• New approaches to small cell lung cancer therapy : from the laboratory to the clinic

      Poirier, JT; George, J; Owonikoko, TK; Berns, A; Brambilla, E; Byers, LA; Carbone, D; Chen, HJ; Christensen, CL; Dive, Caroline; et al. (2020)
      Small cell lung cancer patient outcomes have not yet been significantly impacted by the revolution in precision oncology, primarily due to a paucity of genetic alterations in actionable driver oncogenes. Nevertheless, systemic therapies that include immunotherapy are beginning to show promise in the clinic. While these results are encouraging, many patients do not respond to or rapidly recur after current regimens, necessitating alternative or complementary therapeutic strategies. In this review, we discuss ongoing investigations into the pathobiology of this recalcitrant cancer and the therapeutic vulnerabilities that are exposed by the disease state. Included within this discussion is a snapshot of the current biomarker and clinical trial landscapes for small cell lung cancer. Finally, we identify key knowledge gaps that should be addressed in order to advance the field in pursuit of reduced small cell lung cancer mortality. This review largely summarizes work presented at the Third Biennial IASLC Small Cell Lung Cancer Meeting.
    • Statins may reduce disease recurrence in patients with ulcerated primary melanoma

      von Schuckmann, LA; Khosrotehrani, K; Ghiasvand, R; Hughes, MCB; van der Pols, JC; Malt, M; Smithers, BM; Green, Adèle C; Population Health Department, QIMR Berghofer Medical Research Institute, Australia (2020)
    • ATF2 and ATF7 are critical mediators of intestinal epithelial repair

      Meijer, BJ; Giugliano, FP; Baan, B; Van der Meer, JHM; Meisner, S; Van Roest, M; Koelink, PJ; De Boer, RJ; Jones, N; Breitwieser, Wolfgang; et al. (2020)
      BACKGROUND & AIMS: Activation factor-1 transcription factor family members activating transcription factors 2 and 7 (ATF2 and ATF7) have highly redundant functions owing to highly homologous DNA binding sites. Their role in intestinal epithelial homeostasis and repair is unknown. Here, we assessed the role of these proteins in these conditions in an intestine-specific mouse model. METHODS: We performed in vivo and ex vivo experiments using Villin-CreERT2Atf2fl/flAtf7ko/ko mice. We investigated the effects of intestinal epithelium-specific deletion of the Atf2 DNA binding region in Atf7-/- mice on cellular proliferation, differentiation, apoptosis, and epithelial barrier function under homeostatic conditions. Subsequently, we exposed mice to 2% dextran sulfate sodium (DSS) for 7 days and 12 Gy whole-body irradiation and assessed the response to epithelial damage. RESULTS: Activating phosphorylation of ATF2 and ATF7 was detected mainly in the crypts of the small intestine and the lower crypt region of the colonic epithelium. Under homeostatic conditions, no major phenotypic changes were detectable in the intestine of ATF mutant mice. However, on DSS exposure or whole-body irradiation, the intestinal epithelium showed a clearly impaired regenerative response. Mutant mice developed severe ulceration and inflammation associated with increased epithelial apoptosis on DSS exposure and were less able to regenerate colonic crypts on irradiation. In vitro, organoids derived from double-mutant epithelium had a growth disadvantage compared with wild-type organoids, impaired wound healing capacity in scratch assay, and increased sensitivity to tumor necrosis factor-?-induced damage. CONCLUSIONS: ATF2 and ATF7 are dispensable for epithelial homeostasis, but are required to maintain epithelial regenerative capacity and protect against cell death during intestinal epithelial damage and repair.
    • Androgen receptor and poly(ADP-ribose) glycohydrolase inhibition increases efficiency of androgen ablation in prostate cancer cells

      Zhang, M; Lai, Y; Vasquez, JL; James, Dominic I; Smith, Kate M; Waddell, Ian D; Ogilvie, Donald J; Liu, Y; Agoulnik, IU; Biochemistry Ph.D. Program, Florida International University, Miami, FL, (2020)
      There is mounting evidence of androgen receptor signaling inducing genome instability and changing DNA repair capacity in prostate cancer cells. Expression of genes associated with base excision repair (BER) is increased with prostate cancer progression and correlates with poor prognosis. Poly(ADP-ribose) polymerase (PARP) and poly(ADP-ribose) glycohydrolase (PARG) are key enzymes in BER that elongate and degrade PAR polymers on target proteins. While PARP inhibitors have been tested in clinical trials and are a promising therapy for prostate cancer patients with TMPRSS2-ERG fusions and mutations in DNA repair genes, PARG inhibitors have not been evaluated. We show that PARG is a direct androgen receptor (AR) target gene. AR is recruited to the PARG locus and induces PARG expression. Androgen ablation combined with PARG inhibition synergistically reduces BER capacity in independently derived LNCaP and LAPC4 prostate cancer cell lines. A combination of PARG inhibition with androgen ablation or with the DNA damaging drug, temozolomide, significantly reduces cellular proliferation and increases DNA damage. PARG inhibition alters AR transcriptional output without changing AR protein levels. Thus, AR and PARG are engaged in reciprocal regulation suggesting that the success of androgen ablation therapy can be enhanced by PARG inhibition in prostate cancer patients.
    • Intermediate risk prostate cancer: disease heterogeneity linked to measurable biological features

      Rebello, Richard; Bristow, Robert G; Translational Oncogenomics Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester Cancer Research Centre, Manchester (2020)
    • Cell-free DNA analysis reveals POLR1D-mediated resistance to bevacizumab in colorectal cancer

      Zhou, Q; Perakis, SO; Ulz, P; Mohan, Sumitra; Riedl, JM; Talakic, E; Lax, S; Totsch, M; Hoefler, G; Bauernhofer, T; et al. (2020)
      BACKGROUND: Bevacizumab, a monoclonal antibody against soluble VEGFA, is an approved and commonly administered anti-angiogenic drug in patients with metastasized colorectal cancer (mCRC). The survival benefit of anti-VEGF therapy in mCRC patients is limited to a few months, and acquired resistance mechanisms are largely unknown. Here, we employed whole-genome sequencing of plasma DNA to evaluate the tumor genome of patients undergoing treatment with bevacizumab to determine novel aberrations associated with resistance. METHODS: Using longitudinal plasma analyses, we studied the evolution of tumor genomes in a mCRC cohort (n = 150) and conducted analyses of CRC cases from The Cancer Genome Atlas (TCGA) database (n = 619) to identify associations between genomic aberrations and clinical features. We employed whole-genome sequencing to identify the most frequently occurring focal somatic copy number alterations (SCNAs). Using the TCGA data as a comparative and supporting dataset, we defined the minimally amplified overlapping region and studied the mechanistic consequences of copy number gain of the involved genes in this segment. In addition, we established an in vitro cell model and conducted downstream gene expression and cell viability assays to confirm our findings from the patient dataset. RESULTS: We observed a recurrent focal amplification (8.7% of cases) on chromosome 13q12.2. Analysis of CRC cases from the TCGA database suggested that this amplicon is associated with more advanced stages. We confirmed that this 13q12.2 amplicon frequently emerges later during the clinical course of disease. After defining the minimally amplified region, we observed that the amplification and expression of one gene, POLR1D, impacted cell proliferation and resulted in upregulation of VEGFA, an important regulator of angiogenesis which has been implicated in the resistance to bevacizumab treatment. In fact, in several patients, we observed the emergence of this 13q12.2 amplicon under bevacizumab treatment, which was invariably associated with therapy resistance. CONCLUSIONS: Non-invasive analyses of cell-free DNA from patients undergoing treatment with bevacizumab enabled the tracking of evolving tumor genomes and helped identify a recurrent focal SCNA of clinical relevance. Here, we describe a novel resistance mechanism against a widely applied treatment in patients with mCRC which will impact the clinical management of patients.
    • TH1579, MTH1 inhibitor, delays tumour growth and inhibits metastases development in osteosarcoma model

      Moukengue, B; Brown, HK; Charrier, C; Battaglia, S; Baud'huin, M; Quillard, T; Pham, TM; Pateras, IS; Gorgoulis, Vassilis G; Helleday, T; et al. (2020)
      BACKGROUND: Osteosarcoma (OS) is the most common primary malignant bone tumour. Unfortunately, no new treatments are approved and over the last 30 years the survival rate remains only 30% at 5 years for poor responders justifying an urgent need of new therapies. The Mutt homolog 1 (MTH1) enzyme prevents incorporation of oxidized nucleotides into DNA and recently developed MTH1 inhibitors may offer therapeutic potential as MTH1 is overexpressed in various cancers. METHODS: The aim of this study was to evaluate the therapeutic benefits of targeting MTH1 with two chemical inhibitors, TH588 and TH1579 on human osteosarcoma cells. Preclinical efficacy of TH1579 was assessed in human osteosarcoma xenograft model on tumour growth and development of pulmonary metastases. FINDINGS: MTH1 is overexpressed in OS patients and tumour cell lines, compared to mesenchymal stem cells. In vitro, chemical inhibition of MTH1 by TH588 and TH1579 decreases OS cells viability, impairs their cell cycle and increases apoptosis in OS cells. TH1579 was confirmed to bind MTH1 by CETSA in OS model. Moreover, 90 mg/kg of TH1579 reduces in vivo tumour growth by 80.5% compared to non-treated group at day 48. This result was associated with the increase in 8-oxo-dG integration into tumour cells DNA and the increase of apoptosis. Additionally, TH1579 also reduces the number of pulmonary metastases. INTERPRETATION: All these results strongly provide a pre-clinical proof-of-principle that TH1579 could be a therapeutic option for patients with osteosarcoma. FUNDING: This study was supported by La Ligue Contre le Cancer, la SFCE and Enfants Cancers Santé.
    • Diffusion model comparison identifies distinct tumor sub-regions and tracks treatment response

      McHugh, Damien J; Lipowska-Bhalla, Grazyna; Babur, M; Watson, Y; Peset, Isabel; Mistry, Hitesh; Hubbard, Cristinacce PL; Naish, JH; Honeychurch, Jamie; Williams, KJ; et al. (2020)
      PURPOSE: MRI biomarkers of tumor response to treatment are typically obtained from parameters derived from a model applied to pre-treatment and post-treatment data. However, as tumors are spatially and temporally heterogeneous, different models may be necessary in different tumor regions, and model suitability may change over time. This work evaluates how the suitability of two diffusion-weighted (DW) MRI models varies spatially within tumors at the voxel level and in response to radiotherapy, potentially allowing inference of qualitatively different tumor microenvironments. METHODS: DW-MRI data were acquired in CT26 subcutaneous allografts before and after radiotherapy. Restricted and time-independent diffusion models were compared, with regions well-described by the former hypothesized to reflect cellular tissue, and those well-described by the latter expected to reflect necrosis or oedema. Technical and biological validation of the percentage of tissue described by the restricted diffusion microstructural model (termed %MM) was performed through simulations and histological comparison. RESULTS: Spatial and radiotherapy-related variation in model suitability was observed. %MM decreased from a mean of 64% at baseline to 44% 6 days post-radiotherapy in the treated group. %MM correlated negatively with the percentage of necrosis from histology, but overestimated it due to noise. Within MM regions, microstructural parameters were sensitive to radiotherapy-induced changes. CONCLUSIONS: There is spatial and radiotherapy-related variation in different models' suitability for describing diffusion in tumor tissue, suggesting the presence of different and changing tumor sub-regions. The biological and technical validation of the proposed %MM cancer imaging biomarker suggests it correlates with, but overestimates, the percentage of necrosis.
    • Use of antidepressants and risk of cutaneous melanoma: a prospective registry-based case-control study

      Berge, LAM; Andreassen, BK; Stenehjem, JS; Heir, T; Furu, K; Juzeniene, A; Roscher, I; Larsen, IK; Green, Adèle C; Veierod, MB; et al. (2020)
      PURPOSE: Melanoma is the cancer with the most rapidly rising incidence rate in Norway. Although exposure to ultraviolet radiation (UVR) is the major environmental risk factor, other factors may also contribute. Antidepressants have cancer inhibiting and promoting side effects, and their prescription rates have increased in parallel with melanoma incidence. Thus, we aimed to prospectively examine the association between use of antidepressants and melanoma by using nation-wide data from the Cancer Registry of Norway, the National Registry, the Norwegian Prescription Database and the Medical Birth Registry of Norway. PATIENT AND METHODS: All cases aged 18-85 with a primary cutaneous invasive melanoma diagnosed during 2007-2015 (n=12,099) were matched to population controls 1:10 (n=118,467) by sex and year of birth using risk-set sampling. We obtained information on prescribed antidepressants and other potentially confounding drug use (2004-2015). Conditional logistic regression was used to estimate adjusted rate ratios (RRs) and 95% confidence intervals (CIs) for the association between overall and class-specific use of antidepressants and incident melanoma. RESULTS: Compared with ≤1 prescription, ≥8 prescriptions of antidepressants overall were negatively associated with melanoma (RR 0.81 CI 0.75-0.87). Class-specific analyses showed decreased RRs for selective serotonin reuptake inhibitors (RR 0.82 CI 0.73-0.93) and mixed antidepressants (RR 0.77 CI 0.69-0.86). The negative association was found for both sexes, age ≥50 years, residential regions with medium and highest ambient UVR exposure, all histological subtypes, trunk, upper and lower limb sites and local disease. CONCLUSION: Use of antidepressants was associated with decreased risk of melanoma. There are at least two possible explanations for our results; cancer-inhibiting actions induced by the drug and less UVR exposure among the most frequent users of antidepressants.
    • Prevention versus early detection for long-term control of melanoma and keratinocyte carcinomas: a cost-effectiveness modelling study

      Gordon, L; Olsen, C; Whiteman, DC; Elliott, TM; Janda, M; Green, Adèle C; Department of Population Health, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia (2020)
      OBJECTIVE: To compare the long-term economic impact of melanoma prevention by sun protection, with the corresponding impact of early detection of melanoma to decrease melanoma deaths. DESIGN: Cost-effectiveness analysis using Markov cohort model. Data were primarily from two population-based randomised controlled trials, epidemiological and costing reports, and included flow-on effects for keratinocyte cancers (previously non-melanoma skin cancers) and actinic keratoses. SETTING: Queensland, Australia. PARTICIPANTS: Men and women with a mean age 50 years modelled for 30 years. INTERVENTIONS: Daily sunscreen use (prevention) compared with annual clinical skin examinations (early detection) and comparing these in turn with the status quo. PRIMARY AND SECONDARY OUTCOMES: Costs, counts of melanoma, melanoma deaths, keratinocyte cancers, life years and quality-adjusted life years. RESULTS: Per 100 000 individuals, for early detection, primary prevention and without intervention, there were 2446, 1364 and 2419 new melanomas, 556, 341 and 567 melanoma deaths, 64 452, 47 682 and 64 659 keratinocyte cancers and £493.5, £386.4 and £406.1 million in economic costs, respectively. There were small differences between prevention and early detection in life years saved (0.09%) and quality-adjusted life years gained (0.10%). CONCLUSIONS: Compared with early detection of melanoma, systematic sunscreen use at a population level will prevent substantial numbers of new skin tumours, melanoma deaths and save healthcare costs. Primary prevention through daily use of sunscreen is a priority for investment in the control of melanoma.
    • Cooperative behaviour and phenotype plasticity evolve during melanoma progression

      Rowling, E; Miskolczi, Z; Nagaraju, R; Wilcock, DJ; Wang, P; Telfer, B; Li, Y; Lasheras-Otero, I; Redondo-Munoz, M; Sharrocks, AD; et al. (2020)
      A major challenge for managing melanoma is its tumour heterogeneity based on individual co-existing melanoma cell phenotypes. These phenotypes display variable responses to standard therapies, and they drive individual steps of melanoma progression; hence, understanding their behaviour is imperative. Melanoma phenotypes are defined by distinct transcriptional states, which relate to different melanocyte lineage development phases, ranging from a mesenchymal, neural crest-like to a proliferative, melanocytic phenotype. It is thought that adaptive phenotype plasticity based on transcriptional reprogramming drives melanoma progression, but at which stage individual phenotypes dominate and moreover, how they interact is poorly understood. We monitored melanocytic and mesenchymal phenotypes throughout melanoma progression and detected transcriptional reprogramming at different stages, with a gain in mesenchymal traits in circulating melanoma cells (CTCs) and proliferative features in metastatic tumours. Intriguingly, we found that distinct phenotype populations interact in a cooperative manner, which generates tumours of greater "fitness," supports CTCs and expands organotropic cues in metastases. Fibronectin, expressed in mesenchymal cells, acts as key player in cooperativity and promotes survival of melanocytic cells. Our data reveal an important role for inter-phenotype communications at various stages of disease progression, suggesting these communications could act as therapeutic target.
    • Long-term deaths from melanoma according to tumor thickness at diagnosis

      Baade, PD; Whiteman, DC; Janda, M; Cust, AE; Neale, RE; Smithers, BM; Green, Adèle C; Khosrotehrani, K; Mar, V; Soyer, HP; et al. (2020)
      There is little long-term follow-up information about how the number of melanoma deaths and case fatality vary over time according to the measured thickness of melanoma at diagnosis. This population-based longitudinal cohort study examines patterns and trends in case fatality among 44,531 people in Queensland (Australia) diagnosed with a single invasive melanoma (International Classification of Diseases for Oncology, third revision [ICD-O-3], C44, Morphology 872-879) between 1987 and 2011, including 11,883 diagnosed between 1987 and 1996, with up to 20 years follow-up (to December 2016). The 20-year case fatality increased by thickness, with the percentage of melanoma deaths within 20 years of diagnosis being up to 4.8% for melanomas with measured thickness <0.80 mm, 10.6% for tumors 0.8 to <1.0 mm and generally more than 30% for melanomas measuring 3 mm and more. For melanomas <1.0 mm, most deaths occurred between 5 and 20 years after diagnosis, whereas for thicker melanomas the reverse was true with most deaths occurring within the first 5 years. Five-year case fatality decreased over successive calendar time periods for melanomas <1.0 mm, but not for melanomas ≥1.0 mm. These findings demonstrate that the time course for fatal melanomas varies markedly according to tumor thickness at diagnosis. Improved understanding of the patient factors and characteristics of melanomas, in addition to tumor thickness, which increase the likelihood of progression, is needed to guide clinical diagnosis, communication with patients and ongoing surveillance pathways of patients with potentially fatal lesions.
    • A randomized phase II study of nivolumab plus ipilimumab versus standard of care in previously untreated and advanced non-clear cell renal cell carcinoma (Suniforecast)

      Ahrens, M; Escudier, B; Boleti, E; Grimm, MO; Goupir, MG; Barthelemy, P; Gravis, G; Bedekes, J; Ivanyi, P; Panic, A; et al. (2020)
    • Conditioning attenuates kidney and heart injury in rats following transient suprarenal occlusion of the abdominal aorta

      Karageorgiadi, DM; Tsilimigras, DI; Selemenakis, P; Vlachou, V; de Lastic, AL; Rodi, M; Chatziathanasiou, D; Savvatakis, K; Antoniou, N; Deli, AC; et al. (2020)
    • Biological optimization for mediastinal lymphoma radiotherapy - a preliminary study

      Rechner, LA; Modiri, A; Stick, LB; Maraldo, MV; Aznar, Marianne Camille; Rice, SR; Sawant, A; Bentzen, SM; Vogelius, IR; Specht, L; et al. (2020)
    • A CINful way to overcome addiction: how chromosomal instability enables cancer to overcome its oncogene addiction

      Bronder, Daniel; Bakhoum, SF; Genetics Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD, USA. (2020)
    • Reprogramming of amino acid transporters induces Aspartate and Glutamate dependency and drives endocrine resistance in breast cancer

      Bacci, M; Lorito, N; Ippolito, L; Ramazzotti, M; Parri, M; Simoes, Bruno M; Martin, LA; Marangoni, E; Mazzone, M; Chiarugi, P; et al. (2020)
    • Exploiting the zebrafish to study lymphocyte infiltration in MYCN-driven neuroblastoma

      Qin, XD; Lam, A; Xhang, XK; Hurlstone, Adam; Feng, H; Departments of Pharmacology and Medicine, Section of Hematology and Medical Oncology, Cancer Research Center, Boston University School of Medicine, Boston, (2020)
    • The breast cancer trainees research collaborative group

      Copson, E; Cole, C; Kirwan, Cliona C; McIntosh, S; Palmieri, C; Rea, D; Cancer Sciences Academic Unit, University of Southampton, Somers Cancer Sciences Building, Southampton General Hospital, Southampton, (2020)
    • Substituting angiotensin-(1-7) to prevent lung damage in SARSCoV2 infection?

      Peiro, C; Moncada, Salvador; Department of Pharmacology, School of Medicine, Universidad Autonoma de Madrid, Madrid, Spain (2020)