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ZP1 Central platform biomarkers for ion therapy

The central platform ZO1 plays an integrative role for all clinically (TP1-4) and biologically (TP5/6) oriented projects within KFO214. The platform serves to define  and investigate superordinated questions and provides the possibility to verify preclinical findings in the clinical context (from bench to bedside) and vice versa to further investigate phenomena found during patient treatment („bed to benchside translation“).

Aims:

1) Development of genomic and proteomic biomarkers for ion therapy from peripheral blood

  • Validation of micro-metastases and operability signatures within clinical trial data and discovery of heavy ion-specific signatures.
  • Investigation of known ligands and regulators of VEGF and EGFR pathways, hypoxia signature candidates and  sets of genes/proteins of pro-angiogenic and pro-inflamatory cytokines applying qRT-PCR, ELISA und Luminex techniques.
Integrative analysis of the transkriptom, genome und proteom in the context of radiotherapy. Scheme depicts the integration of multiscale data to identify gene regulatory networks and important „hub“ pathways. Quelle: Universitätsklinikum Heidelberg

2) Evaluation of circulating tumor cells (CTCs) as predictive markers for therapy response

This subproject focuses on the correlation of CTC number with tumor staging before start of therapy and tumor response to radiotherapy with heavy ions.
CTCs are isolated with a Laser-Scanning-Cytometer (LSC, Compucyte) and are analyzed qualitatively and quantitatively. This method was successfully established for a small number of patients with lung and hepatocellular carcinoma which were treated with ion therapy.
Our aim is now to expand this method to patients with other tumor entities.


3) Evaluation of metabolic and pathophysiologic parameters of tumor response to ion therapy

Based on preclinical work, there is already an extensive metabolic and pathophysiologic monitoring program for the CINDERELLA trial which investigates the role of heavy ion therapy in patients with recurrent glioma. After completion of dose escalation the study is devided in 2 arms and iso-effective doses of protons and heavy ions are compared. In cooperation with the department of neuroradiology we have established an extensive pathophysiologic imaging program based on 3T- magnetic resonance tomography (3T-MRT).
These examinations include conventional and anatomical imaging of:

  • Tumor morphology (T1 pre-/post contrast medium & FLAIR),
  • Tumor cellularity/invasion (DWI, incl. diffusions-tensor-imaging DTI in 6 dimensions),
  • Tumor perfusion (T1-dynamics and T2*-dynamics),
  • Susceptibility weighted imaging (SWI),
  • pH-value via chemical exchange saturation transfer (CEST),
  • Oxygenation (R2' relaxometry)
  • Tumor necrosis (natrium)


MR imaging is performed before and immediately after ion therapy as well as on all follow-ups.

Moreover, tumor metabolism was assessed by amino acid imaging (fluoroethyltyrosine, FET-PET) and will be compared with MRI data.

The fact that patients within the CINDERELLA, IPI and PROMETHEUS trial are exclusively treated with heavy ions we have the unique possibility to directly compare the physiologic effects of the different radiation qualities in the respective tumor entity.


Selected publications

Almog N, Ma L, Schwager C, Brinkmann BG, Beheshti A, Vajkoczy P, Folkman J, Hlatky L, Abdollahi A. Consensus micro RNAs governing the switch of dormant tumors to the fast-growing angiogenic phenotype. PLoS One. 2012;7(8):e4400

Almog N, Ma L, Raychowdhury R, Schwager C, Erber R, Short S, Hlatky L, Vajkoczy P, Huber PE, Folkman J, Abdollahi A. Transcriptional switch of dormant tumors to fast-growing angiogenic phenotype. Cancer Res. 2009 Feb 1;69(3):836-44

Krempien R, Muenter MW, Huber PE, Nill S, Friess H, Timke C, Didinger B, Buechler P, Heeger S, Herfarth KK, Abdollahi A, Buchler MW, Debus J. Randomized phase II--study evaluating EGFR targeting therapy with cetuximab in combination with radiotherapy and chemotherapy for patients with locally advanced pancreatic cancer--PARC: study protocol BMC Cancer. 2005 Oct 11;5:131



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