In vivo optical imaging of cancer
Project no. 911388 outlined 3 major aims to be addressed; Development of novel optical reporter systems, implementation of these reporters and probes in optical imaging of cancer and in translational therapeutic imaging. Results are very encouraging with publications resulting in prestigious journals. Gjerdrum et al. (2010) employed the use of novel imaging the impact of shRNA knockdown in vivo, while novel time-domain technique was described to image fluorescent reporters in vivo (Rosland et al. 2009, Torsvik et al. 2009). Combination of novel imaging strategy and near-infrared labeled mAbs and dextrans permitted visualization of drug uptake (McCormack et al. 2009), while Wang et al. (2010), Karlsen et. al. (2012) and 2 further manuscripts (McCormack et al. Submitted 2011/2) detail novel imaging strategies and reporters for in vivo imaging of patient xenografts. Translational application of cancer models and imaging are detailed in Erikstein et al. (2010), McCormack et al. (2010), and in particular Gausdal et al. (2008) and McCormack et al. (2011) demonstrated combinational therapies for acute leukaemia through an array of animal models and imaging, providing the preclinical basis for further translational development. McCormack and group members have also won prizes at the research school of clinical medicine in 2007-09 (3rd, 1st and 2nd) and scholarships to the world molecular imaging conference (2008 and 2010). McCormack also won the prestigious BFS in 2009.
Throughout this project we have focussed on the development of preclinical imaging methods in cancer and development of therapeutics. Thus, the translational nature of the project will have important implications on future therapies for clinical development. Gausdal et al. (Blood 2008), Gjerdrum et al. (PNAS 2010) and McCormack et al (Leukemia 2011) all outline the preclinical development of novel therapeutic strategies, otherwise impossible without the developments generated by this project. In particular the work described in Gjerdrum et al., a paper relying heavily upon optical imaging strategies developed in this project, has resulted recent funding for the clinical development of an Axl kinase inhibitor by the Bergen company BerGenBio. Furthermore, McCormack et al. describes a novel combinational therapy (Valproic acid and Nutlin-3a) evaluated through preclinical imaging of novel mouse xenografts with wt p53. The results from this paper have direct clinical implications and may result in future clinical trialling of these drugs in elderly AML.
Development of a number of further preclinical imaging strategies continues as an evolution to this project and further publications involving a novel reporter gene (McCormack et al. Submitted 2011) and imaging of patient derived xenografts (McCormack et al. Submitted 2012) are anticipated early 2012. In conclusion, results derived from this project are anticipated to speed translation of new therapeutics to the clinic.
In vivo Optical Imaging of Cancer
Advances in geno- and proteomic methods have identified differentially expressed proteins and genes unearthing many new targets in a wide variety of cancers. However, the methods employed to authenticate these targets in vivo tend to be protracted with validation and preclinical testing remaining the rate-limiting step in clinical translation.
There is a essential need for integrated approaches combining state-of-the-art methodologies in proteomics and preclinical in vivo imaging to accelerate validation of nanomedicines, drugs, imaging agents and gene vectors. Employing of time-domain optical imaging and quantification of fluorescently labelled dextrans and targeted monoclonal antibodies, McCormack/Hoffmann et al. demonstrated a novel concept of increased therapeutic delivery of macromolecules to preclinical models of cancer exhibiting high tumour interstitial fluid pressure. Demonstration and qualification of the in vivo results through optical imaging was a key asset of this paper and methodology. Optical imaging of GFP expressing transformed mesenchymal cells (TMC) and time-domain gating of this fluorescence from endogeneous autofluorescence was critical to demonstrating that these cells can engraft and develop xenografted tumours in this important Cancer Research article (see Røsland et al). Furthermore, the importance of Axl in the development of metastatic breast cancer was firmly established through innovative optical imaging of Axl knockdown in preclinical models of metastatic disease, the results of which have been accepted for publication in PNAS (see Gjerdrum C et al). Use of imaging technology and development of relevant animal models of cancer were used to illustrate the synergy of PKA activators and TTA in vivo (Eriskstein et al) and the safety of the immunomodulating agent lentinan in an aggressive model of AML (McCormack et al). Further work continues on the development of novel imaging strategies and reporters, particularly in the development of a novel NIR reporter system and in p53 targeted drug therapy.
Through force majeure, the remaining 1-year of guaranteed funding for this project was not applied for in 2009 for 2010. Instead the remaining 1-years granted funding will be applied for in 2010 for 2011.
In vivo imaging of cancer
Novel advances in imaging of molecules, particularly optical technologies, are being used more progressively to understand the intricacy and in vivo behaviour of cancers. 'Omic' advances provide broad 'snapshots' of biological signatures, or biomarkers of cancer, but imaging takes this information further, showing activity of these markers in vivo.
Photons traveling through tissue and interacting with tissue components form the basis of optical imaging techniques. While endogenous tissue scattering and absorption of light can be useful in determining changes in blood flow and perfusion, exploitation of fluorescent proteins or enzymes capable of inducing fluorescence of cancer biomarkers of interest and luciferase imaging permit us to interrogate not only tumour dynamics and its microenvironment but also therapeutic efficacy of molecularly targeted drugs. Employing preclinical optical imaging UiB researchers are investigating cancers in unprecedented detail.
Of note, Gausdal et al. demonstrated a novel combination therapy for acute leukaemia through an array of animal models of leukaemia, providing the preclinical basis for further translational development. Furthermore, McCormack et al. (ASH) verified the in vivo efficacy of a novel, molecularly targeted, combinatorial chemotherapeutic regime for cancers exhibiting wt p53 through optical imaging. Building from this McCormack et al., explores novel methodologies to increase the concentration of targeted antibody therapeutics in xenograft models of cancer, visualised in vivo through optical imaging, Silden et al. a new reporter system to image longitudinal cancer disease progression. While Tiron et al. and Karlsen et al. demonstrate innovative use of optical imaging in monitoring the role of Axl in metastatic breast cancer and quantification of lymph flow in primary lymphodema. Furthermore, the original application of optical monitoring of primary human xenografts of leukaemia, never previously demonstrated, was presented to an appreciative audience at the EHA meeting. Further translational development proceeds with pilot studies employing PET/CT at Helse Bergen, and further expansion of primary human xenografts from biobanked cancer material, generating more relevant models of cancer for drug development.
Synergistic induction of p53 mediated apoptosis by valproic acid and nutlin-3 in acute myeloid leukemia.
Leukemia 2012 May;26(5):910-7. Epub 2011 nov 8
Reprogramming of cell junction modules during stepwise epithelial to mesenchymal transition and accumulation of malignant features in vitro in a prostate cell model.
Exp Cell Res 2011 Jan;317(2):234-47. Epub 2010 okt 20
A novel brain metastases model developed in immunodeficient rats closely mimics the growth of metastatic brain tumours in patients.
Neuropathol Appl Neurobiol 2011 Feb;37(2):189-205.
Protein kinase A activators and the pan-PPAR agonist tetradecylthioacetic acid elicit synergistic anti-leukaemic effects in AML through CREB.
Leuk Res 2010 Jan;34(1):77-84. Epub 2009 sep 27
Increased plasma colloid osmotic pressure facilitates the uptake of therapeutic macromolecules in a xenograft tumor model.
Neoplasia 2009 Aug;11(8):812-22.
Long-term cultures of bone marrow-derived human mesenchymal stem cells frequently undergo spontaneous malignant transformation.
Cancer Res 2009 Jul;69(13):5331-9. Epub 2009 jun 9
Erythropoietin a safe bet in haemorrhagic shock?
Acta Anaesthesiol Scand 2008 May;52(5):585-6.
Abolition of stress-induced protein synthesis sensitizes leukemia cells to anthracycline-induced death.
Blood 2008 Mar;111(5):2866-77. Epub 2008 jan 8
Review: genetic models of acute myeloid leukaemia.
Oncogene 2008 Jun;27(27):3765-79. Epub 2008 feb 11
Minimally invasive quantification of lymph flow in mice and rats by imaging depot clearance of near-infrared albumin.
Am J Physiol Heart Circ Physiol 2012 Jan;302(2):H391-401. Epub 2011 nov 18 PMID: 22101523
Development of a novel near-infrared reporter system for in vitro and in vivo imaging of cancer
Focus on Microscopy 2009, Krakow, Poland. Apr 5-9, 2009
GFP celler og konjugering av antistoff brukt i in vivo studier med imaging og flowcytometri
Norsk Flowcytometri Forening Møte, Bergen, Norway. 2-3 Jun 2009
Identification of Molecular Targets of AML by Phosphoproteomic Screening of Valproic Acid Treated BNML and C. Elegans RNAi Val
Blood (ASH Annual Meeting Abstracts) 2009 114: 4151
Lentinan: Haematopoietic, immunological and efficacy studies in a syngeneic model of acute myeloid leukaemia.
Nutr Cancer [Accepted for publication 2009]
Axl is an essential epithelial-to-mesenchymal transition-induced regulator of breast cancer metastasis and patient survival
PNAS [Accepted for publication 2009]
Seeing the wood through the trees: In vivo imaging of Cancer
The Norwegian Biochemical Society 46th Contact Meeting, Storefjell, Norway. Jan 14-17 2010, I5;29
Hybrid inhibitors for tumour angiogenesis/vasculature
Patent application in Ireland 26th Sept 2008 P. 1-125
Towards the development of a Novel Near-Infrared Reporter system for in vivo imaging of cancer
1st meeting on cancer and control of genomic integrity, Copenhagen, Denmark, 26-28 Sept. 2008. * Both authors contributed equally to this work
The receptor tyrosine kinase Axl is required for tumor formation
9th Bergen Conference on Cancer Research, 23-24 May. 2008
Quantification of lymph flow in primary lymphedema mice using optical imaging
Beijing Joint Conference on Physiological Sciences, 19-22 Oct. 2008
Evaluation of Combinational Therapy of MDM2 antagonist Nutlin-3 and HDAC-inhibitor Valproic acid in Acute Myeloid Leukaemia
Blood (ASH Annual Meeting Abstracts), Nov 2008; 112: 2981
TIME-DOMAIN OPTICAL IMAGING OF AML XENOGRAFTS WITH NEAR-INFRARED CONJUGATED MONOCLONAL ANTIBODIES
Haematologica (Congress of the European Hematology Association) June 2008; 93 (s1): 201