Project details

Click here to search on field of study or keyword

Imaging of Cancer Cell Death: pre-clinical development of new probes for quantification of caspase-3 activity and PS exposure
Keywords: pre-clinical imaging cancer cell apoptosis kinetic modeling
Researchers: prof. dr. S. de Jong dr. H.H. Boersma dr. A. Rybczynska prof. dr. R.A. Dierckx Prof. dr. P.H. Elsinga
Nature of the research: Translational research
Fields of study: oncology molecular biology nuclear medicine

Background / introduction

Most anticancer therapies used in clinical practice such as chemotherapy, immunotherapy and radiotherapy induce apoptosis (programmed cell death) in cancer cells (1). However, current clinically used markers for evaluation of anti-cancer therapy monitor changes in cell division and/or metabolic status of the cell, but do not directly determine apoptosis (2). Therefore, quantification of changes in cell division or metabolism frequently leads to false prognoses. This is particularly true for more complicated treatment regimes that originate from several different apoptotic signaling routes, such as combination treatment with herceptin and docetaxel (3,4). Therefore, a novel imaging tool for direct measurement of apoptosis is essential for improved monitoring during anti-cancer treatment.

Until recently, this direct information on therapy induced apoptosis in patients suffering from cancer could be obtained only by repeated biopsies. However, such biopsies are invasive, liable to sampling errors and depend critically on the accessibility of tumor tissue. Furthermore, biopsies cannot provide information about total tumor burden in patient. Because of these shortcomings, it is of major interest to develop a tracer for quantification of apoptosis in humans using non-invasive Positron Emission Tomography (PET) or single-photon emission computed tomography (SPECT) (5,6). To date, the only tracer capable of directly measuring apoptosis in humans is radiolabeled Annexin A5 (7,8). However, its scarcity and complexity make this tracer potentially more difficult for application in human cancer imaging. In addition, the large size of Annexin A5 (36 kDa) delays cell death quantification due to a slower distribution and clearance from the body.

Thus, a new imaging tool which DIRECTLY measures cell death is urgently needed for improved monitoring during anti-cancer treatment.

Research question / problem definition

Two hallmark features of cancer cell death are: caspase-3 activation and phosphatidylserine (PS) exposure. Caspase-3 (a cysteine-aspartic protease) is the central executioner of programmed cell death (apoptosis) and phosphatidyl serine (PS) is a lipid which translocates in dying cells from an intracellular to an extracellular leaflet of the cell membrane (1,9,10). Therefore, imaging the activity of caspase-3 or PS exposure can rapidly provide us information on how effective is a certain treatment. As we have access to a novel caspase-3 based tracer (18F-CP18) (11–13) and novel PS imaging probes are under development, this compounds will be studied during the planned experiments.

The aim of this project is to pre-clinically evaluate novel cell death imaging probes for nuclear medicine.

Workplan
Techniques used in this project: 1. culturing human cell lines 2. protein production and purification 3. in vivo tumor models 4. optical imaging 5. microPET imaging 6. apoptosis assays 7. immunohistochemistry 8. confocal microscopy

References

1. Fuchs, Y.; Steller, H. Cell 2011, 147, 742–58.

2. Rybczynska, A. A. Sigma receptor ligands: novel applications in cancer imaging and treatment; Dissertation; University of Groningen: Groningen, 2012; pp. 9–23.

3. Van Pelt, A. E.; Mohsin, S.; Elledge, R. M.; Hilsenbeck, S. G.; Gutierrez, M. C.; Lucci, A.; Kalidas, M.; Granchi, T.; Scott, B. G.; Allred, D. C.; Chang, J. C. Clin Breast Cancer 2003, 4, 348–53.

4. Shah, C.; Miller, T. W.; Wyatt, S. K.; McKinley, E. T.; Olivares, M. G.; Sanchez, V.; Nolting, D. D.; Buck, J. R.; Zhao, P.; Ansari, M. S.; Baldwin, R. M.; Gore, J. C.; Schiff, R.; Arteaga, C. L.; Manning, H. C. Clin Cancer Res 2009, 15, 4712–21.

5. Alberini, J.-L.; Edeline, V.; Giraudet, A. L.; Champion, L.; Paulmier, B.; Madar, O.; Poinsignon, A.; Bellet, D.; Pecking, A. P. J Surg Oncol 2011, 103, 602–6.

6. Blankenberg, F. G.; Tait, J.; Ohtsuki, K.; Strauss, H. W. Nucl Med Commun 2000, 21, 241–50.

7. Vangestel, C.; Peeters, M.; Mees, G.; Oltenfreiter, R.; Boersma, H. H.; Elsinga, P. H.; Reutelingsperger, C.; Van Damme, N.; De Spiegeleer, B.; Van de Wiele, C. Mol Imaging 2011, 10, 340–58.

8. Boersma, H. H.; Kietselaer, B. L. J. H.; Stolk, L. M. L.; Bennaghmouch, A.; Hofstra, L.; Narula, J.; Heidendal, G. A. K.; Reutelingsperger, C. P. M. J Nucl Med 2005, 46, 2035–50.

9. Ravichandran, K. S.; Lorenz, U. Nat Rev Immunol 2007, 7, 964–74.

10. Crawford, E. D.; Wells, J. A. Annu Rev Biochem 2011, 80, 1055–87.

11. Kolb, H.; Szardenings, K.; Mocharla, V.; Xia, C.; Liang, Q.; Zhao, T.; Gomez, F.; Chen, G.; Su, H.; Gangadharmath, U.; Secrest, J.; Arteaga, J.; Chaudhary, A.; Walsh, J. EANMMI 2011.

12. Kolb, H.; Walsh, J.; Gangadharmath, U.; Mu, F.; Mocharla, V.; Chaudhary, A.; Chen, G.; Chen, K.; Szardening, K. J Nucl Med 2011, 52 (Supplement 1, 1430).

13. Kolb, H.; Walsh, J.; Mocharla, V.; Liang, Q.; Zhao, T.; Gomez, F.; Chen, G.; Xia, C.; Su, H.; Gangadharmath, U. J Nucl Med 2011, 52 (Supplement 1, 350).

top