- Email: [email protected]
75: Role of inflammation in epidermal carcinogenesis
EACR-23 Oral Presentations, Monday 7 July 2014 / European Journal of Cancer 50, Suppl. 5 (2014) S12–S20 high entropy, representative of a diffuse spatial pattern, of FOXP3+ and CD69+ positive T cells. Conclusion: In this study we report that higher Treg cell counts in a diffuse pattern was associated with favorable prognosis. This supports the importance of Tregs in the tumour microenvironment. It is pertinent to mention that contradictory findings are routinely reported from studies investigating the role of Tregs in solid and haematological malignancies. This is due to the complex interactions between pro-/anti-tumour immune factors present in the tumour microenvironment. The resultant effects are due to the summation of the activities of these factors. It is therefore even more relevant that a method such as exhibited here, capable of defining and measuring the effect on patient outcome of the spatial patterns of multiple cellular phenotypes in the tumor microenvironment is available. Conflict of interest: Other substantive relationships: PerkinElmer employees. 75 Role of inflammation in epidermal carcinogenesis F.M. Watt1 . 1 King’s College London, Centre for Stem Cells and Regenerative Medicine, London, United Kingdom Multilayered epithelia such as the epidermis and oral mucosa are maintained throughout adult life by self-renewal of stem cells and differentiation of their progeny. I will present evidence that both stem cells and differentiating cells can contribute to tumour development. I will describe how aberrant gene expression by differentiated cells can recruit stem cells, fibroblasts and cells of the bone marrow to collaborate to form tumours. No conflict of interest.
Monday 7 July 2014
14:00−15:45
Symposium
Imaging 76 Multiparametric imaging in cancer research ¨ A.K. Buck1 . 1 Nuklearmedizinische Klinik und Poliklinik, Universitatsklinikum Wurzburg, ¨ Germany Besides detection of cancer, staging, restaging and surveillance, modern imaging technologies play a pivotal role for the assessment of cancer therapies. Given the recent developments in magnetic resonance imaging and the multitude of molecular imaging probes becoming available, a wide range of image-derived parameters can be used for guiding the process of treatment individualization. It remains to be determined which parameter or which combination of parameters represents the most effective predictors of response and outcome in varying clinical scenarios. This presentation will highlight the most recent developments in anatomic, functional and molecular imaging (i.e., dual-source CT, multi-parametric MRI, PET, SPECT and fluorescence imaging devices). A particular focus is laid on established and more recent hybrid devices (PET/CT, SPECT/CT, and MR/PET). Based on the non-invasive identification of therapeutic targets, imaging contributes to the decision making process in individual cancer patients. When integrated early in the course of anticancer drug development, these technologies can also aid in selecting the most efficient compounds for evaluation in early clinical trials. Furthermore, with recent technologies, imaging of tumor heterogeneity becomes feasible, including hallmarks of cancer such as deregulated metabolism, hypoxia, receptor expression, proliferation and others. In the near future, multimodal or multiparametric imaging will become reality not only in early preclinical and clinical research but also in the clinical arena. No conflict of interest. 77 Molecular imaging for personalised treatment of cancer W.J.G. Oyen1 . 1 Radboud University Medical Center, Dept. of Radiology and Nuclear Medicine, Nijmegen, Netherlands Molecular imaging using radiolabeled agents for SPECT and especially PET has been evolving rapidly in the last decade. Especially the introduction of hybrid cameras, combining SPECT or PET with CT, has significantly increased the acceptance of these techniques in clinical practice and the use in research protocols. PET using the glucose-analogue FDG, reflecting tumor metabolism and its changes during therapy, has gained wide acceptance for staging, radiation treatment planning and therapy response monitoring. Beyond metabolic imaging, a large number of agents has been developed to depict features of tumors, such as tumor cell proliferation (FLT), hypoxia (e.g. FMISO, FAZA, ATSM), protein synthesis (e.g. FET) and angiogenesis (e.g. labeled bevacuzimab, RGD). These radiopharmaceuticals allow more specific assessment of tumor characteristics and of their changes early during local or systemic therapeutic interventions. This allows tailoring of therapy to the
S19
individual patient before or early after the start of treatment, before a reduction of tumor size becomes apparent on conventional anatomical imaging with CT or MRI. More recently, PET and SPECT imaging of receptor expression and modulation with radiolabeled antibodies and peptides has been introduced as a tool for noninvasive in-vivo assessment of receptor presence, accessibility and heterogeneity between lesions. A typical example is the development of Zr-89 labeled trastuzumab to assess expression of HER2-receptors in metastatic breast cancer. The principle of imaging radiolabeled anti-cancer drugs can also be applied for small molecules such as chemotherapeutics and targeted therapies with TKIs. When these drugs are amenable to labeling with e.g. C-11 it can be visualized whether these drugs actually reach the tumor and accumulate there. Examples are C-11 labeled docetaxel and C-11-lapatinib. In conclusion, the use of molecular imaging in clinical oncology, both for patient care as well as experimental applications opens new perspectives for more detailed assessment of tumor characteristics, paving the way for individualized treatment of cancer patients. New hybrid technology combining PET with MRI will further boost research to develop novel indications. No conflict of interest. 78 Proffered Paper: Dual wavelength near-infrared fluorescence imaging of VEGF and IGF-1R in ovarian cancer patient-derived xenografts T. Tomar1 , N.G. Alkema1 , A.G. Terwisscha van Scheltinga2 , J.A.L. Visser3 , G.J. Meersma1 , E.W. Duiker4 , E.G.E. De Vries3 , A.G.J. Van der Zee1 , G.B.A. Wisman1 , S. De Jong3 . 1 University Medical Center Groningen, Gynecologic Oncology, Groningen, Netherlands, 2 University Medical Center Groningen, Hospital and Clinical Pharmacy, Groningen, Netherlands, 3 University Medical Center Groningen, Medical Oncology, Groningen, Netherlands, 4 University Medical Center Groningen, Pathology and Medical Biology, Groningen, Netherlands Background: Treatment of ovarian cancer patients with personalized targeted therapies would benefit of upfront selection of patients based on the expression of targets within the tumor, like growth factors or growth factors receptor; and early monitoring of tumor responses. Multiple wavelength fluorescent molecular imaging allows assessment of the targeted proteins and therapeutic response at the same time. The aim of our study was to test feasibility and application of dual wavelength near-infrared fluorescence (NIRF) molecular imaging in patient-derived xenograft (PDX) model of mice. We focused on imaging of the secreted vascular endothelial growth factor (VEGF) and the membrane-bound insulin-like growth factor 1 receptor (IGF-1R), both known targets of therapy, in multiple ovarian cancer PDX model. Methods: Monoclonal antibody bevacizumab (anti-VEGF-A) and MAB391 (anti-IGF-1R) were coupled to NIRF dyes IRDye-800CW and IRDye-680RD, respectively. After in-vitro evaluation of fluorescence tracers, specific tumor uptake was determined in a panel of ovarian cancer PDX models in NOD SCID gamma (NSG) mice (n = 10 patients) during 1 week after tracer injection, followed by ex-vivo fluorescence microscopy and pathologic examination. Imaging results were compared with histology and immunostaining of VEGF and IGF-1R on PDX and matched patient tissue. Results: We detected the different fluorescence signals separately of both VEGF (bevacizumab-800CW) and IGF-1R (MAB391–680RD) tracers within the same PDX model simultaneously, which were co-localized with immunostaining. We found background corrected maximum average radiance of 2.53–23.3×106 p/s/cm2 /sr for bevacizumab-800CW and 1.5– 15.5×107 p/s/cm2 /sr for MAB391–680RD. Bevacizumab-800CW NIRF signal intensity was maximal after 24 h and rapidly decreased. MAB391–680RD showed longer residence lifetime in tumors with a constant NIRF signal intensity for 6 days. These results were consistent over all PDXs, except for one. This last PDX showed NIRF signal for bevacizumab800CW but not for MAB391–680RD, which was related to the negative immunohistochemical IGF-1R staining. All results were supported by standard histology, immunohistochemistry, and fluorescence microscopy analysis of tumors derived from PDXs as well as from corresponding patients. Conclusion: These findings encourage future preclinical applications of PDX as reliable cancer models for development of novel cancer therapeutic targets and their validation using molecular optical imaging. This study is supported by the Dutch Cancer Society, KWF Kankerbestrijding (grants RUG 2010-4833 & RUG 2011-5231). No conflict of interest. 79 Imaging as tool for translational research in oncology M. Schwaiger1 . 1 Klinikum rechts der Isar, Nuklearmedizinische Klinik und Poliklinik, Munich, Germany With the advent of multimodality imaging biological information can be visualized in-vivo with high spatial as well as temporal resolution. The excellent structural information obtained by modern CT and MRI instrumentation
Monday 7 July 2014
14:00−15:45
Symposium
Imaging 76 Multiparametric imaging in cancer research ¨ A.K. Buck1 . 1 Nuklearmedizinische Klinik und Poliklinik, Universitatsklinikum Wurzburg, ¨ Germany Besides detection of cancer, staging, restaging and surveillance, modern imaging technologies play a pivotal role for the assessment of cancer therapies. Given the recent developments in magnetic resonance imaging and the multitude of molecular imaging probes becoming available, a wide range of image-derived parameters can be used for guiding the process of treatment individualization. It remains to be determined which parameter or which combination of parameters represents the most effective predictors of response and outcome in varying clinical scenarios. This presentation will highlight the most recent developments in anatomic, functional and molecular imaging (i.e., dual-source CT, multi-parametric MRI, PET, SPECT and fluorescence imaging devices). A particular focus is laid on established and more recent hybrid devices (PET/CT, SPECT/CT, and MR/PET). Based on the non-invasive identification of therapeutic targets, imaging contributes to the decision making process in individual cancer patients. When integrated early in the course of anticancer drug development, these technologies can also aid in selecting the most efficient compounds for evaluation in early clinical trials. Furthermore, with recent technologies, imaging of tumor heterogeneity becomes feasible, including hallmarks of cancer such as deregulated metabolism, hypoxia, receptor expression, proliferation and others. In the near future, multimodal or multiparametric imaging will become reality not only in early preclinical and clinical research but also in the clinical arena. No conflict of interest. 77 Molecular imaging for personalised treatment of cancer W.J.G. Oyen1 . 1 Radboud University Medical Center, Dept. of Radiology and Nuclear Medicine, Nijmegen, Netherlands Molecular imaging using radiolabeled agents for SPECT and especially PET has been evolving rapidly in the last decade. Especially the introduction of hybrid cameras, combining SPECT or PET with CT, has significantly increased the acceptance of these techniques in clinical practice and the use in research protocols. PET using the glucose-analogue FDG, reflecting tumor metabolism and its changes during therapy, has gained wide acceptance for staging, radiation treatment planning and therapy response monitoring. Beyond metabolic imaging, a large number of agents has been developed to depict features of tumors, such as tumor cell proliferation (FLT), hypoxia (e.g. FMISO, FAZA, ATSM), protein synthesis (e.g. FET) and angiogenesis (e.g. labeled bevacuzimab, RGD). These radiopharmaceuticals allow more specific assessment of tumor characteristics and of their changes early during local or systemic therapeutic interventions. This allows tailoring of therapy to the
S19
individual patient before or early after the start of treatment, before a reduction of tumor size becomes apparent on conventional anatomical imaging with CT or MRI. More recently, PET and SPECT imaging of receptor expression and modulation with radiolabeled antibodies and peptides has been introduced as a tool for noninvasive in-vivo assessment of receptor presence, accessibility and heterogeneity between lesions. A typical example is the development of Zr-89 labeled trastuzumab to assess expression of HER2-receptors in metastatic breast cancer. The principle of imaging radiolabeled anti-cancer drugs can also be applied for small molecules such as chemotherapeutics and targeted therapies with TKIs. When these drugs are amenable to labeling with e.g. C-11 it can be visualized whether these drugs actually reach the tumor and accumulate there. Examples are C-11 labeled docetaxel and C-11-lapatinib. In conclusion, the use of molecular imaging in clinical oncology, both for patient care as well as experimental applications opens new perspectives for more detailed assessment of tumor characteristics, paving the way for individualized treatment of cancer patients. New hybrid technology combining PET with MRI will further boost research to develop novel indications. No conflict of interest. 78 Proffered Paper: Dual wavelength near-infrared fluorescence imaging of VEGF and IGF-1R in ovarian cancer patient-derived xenografts T. Tomar1 , N.G. Alkema1 , A.G. Terwisscha van Scheltinga2 , J.A.L. Visser3 , G.J. Meersma1 , E.W. Duiker4 , E.G.E. De Vries3 , A.G.J. Van der Zee1 , G.B.A. Wisman1 , S. De Jong3 . 1 University Medical Center Groningen, Gynecologic Oncology, Groningen, Netherlands, 2 University Medical Center Groningen, Hospital and Clinical Pharmacy, Groningen, Netherlands, 3 University Medical Center Groningen, Medical Oncology, Groningen, Netherlands, 4 University Medical Center Groningen, Pathology and Medical Biology, Groningen, Netherlands Background: Treatment of ovarian cancer patients with personalized targeted therapies would benefit of upfront selection of patients based on the expression of targets within the tumor, like growth factors or growth factors receptor; and early monitoring of tumor responses. Multiple wavelength fluorescent molecular imaging allows assessment of the targeted proteins and therapeutic response at the same time. The aim of our study was to test feasibility and application of dual wavelength near-infrared fluorescence (NIRF) molecular imaging in patient-derived xenograft (PDX) model of mice. We focused on imaging of the secreted vascular endothelial growth factor (VEGF) and the membrane-bound insulin-like growth factor 1 receptor (IGF-1R), both known targets of therapy, in multiple ovarian cancer PDX model. Methods: Monoclonal antibody bevacizumab (anti-VEGF-A) and MAB391 (anti-IGF-1R) were coupled to NIRF dyes IRDye-800CW and IRDye-680RD, respectively. After in-vitro evaluation of fluorescence tracers, specific tumor uptake was determined in a panel of ovarian cancer PDX models in NOD SCID gamma (NSG) mice (n = 10 patients) during 1 week after tracer injection, followed by ex-vivo fluorescence microscopy and pathologic examination. Imaging results were compared with histology and immunostaining of VEGF and IGF-1R on PDX and matched patient tissue. Results: We detected the different fluorescence signals separately of both VEGF (bevacizumab-800CW) and IGF-1R (MAB391–680RD) tracers within the same PDX model simultaneously, which were co-localized with immunostaining. We found background corrected maximum average radiance of 2.53–23.3×106 p/s/cm2 /sr for bevacizumab-800CW and 1.5– 15.5×107 p/s/cm2 /sr for MAB391–680RD. Bevacizumab-800CW NIRF signal intensity was maximal after 24 h and rapidly decreased. MAB391–680RD showed longer residence lifetime in tumors with a constant NIRF signal intensity for 6 days. These results were consistent over all PDXs, except for one. This last PDX showed NIRF signal for bevacizumab800CW but not for MAB391–680RD, which was related to the negative immunohistochemical IGF-1R staining. All results were supported by standard histology, immunohistochemistry, and fluorescence microscopy analysis of tumors derived from PDXs as well as from corresponding patients. Conclusion: These findings encourage future preclinical applications of PDX as reliable cancer models for development of novel cancer therapeutic targets and their validation using molecular optical imaging. This study is supported by the Dutch Cancer Society, KWF Kankerbestrijding (grants RUG 2010-4833 & RUG 2011-5231). No conflict of interest. 79 Imaging as tool for translational research in oncology M. Schwaiger1 . 1 Klinikum rechts der Isar, Nuklearmedizinische Klinik und Poliklinik, Munich, Germany With the advent of multimodality imaging biological information can be visualized in-vivo with high spatial as well as temporal resolution. The excellent structural information obtained by modern CT and MRI instrumentation