ESTRO 36 Abstract Book

S109

ESTRO 36 2017

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radiotherapy and chemotherapeutic agents which act as

radiosensitisers. In assessing the efficacy of drugs as

radiosensitising agents, it is important to determine their

effects on normal tissues as well as tumours. We have

developed a modified crypt assay to assess acute toxicity

on bowel surrounding the bladder

in vivo.

Furthermore, as

murine small intestine is exquisitely sensitive to the doses

of radiation used, we have developed an irradiation

method which avoids the small intestine, using a small

animal radiation research platform (SARRP), to assess late

bowel toxicity associated with bladder cancer

radiotherapy. Our methods should help identify those

agents which may be suitable to take forward to clinical

trials.

SP-0219 Optimising the output of preclinical lung

models to optimize the chances of succes into the

clinic.

E. Deutsch

Institut Gustave Roussy, Villejuif, France

Despite the numerous promising preclinical data,

increasing the therapeutic efficacy of chest radiotherapy

using novel drugs-radiotherapy combinations has often

failed to show promise in the frame of clinical

trials.In

some cases, these novel approaches failed to increase the

anti-tumor efficacy of standard radiotherapy suggesting

that preclinical models were not appropriate enough to

recapitulate the complexity and the most recent advances

in our understanding of tumor biology (i.e. the spectrum

of mutational events, the tumor/immune host

interactions..). In other cases, new drugs- radiotherapy

combinations induced severe toxicities that justified the

discontinuation of clinical development plans. This

underscores the fact that in many circumstances,

preclinical models have been overlooking normal tissue

response to radiotherapy. As an illustration of this, major

monoclonal antibodies used in the clinic such as anti EGFr

or anti VEGF were developed in the clinic on the basis of

preclinical rationale that were not able to detect any

impact on normal tissue response. Another reason for

these limited effects is the fact that many preclinical

experiments fail to associate and to combine with

chemoradiation and use radiation alone as a comparator.

The development of orthotopic, syngenic tumor models

offers the opportunity to evaluate within the same series

of experiments both the normal tissue and the tumor

response. The rising interest in the field of immuno

oncology is also increasing our need for such models since

the immune / stromal component which is not only an

emerging player during tumor response to

radiotherapy. As an illustration of this, we will present

data from our group underscoring the fact that modulating

the immune stroma affects normal response of the normal

lung to radiotherapy. We make the make the assumption

that such models could be a mean to minimize the early

discontinuation of new drugs radiotherapy clinical trials

and eventually to increase the patients’ clinical benefit as

the results of a better selection of novel therapeutic that

would not impair, and if possible enhance, the tumor

versus normal tissue clinical ratio.

OC-0220 Exploiting novel combined-modality

approaches for treatment of highly aggressive pancreas

carcinomas

M. Orth

, L. Posselt

, S. Kirchleitner

, J. Schuster

, C.

Belka

, M. Schnurr

, K. Lauber

LMU Munich, Department of Radiation Oncology,

Munich, Germany

LMU Munich, Department of Clinical Pharmacology,

Munich, Germany

Purpose or Objective

Pancreatic ductal adenocarcinoma (PDAC) is a cancer

entity with growing prevalence and very poor prognosis.

The survival rates are limited to approximately 25% of

patients after one year and only 5% after five years,

respectively. Standard treatment encompasses surgical

resection (if possible) accompanied by radiotherapy,

chemotherapy and/or palliative care. However, treatment

failure is frequent, and inherent resistance towards radio-

and/or chemotherapy is considered as one major reason.

Accordingly, novel treatment approaches are needed,

which can address this resistance and which are able to

create synergisms with the classic therapy modalities.

Material and Methods

A panel of human PDAC cell lines was subjected to

clonogenic survival assays, and scores of radioresistance

were extracted by principal component analysis. Next, the

relative expression levels of DNA damage response (DDR)

genes were analyzed by qRT-PCR, and correlation analyses

were employed in order to identify potential drivers of

radioresistance. Specific inhibitors targeting the

respective candidates were examined in terms of their

potential to sensitize PDAC cell lines towards

radiotherapy. The obtained results were confirmed by RNA

interference. The clinical relevance of the identified

target genes was evaluated in the TCGA PDAC data set.

Finally, an orthotopic PDAC model with fractionated CT-

based irradiation was established in order to evaluate the

therapeutic potential of our approach in vivo.

Results

Using a cohort of nine human PDAC cell lines, we identified

several crucial components of the DNA damage response

(DDR) machinery to be upregulated in the radioresistant

cell lines, including ATM and DNA-PKcs. The impact of both

kinases on clonogenicity was examined both by

pharmacological inhibition and RNA interference. We

found that inhibition and siRNA-mediated knockdown of

DNA-PKcs significantly diminished the clonogenic

potential of radioresistant PDAC cell lines. Using the TCGA

PDAC collective, we found that expression of DNA-PKcs is

elevated in about 11% of all samples and that this

upregulation is associated with a striking decrease in

overall survival. Currently, the in vivo efficacy of DNA-

PKcs inhibition in combination with fractionated

radiotherapy is tested in an orthotopic mouse PDAC

model.

Conclusion

The poor prognosis of pancreatic ductal adenocarcinoma

urgently demands for the development of novel treatment

approaches. We show that pharmacological inhibition of

the DDR-related kinase DNA-PKcs gives rise to a novel,

highly promising treatment approach which should be

further explored in the future.

OC-0221 High-performance radiosensitivity assay to

predict post radiation overreactions

G. Vogin

, L. Bodgi

, A. Canet

, S. Pereira

, J. Gillet-

Daubin

, N. Foray

Institut de Cancérologie de Lorraine & UMR 7365 CNRS-

UL, Academic Department of Radiation Oncology,

VANDOEUVRE-LES-NANCY Cedex, France

Neolys Diagnostics, R&D, Lyon, France

Cancer Center of Lyon- UMR Inserm 1052 CNRS 5286

CLB, Radiobiology, Lyon, France

Purpose or Objective

Between 5 and 15% of patients treated with r adiation

experience toxicity considered "unusual" that can lead to

serious sequelae. Identifying those patients prior

treatment would therefore have sound positive clinical

implications. Retrospective analysis on skin biopsies from

patients treated by radiotherapy to define a

radiobiological parameter with the highest predictive

performance that can be used as a reliable predictor of

post-treatment toxicity.

Material and Methods

Immunofluorescence experiments were performed on the

COPERNIC collection of 116 skin fibroblasts irradiated at 2