73 Tailoring molecular radiosensitizers

73 Tailoring molecular radiosensitizers

Invited Speakers March 12 - 15 mm in diameter. Both imaging modalities rely on the increased choline metabolism of prostate cancer. To some extent, ...

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Invited Speakers

March 12 - 15

mm in diameter. Both imaging modalities rely on the increased choline metabolism of prostate cancer. To some extent, they allow to identify pelvic lymph node metastases, but their primary value currently lies in the identification of the tumour Iocalisation within the prostate for possible dose escalation. In contrast, sentinel lymph node imaging with Technetium-labelled nano-particles and SPECT is not tumour specific, but reveals patient specific pathways of lymph drainage. It cannot form the basis of dose escalation, but may guide the individualized definition of an adjuvant target volume if an adjuvant irradiation is indicated (by PSA, Gleason Score and Staging). Sentinel node imaging for adjuvant target definition has been applied to about 50 patients in an ongoing !MRT trial. While clinical evidence supports dose escalation and hypofractionation, the driving force for dose painting is rather normal tissue tolerance and the mobility of the prostate, which calls for large PTV margins or more elaborate volume concepts. An IGRT concept has to include multiple CT imaging before and possibly during the treatment to quantify the patient individual extent of organ motility. Results: The potential for IGRT dose escalation was explored in a planning study for intermediate and high risk patients by using both MRS and PET images, and sentinel node imaging for elective nodal irradiation in the group of high risk patients. Multiple pre-treatment CT images and setup error probabilities were used to construct a probabilistic patient model. The tolerable normal tissue dose levels were set to limits that were established as safe in the routine IMRT protocols, which include sentinel node imaging for high risk patients. For this level of normal tissue complication, a dose of 88 Gy in 37 fractions to the tumour foci and 74 Gy to remaining prostate appears feasible. A further reduction of dose to the prostate is currently prevented by the low image sensitivity of both MRS and choline PET. Conclusion: Technically, IGRT of prostate is feasible. Its advantage over dose escalation to the entire prostate lies in lower normal tissue doses. 72 TARGETING THE CELL CYCLE I N C O M B I N A T I O N RADIOTHERAPY OR CHEMOTHERAPY

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G.A. McArthul ~'2"3, A. Deans 1,3, J. Raleigh 1, C. Cullinane1, D. Dorow 1, N. Conus 1, R. Hicks 4 iResearch Division and 2DHMO, Peter MacCallum Cancer Centre, Vic, Australia; 3Department of Medicine, University of Melbourne, Vic, Australia; 4Department of Molecular Imaging, Peter MacCallum Cancer Centre, Australia Abnormal regulation of progression from G1 to S phase of the cell cycle by altered activity of cyclin-dependent kinases (CDKs) is a hallmark of cancer. However inhibition of CDKs, particularly CDK2 has not shown selective activity against most cancer cells because the kinase appears to be redundant in control of cell cycle progression. In this paper we will illustrate a novel role of CDKs, specifically CDK2, in the response to DNA damage induced by ionizing radiation. CDK2-/o mouse fibroblasts and siRNA- or small molecule mediated CDK2 inhibition in MCF7 cells lead to delayed damage signalling in response to ionizing radiation. Interestingly inhibition of CDK2 reduced DNA repair as assessed using the single cell COMET assay and a novel endjoining assay. To determine if cancer cells displaying defects in DNA repair pathways were more sensitive to inhibition of CDK2, we examined tumour cells lacking cancer predisposition genes BRCA1 or ATM and demonstrated that these cells are 2-4 fold more sensitive to CDK-inhibitors. These data suggest that inhibitors of CDK2 can be applied to selectively enhance responses of cancer cells to DNA-damaging agents like cytotoxic chemotherapy and radiotherapy. Moreover inhibitors of CDKs may be useful therapeutics in cancers with defects in DNA repair such as mutations in the familial breast cancer gene BRCA1. To develop strategies to monitor the molecular and cellular response of cancers to agents that target the cell cycle in vivo we are utilizing positron-emission tomography (PET) and the thymidine analogue 18F-fluorine-L-thymidine (FLT). Strikingly treatment of PC-3 xenografts with the cytotoxic drug gemcitabine induced a 5-10 fold increase in uptake of FLT that correlated with S-phase arrest as determined by BrdU incorporation or expression of cyclin-A. These data suggest that FLT PET may be able to be used to monitor the response of the

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cell cycle to therapeutic agents that induce cell cycle arrest like radiotherapy or cytotoxic chemotherapy. 73 T A I L O R I N G MOLECULAR R A D I O S E N S I T I Z E R S

S. Bodis, G. Gruber, G. Black~edge, D. Fabbro, M. Pruschy State Hospital Aarau, Novartis Pharma Inc. Basel, AstraZeneca Inc. Macclesfield UK, University Hospital Zurich, Switzerland Objective: Preclinical strategies for succesfull clinical introduction of molecular radiosensitizers in common adult epithelial stage III (locally advanced) tumors. Material and methods: Local control and 5y overall survival of the 7 most frequent epithelial adult tumors (excluding skin cancer) is still unsatisfactory with a range from 15% for stage III lung cancer to 80% of stage III breast cancer. Multimodal therapy including radical Iocoregional radiotherapy is the off-protocol standard. Optimisation of multimodal therapy is the main focus of the currently open clinical trials for these stage III tumors. Strategies to better tailor available treatment modalities including molecular radiosensitizers to tumor entity, tumor stage and patients include integration of the "molecular footprint" of parenchymal tumors cells, the tumor environment and the patient's germ line, respectively. The activity of compounds with a single molecular target in tumor cells (cell surface receptor, signalling cascade, DNAdamage) is more complex in heterogenous stage IH solid tumors compared to e.g. hematologic malignancies. Results for this tumor category have been rather disappointing, so far. Therefore currently available compounds interfering with cellular or tissue specific physiologic growth control processes (like apoptosis, cellular multi-drug resistance, lymph- and blood vessel angiogenesis) might be easier for a rapid transfer into clinical trials. Results: Only very few phase III studies are published or could be identified in the 7 tumor categories using best standard (chemo-) radiotherapy vs. molecular anticancer compound combined with best standard (chemo-)radiotherapy. This is in sharp contrast to randomised Phase III studies comparing best standard chemotherapy vs. molecular anticancer compound combined with standard chemotherapy. The reason is unclear. Both increased efforts for clinical collaboration with pharmaceutical industry as well as presentation of own translational research results and results from phase I/I/ studies at prominent international meetings are needed. Promising compounds in preclinical research and phase I/II studies form Novartis and AstraZeneca will be discussed. Finally selected compounds which are candidates for promising clinical phase III trials in these 7 adult solid tumors will be presented for discussion. Own preclinical/tra nslational research experiments focused on the combination of ionizing radiation with the clinically relevant inhibitor of angiogenesis (PTK787) and the novel microtubule inhibitor patupilone (EPOg06) with efficacy in MDR (multidrug resistant) tumor cells. Both combined modalities were tested in nude mouse xenografts derived from radiation-resistant, p53-mutated human colorectal adenocarcinoma (SW480). Both combined treatment modalities resulted in a supradditive tumor growth delay when treated with a minimally fractionated treatment regimen of 4x3Gy combined with the respective biological modifier. Conclusions: 1.) combination of novel targeted anticancer agents with ionizing radiation are a promising treatment strategy in preclinical research. 2.) selection of succesfull compounds should be based on a) relevant tumor entity b) locally advanced tumors c) valid targets for heterogeneous, locally advanced solid adult tumors. 3.) awareness of this strategy should increase in pharmaceutical companies

74 SELECTIVE RADIOPROTECTION OF NORMAL TISSUE BY B O W M A N - B I R K PROTEINASE I N H I B I T O R

K. Dittrnann, G. Wanner, C. Mayer, H.P. Rodernann Division of Radiobiolegy & Molecular Environmental Research, Dept. of Radiation Oncology, Eberhard Karls University of Tuebingen, Germany Selective radioprotection of normal tissue during radiation therapy would offer new strategies in radiation oncology, especially when organs at risk, are within the radiation field.