/ METOXIA
Metastatic tumours facilitated by hypoxic tumour micro-environment
EU 7th Research Framework Programme
Grant Agreement No. HEALTH-F2-2009-222741 /

Use of Foreground and Dissemination Activities during Period 5: 1.2.2013 -31.7.2014

General comments concerning patenting related to METOXIA:

During the 3rd period an international patent application (PCT) was published which involves the work on the CAIX-inhibitors where we have a product patent filed and involves several partners. While 1/UIO, 2/MAASTRO, 8/UNIMAN, and 9/UNIFI are patent owners, also 3/UEDIN, 4/RUNMC, 6/AUH,AS, 18/IVSAS, 20/GROW-UM and 21/OU-Lyng are today participating in this development with models of specific value for this translational work. In addition 1/UIO has a patent on priming effects of low dose-rate radiation and the protective effect of this priming for development of resistance against certain toxic chemicals. It could well be that some partners have patented inventions during the 4th period which has not been managed through the management team of METOXIA, but in that case no financing have been used by our “Other” –post on the METOXIA budget.

Individual partner’s dissemination:

1/UIO:

  • 12th April 2013 METOXIA sub-group meeting on the theme “The Cyprotex data on PK and PD: How do we proceed with our biological testing to produce an optimal application to CR-UK.” in Munich, Germany. Speakers a) Erik O. Pettersen: Short summing up on history and aim of today’s meeting. b) Jørund Sollid: How should we best commercialize the METOXIA patent portfolio? Objective: To reach a conclusion regarding the further strategy for commercialization of our patented CAIX-inhibitor compounds. Target: Participants of the CAIXi-sub-group of METOXIA.
  • 18th – 20th April 2013.International meeting on carbonic anhydrases titelsed: "Frontiers In CA research : Dissemination activity of the EU project METOXIA” In Montecattini Terme, Italy. Speaker Erik O. Pettersen: METOXIA – a successful network; Perspectives of continuation in the Horizon 2020 program. Objective: To announce the possibility for new networks for continuation of the research performed during METOXIA. Target: International experts on Carbonic Anhydrases..
  • 20th September 2013 METOXIA sub-group meeting on the theme: “How to best commercialize the METOXIA CAIX patent portfolio”. Speakers a) Erik O. Pettersen: Short summing up on history and aim of today’s meeting. Also a brief summing up of data produced so far by Cyprotex Discovery Ltd on compounds DTC-24a, Xanti-15a, DH348, NKP60, DH307, DH338 and Acetazolamide. b) Jørund Sollied:Presentation of the ideas of Inven2 regarding further commercialization of CAIX-inhibitors for cancer treatment with focus on the road-map. Objective: To reach a conclusion regarding the further strategy for commercialization of our patented CAIX-inhibitor compounds. Target: Participants of the CAIXi-sub-group of METOXIA.
  • 3rd November 2013: METOXIA steering group meeting on the theme: “Points for the General Assembly for termination of METOXIA and decisions” in Nice, France. Speaker Erik O. Pettersen: Should we invite the METOXIA partners to co-author a final paper summing up the METOXIA achievements with participation of all groups?” Objective: To get back-up from WP-leaders for this suggestion at the GA-meeting. Target: Work Package leaders of METOXIA.
  • 4th-5th November 2013The 5th General Assembly Meeting of METOXIA in Nice, France. Speakers: a) Erik O. Pettersen: A short resume of to what extent METOXIA in its 4th (and partly its 5th) year reached its goals; planning round-up of the METOXIA project. b) Stine Christoffersen: Combined effect of cyclic hypoxia and ultra-low dose-rate low-LET radiation. Objective: To discuss last year progress of METOXIA and the finalization of the project. Target: All partners of METOXIA.
  • 4th-8th April 2014. The 33rd ESTRO conference, Vienna, Austria. Invited speaker: Eirik Malinen: ”Accounting for uncertainties in imaging and radiation delivery in dose painting trials.” Objective: To give an over-view over the hypoxia-regulatory field.Target:International research scientists within radiation oncology

Scientific articles with acknowledgement for METOXIA-support:

  • Edin NJ, Sandvik JA, Cheng C, Vollan HS, Reger K, Görlach A, Pettersen EO. The role of nitric oxide radicals in removal of hyper-radiosensitivity by priming irradiation. J Radiat Res 2013;54:1015-1028.
  • Larsen BE, Karlsen J, Pettersen EO, Sandvik JA, Melvik JE. Oxygen consumption in T-47D cells immobilized in alginate. Cell Prolif. 2013;46:469-481.
  • Kieninger J, Aravindalochanan K, Sandvik JA, Pettersen EO, Urban GA. Pericellular oxygen monitoring with integrated sensor chips for reproducible cell culture experiments. Cell Prolif 2014; 47:180-188.
  • Edin NJ, Sandvik JA, Cheng C, Bergersen L, Pettersen EO. The roles of TGF-β3 and peroxynitrite in removal of hyper-radiosensitivity by priming irradiation. Int J. Radiat Biol. 2014; 90;527-537.

PhD thesis:

  • Lars Tore Gyland Mikalsen: “Solid Tumour vascular Quantification: A Histopathology Study of Tumour Endothelium”. Faculty of Mathematics and Natural Sciences, The University of Oslo, Oslo, Norway, March 2014.

2/MAASTRO

  • 12th April 2013 METOXIA sub-group meeting on the theme “The Cyprotex data on PK and PD: How do we proceed with our biological testing to produce an optimal application to CR-UK.” in Munich, Germany. Speaker Philippe Lambin: Tumour models for preclinical effect-studies and eventual imaging. Objective: To reach a conclusion regarding the further strategy for commercialization of our patented CAIX-inhibitor compounds. Target: Participants of the CAIXi-sub-group of METOXIA.
  • 8th June 2013. International oxygen conference in Oulu, Finland. Speaker Sarah Peeters.
  • 20th September 2013 METOXIA sub-group meeting on the theme: “How to best commercialize the METOXIA CAIX patent portfolio”. Speaker Nicolas Geûens:History and road ahead for DualTpharma. Objective: To reach a conclusion regarding the further strategy for commercialization of our patented CAIX-inhibitor compounds. Target: Participants of the CAIXi-sub-group of METOXIA.
  • 4th-5th November 2013The 5th General Assembly Meeting of METOXIA in Nice, France. Speaker: Philippe Lambin: Hypoxia-related clinical trials: New imaging biomarkers and new therapeutic interventions. Objective: To discuss last year progress of METOXIA and the finalization of the project. Target: All partners of METOXIA.
  • 4th-8th April 2014. The 33rd ESTRO conference, Vienna, Austria. Invited speakers: a) Philippe Lambin: “Immunocytokines and radiotherapy: preclinical experience.” b) Philippe lambin: “Multi-factorial decision support systems.” Objective: To give an over-view over the hypoxia-regulatory field.Target:International research scientists within radiation oncology

Scientific articles with acknowledgement for EUROXY/METOXIA-support:

  • Lambin P, van Stiphout RG, Starmans MH, Rios-Velazquez E, Nalbantov G, Aerts HJ, Roelofs E, van Elmpt W, Boutros PC, Granone P, Valentini V, Begg AC, De Ruysscher D, Dekker A. Predicting outcomes in radiation oncology--multifactorial decision support systems. Nat Rev Clin Oncol. 2013;10;27-40.
  • Roelofs E, Persoon L, Nijsten S, Wiessler W, Dekker A, Lambin P. Benefits of a clinical data warehouse with data mining tools to collect data for a radiotherapy trial. Radiother Oncol. 2013;108;174-179.
  • Dubois L, Peeters SG, van Kuijk SJ, Yaromina A, Lieuwes NG, Saraya R, Biemans R, Rami M, Parvathaneni NK, Vullo D, Vooijs M, Supuran CT, Winum JY, Lambin P. Targeting carbonic anhydrase IX by nitroimidazole based sulfamides enhances the therapeutic effect of tumor irradiation: a new concept of dual targeting drugs. Radiother Oncol 2013;108;523-538.
  • Buijsen J, Lammering G, Jansen RL, Beets GL, Wals J, Sosef M, Den Boer MO, Leijtens J, Riedl RG, Theys J, Lambin P. Phase I trial of the combination of the Akt inhibitor nelfinavir and chemoradiation for locally advanced rectal cancer. Radiother Oncol. 2013;107;184-188.
  • Rami M, Dubois L, Parvathaneni NK, Alterio V, van Kuijk SJ, Monti SM, Lambin P, De Simone G, Supuran CT, Winum JY. Hypoxia-targeting carbonic anhydrase IX inhibitors by a new series of nitroimidazole-sulfonamides/sulfamides/sulfamates. J Med Chem 2013;56;8512-8520.
  • Rouschop KM1, Dubois LJ, Keulers TG, van den Beucken T, Lambin P, Bussink J, van der Kogel AJ, Koritzinsky M, Wouters BG. PERK/eIF2α signaling protects therapy resistant hypoxic cells through induction of glutathione synthesis and protection against ROS. Proc Natl Acad Sci U S A. 2013;110;4622-4627.
  • van Elmpt W, Das M, Hüllner M, Sharifi H, Zegers CM, Reymen B, Lambin P, Wildberger JE, Troost EG, Veit-Haibach P, De Ruysscher D. Characterization of tumor heterogeneity using dynamic contrast enhanced CT and FDG-PET in non-small cell lung cancer. Radiother Oncol. 2013;109;65-70.
  • Leijenaar RT, Carvalho S, Velazquez ER, van Elmpt WJ, Parmar C, Hoekstra OS, Hoekstra CJ, Boellaard R, Dekker AL, Gillies RJ, Aerts HJ, Lambin P. Stability of FDG-PET Radiomics features: an integrated analysis of test-retest and inter-observer variability. Acta Oncol. 2013;52;1391-1397.
  • Carvalho S, Leijenaar RT, Velazquez ER, Oberije C, Parmar C, van Elmpt W, Reymen B, Troost EG, Oellers M, Dekker A, Gillies R, Aerts HJ, Lambin P. Prognostic value of metabolic metrics extracted from baseline positron emission tomography images in non-small cell lung cancer. Acta Oncol. 2013;52;1398-1404.
  • Nalbantov G, Kietselaer B, Vandecasteele K, Oberije C, Berbee M, Troost E, Dingemans AM, van Baardwijk A, Smits K, Dekker A, Bussink J, De Ruysscher D, Lievens Y, Lambin P. Cardiac comorbidity is an independent risk factor for radiation-induced lung toxicity in lung cancer patients. Radiother Oncol. 2013;109;100-106.
  • Zegers CM, van Elmpt W, Wierts R, Reymen B, Sharifi H, Öllers MC, Hoebers F, Troost EG, Wanders R, van Baardwijk A, Brans B, Eriksson J, Windhorst B, Mottaghy FM, De Ruysscher D, Lambin P. Hypoxia imaging with [¹⁸F]HX4 PET in NSCLC patients: defining optimal imaging parameters. Radiother Oncol. 2013;109;58-64.
  • Lambin P, Roelofs E, Reymen B, Velazquez ER, Buijsen J, Zegers CM, Carvalho S, Leijenaar RT, Nalbantov G, Oberije C, Scott Marshall M, Hoebers F, Troost EG, van Stiphout RG, van Elmpt W, van der Weijden T, Boersma L, Valentini V, Dekker A. 'Rapid Learning health care in oncology' - an approach towards decision support systems enabling customised radiotherapy'. Radiother Oncol. 2013;109;159-64.
  • Velazquez ER, Parmar C, Jermoumi M, Mak RH, van Baardwijk A, Fennessy FM, Lewis JH, De Ruysscher D, Kikinis R, Lambin P, Aerts HJ. Volumetric CT-based segmentation of NSCLC using 3D-Slicer. Sci Rep. 2013 Dec 18;3:3529. doi: 10.1038/srep03529.
  • Roelofs E, Dekker A, Meldolesi E, van Stiphout RG, Valentini V, Lambin P. International data-sharing for radiotherapy research: an open-source based infrastructure for multicentric clinical data mining. Radiother Oncol. 2014;110;370-374.
  • Hoeben BA, Starmans MH, Leijenaar RT, Dubois LJ, van der Kogel AJ, Kaanders JH, Boutros PC, Lambin P, Bussink J. Systematic analysis of 18F-FDG PET and metabolism, proliferation and hypoxia markers for classification of head and neck tumors. BMC Cancer 2014 Feb 26;14:130. doi: 10.1186/1471-2407-14-130
  • Fox NS, Starmans MH, Haider S, Lambin P, Boutros PC. Ensemble analyses improve signatures of tumour hypoxia and reveal inter-platform differences.BMC Bioinformatics. 2014 Jun 6;15:170. doi: 10.1186/1471-2105-15-170.
  • Parmar C, Rios Velazquez E, Leijenaar R, Jermoumi M, Carvalho S, Mak RH, Mitra S, Shankar BU, Kikinis R, Haibe-Kains B, Lambin P, Aerts HJ. Robust Radiomics feature quantification using semiautomatic volumetric segmentation. PLoS One. 2014 Jul 15;9(7):e102107. doi: 10.1371/journal.pone.0102107. eCollection 2014.
  • Aerts HJ, Velazquez ER, Leijenaar RT, Parmar C, Grossmann P, Cavalho S, Bussink J, Monshouwer R, Haibe-Kains B, Rietveld D, Hoebers F, Rietbergen MM, Leemans CR, Dekker A, Quackenbush J, Gillies RJ, Lambin P.Decoding tumour phenotype by noninvasive imaging using a quantitative radiomics approach. Nat Commun. 2014 Jun 3;5:4006. doi: 10.1038/ncomms5006.
  • Buijsen J, van Stiphout RG, Menheere PP, Lammering G, Lambin P. Blood biomarkers are helpful in the prediction of response to chemoradiation in rectal cancer: a prospective, hypothesis driven study on patients with locally advanced rectal cancer. Radiother Oncol. 2014;111;237-242.

3/UEDIN:

  • 12th April 2013 METOXIA sub-group meeting on the theme “The Cyprotex data on PK and PD: How do we proceed with our biological testing to produce an optimal application to CR-UK.” in Munich, Germany. Speaker Simon Langdon: Novel CAIX inhibitors in preclinical breast cancer models (S4, FC9-403, FC9-398, FC9-396). Objective: To reach a conclusion regarding the further strategy for commercialization of our patented CAIX-inhibitor compounds. Target: Participants of the CAIXi-sub-group of METOXIA.
  • 18th-21st June 2013. Pathology Society Meeting, Edinburgh, UK. Speakers Carol Ward:An Ex-Vivo Tumour Model Using Core Biopsy Explants Validate Carbonic Anhydrase IX (CAIX) as a Therapeutic Target in Breast Cancer. James Meehan: A Comparison of the Effects of Novel Carbonic Anhydrase Inhibitors on the Growth and Invasion of Breast and Ovarian Cancer Cells. Objective: To focus attention to the newly developed biological models.Target: pathology experts
  • September 2013. Edinburgh Radiation Research Meeting, Edinburgh, UK. Speakers: Simon Langdon and carol Ward: Targeting the Hypoxic Microenvironment with CAIX inhibitors. Objective: To focus attention to the hypoxic micro-environment. Target: Radiotherapy and radiobiology experts.
  • October 2013. Scottish Radiotherapy Research Forum Meeting in Stirling University, UK. Speaker: Simon Langdon: Targeting the Hypoxic Microenvironment. Objective: To focus attention to the hypoxic micro-environment. Target: Radiotherapy experts.
  • 4th October 2013. Perth Radiation Oncology, Perth, Australia. Speaker: Ian Kunkler: Biologically adapted radiotherapy for breast cancer. Objective: To focus attention to the hypoxic micro-environment. Target: Radiotherapy experts.
  • 10th October 2013. Royal Park Hotel, Sydney, AustraliaSpeaker: Ian Kunkler: Biologically adapted radiotherapy for breast cancer. Objective: To focus attention to the hypoxic micro-environment. Target: Radiotherapy experts.
  • 14th October 2013. Radiation Oncology, Mater Centre, Brisbane, AustraliaSpeaker: Ian Kunkler: Biologically adapted radiotherapy for breast cancer. Objective: To focus attention to the hypoxic micro-environment. Target: Radiotherapy experts.
  • 17th -20th October 2013. 64th RANZCR Annual Scientific Meeting Auckland, New Zealand Speaker: Ian Kunkler: . Diagnostic and therapeutic radiology in treatment planning: marriage, divorce and second marriage. Objective: To focus attention to the hypoxic micro-environment. Target: Radiotherapy experts.
  • 4th-5th November 2013The 5th General Assembly Meeting of METOXIA in Nice, France. Speaker: Carol Ward: CA9 inhibitors and radiation: A pre-clinical study using a breast tumour explant model. Objective: To discuss last year progress of METOXIA and the finalization of the project. Target: All partners of METOXIA.
  • 20th -22nd February 2014. Kyoto Breast Cancer Consensus Conference, Kyoto, Japan. Speaker Ian Kunkler: Towards the personalisation of radiotherapy for breast cancer. Objective: To focus attention to the need for personalized treatment. Target: Oncologists.

Scientific articles with acknowledgement for METOXIA-support:

  • Ward C, Langdon SP, Mullen P, Harris AL, Harrison DJ, Supuran CT, Kunkler IH. New strategies for targeting the hypoxic tumour microenvironment in breast cancer. Cancer Treat Rev 2013. 39: 171 – 179
  • Ward, C., Meehan, J., Harrison, D. J., Kunkler, I. H. & Langdon, S. P.An Ex-Vivo Tumour Model Using Core Biopsy Explants Validate Carbonic Anhydrase IX (CAIX) as a Therapeutic Target in Breast Cancer. J. pathol 2013; 231:24
  • Meehan, J., Ward, C., Supuran, C., Langdon, S. P. & Kunkler, I. The Effects of Novel Carbonic Anhydrase Inhibitors on the Proliferation and Invasion of Breast and Ovarian Cancer Cells. J. Pahol. 2013; 231;36
  • Ward C, James Meehan, Peter Mullen, Claudiu Supuran, J Michael Dixon, Jeremy S Thomas, Jean-Yves Winum Philippe Lambin, Ludwig Dubois, Nanda-Kumar Pavathaneni, Edward J Jarman, Lorna Renshaw, InHwa Um, Charlene Kay, Ian H Kunkler, David J Harrison, Simon P Langdon. Evaluation of Carbonic Anhydrase IX as a Therapeutic Target for Inhibition of Breast Cancer Invasion and Metastasis Using a Series of in vitro Breast Cancer Models. Clin Cancer Res (submitted).

4/RUNMC:

  • 19th-23rd April 2013. European Society for Therapeutic Radiology and Oncology Annual Meeting (ESTRO-Forum), Geneva, Switzerland. Speaker Hans Kaanders.
  • 10th-13th June 2013. Biological Image Guided Adaptive Radiotherapy Scientific Meeting, Aarhus, Denmark. Speaker Hans Kaanders.
  • 4th-5th November 2013The 5th General Assembly Meeting of METOXIA in Nice, France. Speaker: Johannes HAM Kaanders: Early radiotherapy-induced changes in head and neck cancers. (Hans Kaanders got ill and could not present his paper, but submitted conclusions to be included in the meeting report). Objective: To discuss last year progress of METOXIA and the finalization of the project. Target: All partners of METOXIA.
  • 4th-8th April 2014. 33rdEuropean Society for Therapeutic Radiology and Oncology (ESTRO) Annual Meeting, Vienna Austria. Speaker Jan Bussink: Is hypoxia an immunological niche? Bussink Objective: To give an over-view over the hypoxia-regulatory field.Target:International research scientists within radiation oncology.

Scientific articles with acknowledgement for METOXIA-support:

  • Rademakers SE, Hoogsteen IJ, Rijken PF, Terhaard CH, Doornaert PA, Langendijk JA, van den Ende P, van der Kogel AJ, Bussink J, Kaanders JH. Prognostic value of the proliferation marker Ki-67 in laryngeal carcinoma: Results of the Accelerated Radiotherapy with Carbogen Breathing and Nicotinamide phase III randomized trial. Head Neck. 2013 Dec 17. doi: 10.1002/hed.23569. [Epub ahead of print]
  • Rademakers SE, Hoogsteen IJ, Rijken PF, Oosterwijk E, Terhaard CH, Doornaert PA, Langendijk JA, van den Ende P, Takes R, De Bree R, van der Kogel AJ, Bussink J, Kaanders JH. Pattern of CAIX expression is prognostic for outcome and predicts response to ARCON in patients with laryngeal cancer treated in a phase III randomized trial. Radiother Oncol. 2013;108;517-522.
  • Hypoxia, metabolism, and growth factor signaling in head and neck squamous cell carcinoma: Correlation between primary and xenograft tumors. Stegeman H, Rademakers SE, Span PN, Takes RP, van der Kogel AJ, Kaanders JH, Bussink J. Head Neck. 2014;36;1288-1295.
  • Meijer TW, Bussink J, Zatovicova M, Span PN, Lok J, Supuran CT, Kaanders JH. Tumor microenvironmental changes induced by the sulfamate carbonic anhydrase IX inhibitor S4 in a laryngeal tumor model. Submitted.

5/UOXF.BP:

  • 4th-5th November 2013The 5th General Assembly Meeting of METOXIA in Nice, France. Speaker: Dean Singleton: Hypoxic regulation of RIOK3 promotes cell invasion through remodelling of the actin cytoskeleton. Objective: To discuss last year progress of METOXIA and the finalization of the project. Target: All partners of METOXIA.

International scientific meetings with Adrian Harris as speaker:

Scientific articles with acknowledgement for METOXIA-support:

  • Eustace, A., Mani, N., Span, P.N., Irlam, J.J., Taylor, J., Betts, G.N., Denley, H., Miller, C.J., Homer, J.J., Rojas, A.M., Hoskin, P.J., Buffa, F.M., Harris, A.L., Kaanders, J.H., and West, C.M. A 26-Gene Hypoxia Signature Predicts Benefit from Hypoxia-Modifying Therapy in Laryngeal Cancer but Not Bladder Cancer. Clin Cancer Res2013;19;4879-4888.
  • Gieling, R.G., Parker, C.A., De Costa, L.A., Robertson, N., Harris, A.L., Stratford, I.J., and Williams, K.J. Inhibition of carbonic anhydrase activity modifies the toxicity of doxorubicin and melphalan in tumour cells in vitro. J Enzyme Inhib Med Chem 2013;28;360-369.
  • Kumar, K., Wigfield, S., Gee, H.E., Devlin, C.M., Singleton, D., Li, J.L., Buffa, F., Huffman, M., Sinn, A.L., Silver, J., Turley, H., Leek, R., Harris, A.L., and Ivan, M. Dichloroacetate reverses the hypoxic adaptation to bevacizumab and enhances its antitumor effects in mouse xenografts. J Mol Med (Berl) 2013;91;749-758.
  • Singleton, D.C., and Harris, A.L. Microenvironmental induced essentiality of autophagy. Clin Cancer Res2013;19;2791-2793.
  • Ward, C., Langdon, S.P., Mullen, P., Harris, A.L., Harrison, D.J., Supuran, C.T., and Kunkler, I.H. (2013). New strategies for targeting the hypoxic tumour microenvironment in breast cancer. Cancer Treat Rev 39, 171-179.
  • Gómez-Maldonado L, Tiana M1, Roche O, Prado-Cabrero A, Jensen L, Fernandez-Barral A, Guijarro-Muñoz I, Favaro E, Moreno-Bueno G, Sanz L4, Aragones J, Harris A, Volpert O, Jimenez B, Del Peso L. EFNA3 long noncoding RNAs induced by hypoxia promote metastatic dissemination. Oncogene. 2014 Jul 14;0. doi: 10.1038/onc.2014.200. [Epub ahead of print]
  • Singleton, DC, Rouhi, P, Haider, S, Li, JL, Kessler, B, Cao, Y, Harris, AL. Hypoxic regulation of RIOK3 is a major mechanism for cancer cell invasion and metastasis. (submitted).

6/AUH,AS: