ESTRO 36 Abstract Book

S206 ESTRO 36 _______________________________________________________________________________________________

SP-0381 Clinical challenges we currently face E. Troost 1 1 TU Dresden- Med. Faculty Carl Gustav Carus, Radiotherapy and Radiation Oncology, Dresden, Germany Proton beam therapy poses numerous challenges to modern radiotherapy. Aspects that will be discussed during the lecture include: strategies for patient selection, challenges irradiating moving targets, obstacles arising from imaging modalities available at the gantry or in the treatment room and outcome assessment.

normoxic conditions, demonstrating that the HDAC inhibitor had counteracted the radioresistant hypoxic phenotype. Next, we conducted the Pelvic Radiation and Vorinostat (PRAVO) phase 1 study. This trial for symptom palliation in advanced gastrointestinal cancer was undertaken in sequential patient cohorts exposed to escalating doses of vorinostat combined with standard-fractionated palliative radiotherapy to pelvic target volumes, and was the first to report on the therapeutic use of an HDAC inhibitor in clinical radiotherapy. It was designed to demonstrate that vorinostat reached the radiotherapy target (detection of tumor histone hyperacetylation) and the applicability of non-invasive tumor response assessment (using functional imaging). Following gene expression array analysis of study patients’ peripheral blood mononuclear cells (PBMC), we identified markers of vorinostat activity related to cell cycle progression and reflecting the appropriate timing of drug administration in the fractionated radiotherapy protocol. Because common side effects of vorinostat single-agent therapy include intestinal toxicities, the primary objective of the PRAVO study was to determine tolerability to vorinostat in combination with pelvic radiation. Of note, in PBMC from the patient cohort that specifically experienced dose- limiting intestinal toxicities from vorinostat, genes implicated in cell death were significantly enriched. Using preclinical models at relevant drug concentrations, apoptotic and autophagic features in cultured normal intestinal epithelial cells and significant weight loss in mice following administration of the compound were observed as functional endpoints. These findings underscored that apoptosis and autophagy may play a central role in treatment toxicity from HDAC inhibitors and should be taken into consideration in the clinical context. In conclusion, epigenetic mechanisms may be exploited in radiation oncology. As illustrated by our research program involving targeting of histone acetylation, the combined clinical and translational approach for studying tumor radiosensitization, systemic normal tissue responses, and organ-confined radiation adverse effects may be part of a template for future preclinical and early-phase clinical studies assessing radiation combined with molecularly targeted therapeutics in general and epigenetic modifiers in particular. SP-0383 State of the art and future improvements for in-room cone-beam CT image quality D. Moseley 1 1 Princess Margaret Cancer Centre University Health Network, Radiation Medicine Program, Toronto, Canada Cone-beam CT systems are standard features on most medical linear accelerators. These systems are routinely used to deliver image-guided radiation therapy. The "cone-beam" geometry presents several challenges for computed tomography reconstruction. These challenges are both due to the physics of the situation and engineering limitations. These limitation include x-ray scatter as well as object truncation due to a limited FOV. In addition, a key component in the cone-beam CT system is the amorphous silicone flat-panel detectors which acquire the 2D projection images. These devices have slower readout, increased image noise and increased image lag as compared to slice-based helical CT detectors. This talk will introduce some of the challenges to image quality for in-room cone-beam CT. How do these limitations affect their use in patient setup correction, Teaching Lecture: State of the art and future improvements in in-room cone beam CT image quality

Teaching Lecture: Targeting histones and epigenetic mechanisms in radiation biology and oncology

SP-0382 Targeting histones and epigenetic mechanisms in radiation biology and oncology A.H. Ree 1 1 Akershus University Hospital, Department of Oncology, Lørenskog, Norway In modern radiation oncology, new insights into molecular radiobiology provide an opportunity for the rational integration of molecularly targeted therapeutics in clinical radiotherapy in an effort to optimize radiation effects. Recognizing the 4Rs of classic radiobiology – reoxygenation, redistribution within the cell cycle, recovery from DNA damage, and repopulation – each contributing either to improved or impaired tumor control in fractionated radiotherapy, an appealing strategy for enhancing radiation efficacy may be to target fundamental biological mechanisms governing all of the processes. In that context, epigenetic modifications have become a topic of renewed interest. DNA is normally tightly wrapped in histone octamers to form nucleosomes, dynamic structures that can be remodeled by a range of molecular processes including DNA methylation and methylation or acetylation of histones. Furthermore, because epigenetic alterations can be reversed by certain classes of drugs, they are interesting candidates as targets for radiation sensitizers. For example, conveyed by alterations in DNA methylation or histone acetylation patterns, inhibitors of DNA methyltransferases or histone deacetylases (HDAC) may cause perturbations in the regulation of genes implicated in tumor hypoxia, cell cycle progression, DNA damage repair, and cell death. From our research program on HDAC inhibitors combined with radiotherapy for colorectal cancer, we have observed: 1. Enhanced radiation-induced suppression of tumor cell clonogenicity in vitro . 2. Prolonged radiation-induced tumor growth delay of normoxic and hypoxic in vivo models. 3. Histone hyperacetylation of patients’ tumors. 4. Clinical treatment responses. 5. Overlapping but acceptable toxicities from the two treatment modalities. 6. Biological markers of treatment toxicity in patients’ surrogate tissue. 7. Normal tissue apoptosis and autophagy in experimental models. We initially reported on tumor cell radiosensitization and associated cell cycle effects in human colorectal carcinoma cell lines exposed to HDAC inhibitors. In human colorectal carcinoma xenograft models, we observed significant tumor growth delay following fractionated radiation combined with daily injections of the mice with the HDAC inhibitor vorinostat, compared to the radiation treatment alone. Furthermore, there was a similar tumor volume effect in irradiated hypoxic xenografts in mice injected with vorinostat and xenografts irradiated under