence offer the opportunity to repurpose this drug for the treatment of MPNs. We demonstrate that AXL is upregulated and activated in JAK2 associated MPNs. Further we show that inhibition of AXL preferentially kills early hemopoietic stem cells from PV patients and as such represents a promising therapeutic approach for JAK2 driven MPNs
    • Identification of gene specific cis-regulatory elements during differentiation of mouse embryonic stem cells: An integrative approach using high-throughput datasets

      Vijayabaskar, MS; Goode, DK; Obier, N; Lichtinger, M; Emmett, AML; Abidin, FNZ; Shar, N; Hannah, R; Assi, SA; Lie-A-Ling, Michael; et al. (2019)
      Gene expression governs cell fate, and is regulated via a complex interplay of transcription factors and molecules that change chromatin structure. Advances in sequencing-based assays have enabled investigation of these processes genome-wide, leading to large datasets that combine information on the dynamics of gene expression, transcription factor binding and chromatin structure as cells differentiate. While numerous studies focus on the effects of these features on broader gene regulation, less work has been done on the mechanisms of gene-specific transcriptional control. In this study, we have focussed on the latter by integrating gene expression data for the in vitro differentiation of murine ES cells to macrophages and cardiomyocytes, with dynamic data on chromatin structure, epigenetics and transcription factor binding. Combining a novel strategy to identify communities of related control elements with a penalized regression approach, we developed individual models to identify the potential control elements predictive of the expression of each gene. Our models were compared to an existing method and evaluated using the existing literature and new experimental data from embryonic stem cell differentiation reporter assays. Our method is able to identify transcriptional control elements in a gene specific manner that reflect known regulatory relationships and to generate useful hypotheses for further testing.
    • Raman microscopy for the identification of an aggressive variant of prostate cancer, intraductal carcinoma of the prostate

      Trudel, D; Grosset, AA; Dallaire, F; Nguyen, T; Kougioumoutzakis, A; Azzi, F; Aubertin, K; Saad, F; Latour, M; Albadine, R; et al. (2019)
    • Evaluation of acute esophageal radiation-induced damage using magnetic resonance imaging: a feasibility study in mice

      Jelvehgaran, P; Steinberg, JD; Khmelinskii, A; Borst, G; Song, JY; de Wit, N; de Bruin, DM; van Herk, Marcel; Department of Biomedical Engineering and Physics, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands (2019)
      BACKGROUND: Thoracic and head and neck cancer radiation therapy (RT) can cause damage to nearby healthy organs such as the esophagus, causing acute radiation-induced esophageal damage (ARIED). A non-invasive method to detect and monitor ARIED can facilitate optimizing RT to avoid ARIED while improving local tumor control. Current clinical guidelines are limited to scoring the esophageal damage based on the symptoms of patients. Magnetic resonance imaging (MRI) is a non-invasive imaging modality that may potentially visualize radiation-induced organ damage. We investigated the feasibility of using T2-weighted MRI to detect and monitor ARIED using a two-phased study in mice. METHODS: The first phase aimed to establish the optimal dose level at which ARIED is inducible and to determine the time points where ARIED is detectable. Twenty four mice received a single dose delivery of 20 and 40?Gy at proximal and distal spots of 10.0?mm (in diameter) on the esophagus. Mice underwent MRI and histopathology analysis with esophageal resection at two, three, and 4 weeks post-irradiation, or earlier in case mice had to be euthanized due to humane endpoints. In the second phase, 32 mice received a 40?Gy single dose and were studied at two, three, and 7 days post-irradiation. We detected ARIED as a change in signal intensity of the MRI images. We measured the width of the hyperintense area around the esophagus in all mice that underwent MRI prior to and after irradiation. We conducted a blind qualitative comparison between MRI findings and histopathology as the gold standard. RESULTS/CONCLUSIONS: A dose of 40?Gy was needed to induce substantial ARIED. MRI detected ARIED as high signal intensity, visible from 2 days post-irradiation. Quantitative MRI analysis showed that the hyperintense area around the esophagus with severe ARIED was 1.41?mm wider than with no damage and MRI-only mice. The overall sensitivity and specificity were 56 and 43% respectively to detect any form of ARIED. However, in this study MRI correctly detected 100% of severe ARIED cases. Our two-phased preclinical study showed that MRI has the potential to detect ARIED as a change in signal intensity and width of enhancement around the esophagus.
    • International variation in childhood cancer mortality rates from 2005 to 2015

      Smith, L; Stiller, C; Johannesen, T; McBride, M; McCabe, Martin; Pritchard-Jones, K; Steliarova-Foucher, E; Winther, JF; Zeller, B; Glaser, A; et al. (2019)
    • Cistrome partitioning reveals convergence of somatic mutations and risk variants on master transcription regulators in primary prostate tumors

      Mazrooei, P; Kron, KJ; Zhu, Y; Zhou, S; Grillo, G; Mehdi, T; Ahmed, M; Severson, TM; Guilhamon, P; Armstrong, NS; et al. (2019)
      Thousands of noncoding somatic single-nucleotide variants (SNVs) of unknown function are reported in tumors. Partitioning the genome according to cistromes reveals the enrichment of somatic SNVs in prostate tumors as opposed to adjacent normal tissue cistromes of master transcription regulators, including AR, FOXA1, and HOXB13. This parallels enrichment of prostate cancer genetic predispositions over these transcription regulators' tumor cistromes, exemplified at the 8q24 locus harboring both risk variants and somatic SNVs in cis-regulatory elements upregulating MYC expression. However, Massively Parallel Reporter Assays reveal that few SNVs can alter the transactivation potential of individual cis-regulatory elements. Instead, similar to inherited risk variants, SNVs accumulate in cistromes of master transcription regulators required for prostate cancer development.
    • Cellular senescence: defining a path forward

      Gorgoulis, Vassilis G; Adams, PD; Alimonti, A; Bennett, DC; Bischof, O; Bishop, C; Campisi, J; Collado, M; Evangelou, K; Ferbeyre, G; et al. (2019)
      Cellular senescence is a cell state implicated in various physiological processes and a wide spectrum of age-related diseases. Recently, interest in therapeutically targeting senescence to improve healthy aging and age-related disease, otherwise known as senotherapy, has been growing rapidly. Thus, the accurate detection of senescent cells, especially in vivo, is essential. Here, we present a consensus from the International Cell Senescence Association (ICSA), defining and discussing key cellular and molecular features of senescence and offering recommendations on how to use them as biomarkers. We also present a resource tool to facilitate the identification of genes linked with senescence, SeneQuest (available at http://Senequest.net). Lastly, we propose an algorithm to accurately assess and quantify senescence, both in cultured cells and in vivo.
    • Second primary cancers in people who had cancer as children: an Australian Childhood Cancer Registry population-based study

      Youlden, DR; Baade, PD; Green, Adele C; Valery, PC; Moore, AS; Aitken, JF; Cancer Council Queensland, Brisbane, QLD (2019)
      OBJECTIVE: To investigate the incidence of second primary cancers in people diagnosed with cancer during childhood. DESIGN, SETTING: Retrospective, population-based study; analysis of Australian Childhood Cancer Registry data. PARTICIPANTS: People alive at least two months after being diagnosed before the age of 15 years with a primary cancer, 1983-2013, followed until 31 December 2015 (2-33 years' follow-up). MAIN OUTCOME MEASURES: Risks of second primary cancer compared with the general population, expressed as standardised incidence ratios (SIRs). RESULTS: Among 18 230 people diagnosed with cancer during childhood, 388 (2%) were later diagnosed with second primary cancers; the estimated 30-year cumulative incidence of second cancers was 4.4% (95% CI, 3.8-5.0%). The risk of a new primary cancer was five times as high as for the general population (SIR, 5.13; 95% CI, 4.65-5.67). Relative risk of a second primary cancer was greatest for people who had childhood rhabdomyosarcoma (SIR, 19.9; 95% CI, 14.4-27.6). Relative risk was particularly high for children who had undergone both chemotherapy and radiotherapy (SIR, 9.80; 95% CI, 8.35-11.5). Relative risk peaked during the 5 years following the first diagnosis (2 to less than 5 years: SIR, 10.3; 95% CI, 8.20-13.0), but was still significant at 20-33 years (SIR, 2.58; 95% CI, 2.02-3.30). The most frequent second primary cancers were thyroid carcinomas (65 of 388, 17%) and acute myeloid leukaemias (57, 15%). CONCLUSIONS: Survivors of childhood cancer remain at increased risk of a second primary cancer well into adulthood. As the late effects of cancer treatment probably contribute to this risk, treatments need to be refined and their toxicity reduced, without reducing their benefit for survival.
    • Circulating biomarkers

      Dive, Caroline; Cancer Research UK Manchester Institute, Manchester/GB (2019)
    • Development of a novel genetically engineered mouse model of malignant pleural mesothelioma?

      Gyuraszova, K; Monteverde, Tiziana; Chernova, T; Duffin, R; Blyth, K; Berns, A; Macfarlane, M; Murphy, D; Institute for Cancer Sciences/Beatson Institute, University of Glasgow, Glasgow/GB (2019)
    • Patterns of recurrence and survival in the randomized Portec-3 trial of chemoradiotherapy for high-risk endometrial cancer

      de Boer, S; Powell, ME; Mileshkin, L; Katsaros, D; Bessette, P; Haie-Meder, C; Ottevanger, PB; Ledermann, JA; Khaw, P; Colombo, A; et al. (2019)
    • Coordinated alterations in RNA splicing and epigenetic regulation drive leukaemogenesis

      Yoshimi, A; Lin, KT; Wiseman, Daniel H; Rahman, MA; Pastore, A; Wang, B; Lee, SC; Micol, JB; Zhang, XJ; de, BS; et al. (2019)
    • A phase I pilot study of preoperative radiotherapy for prostate cancer: long-term toxicity and oncologic outcomes

      Sanmamed, N; Glicksman, R; Thoms, J; Zlotta, A; Finelli, A; van der Kwast, T; Sweet, J; Jewett, M; Klotz, L; Rosewall, T; et al. (2019)
    • The molecular hallmarks and clinical consequences of tumor hypoxia in prostate cancer

      Vinayak, B; Liu, L; Espirritu, S; Lalonde, E; Yamaguchi, T; Heisler, L; Livingstone, J; Huang, V; Shiah, YJ; Sabelnykova, V; et al. (2019)
    • The impact of intratumoral heterogeneity on prognostic biomarkers in localized prostate cancer

      Brastianos, H; Murgic, J; Salcedo, A; Chua, MLK; Meng, A; Fraser, M; Brundage, MD; Fleshner, NE; van der Kwast, T; Bristow, Robert G; et al. (2019)
    • Cardiac disease in childhood cancer survivors treated with radiotherapy: final results from the PENTEC group

      Bates, JE; Keshavarz, H; Rancati, T; Gagliardi, G; Aznar, Marianne Camille; Moiseenko, V; Yorke, ED; Armenian, S; Kremer, L; Chen, MH; et al. (2019)
    • Requite: validating predictive models and biomarkers of radiotherapy toxicity to reduce side-effects and improve quality-of-life in cancer survivors

      Rosenstein, BS; Azria, D; Chang-Claude, J; de Ruysscher, D; Elliott, Rebecca M; Gutierrez-Enriquez, S; Rancati, T; Seibold, P; Talbot, C; Vega, A; et al. (2019)
    • Breast cancer cells and PD-1/PD-L1 blockade upregulate the expression of PD-1, CTLA-4, TIM-3 and LAG-3 immune checkpoints in CD4(+) T cells

      Saleh, R; Toor, SM; Khalaf, S; Elkord, Eyad; Cancer Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha 34110, Qatar (2019)
    • Melanocyte specific deletion of Map3k1 reveals its role in BRAF(V600E)-driven melanoma

      Trucco, Lucas D; Mundra, Piyushkumar A; Garcia-Martinez, Pablo; Hogan, Kate; Dhomen, Nathalie; Pavet, Valeria R; Marais, Richard; Cancer Research UK Manchester Institute, Manchester (2019)
    • Multicenter evaluation of circulating tumor DNA assays

      Brudzewsky, D; Lampignano, R; Weber, S; Sartori, A; Mohan, Sumitra; Konigshofer, Y; Davis, L; Rothwell, Dominic G; Schuuring, E; Garlick, RK; et al. (2019)