ESTRO 2024 - Abstract Book

S5335

Radiobiology - Tumour biology

ESTRO 2024

This project aims to further explore this correlation and to radiosensitize PDAC cells by MYC inhibition, which may lead to future treatment options for patients.

Material/Methods:

For this project, genetically diverse murine PDAC cell lines were used, and treated with indirect MYC inhibitors, such as the HDAC inhibitor MS 275 and the SUMO inhibitors TAK 981 and ML 792, and irradiation.

To affirm the correlation between MYC expression and radioresistance, western blots were performed, investigating different phosphorylation sites of MYC.

The radiosensitivity and the survival after inhibitor treatment of the different cell lines were determined by colony formation assays.

The impact of MYC inhibition on the cell cycle (propidium iodide) and double-strand breaks (yH2AX) was evaluated by flow cytometry.

Additionally, we used fluorescence and light microscopy to observe the inhibitor treatment's effects on cellular morphology.

Until recently, a combination treatment of intraperitoneal injection of MS 275 and 10 Gy image-guided irradiation was established in a syngeneic, subcutaneous tumor mouse model.

Results:

The heterogenous radiosensitivity observed in patients was demonstrated in vitro by CFAs, which made it possible to divide the cells into a radioresistant and a radiosensitive group.

The association between high radioresistance and strong MYC expression was confirmed by western blot.

We observed a dose-dependent reduction of clonogenic survival after inhibitor treatment with an IC50 (half maximal inhibitor concentration) in the lower micromolar (MS 275, ML 792) or nanomolar (TAK 981) range.

Additionally, the treatment influenced the cell cycle distribution with a significant dose-dependent cell cycle arrest in the G0/G1 or G2/M phase, depending on the inhibitor and the cell line. MYC inhibition also increased DNA double strand breaks, indicating DNA damage.

Treatment with MS 275 led to cellular morphology changes, such as enlargement and rounding of cells and the nucleus.

A significant dose-dependent radiosensitization was found only for the radioresistant cell lines.

Without the occurrence of toxicity, we could establish a combination treatment consisting of MS 275 and local irradiation in a syngeneic tumor mouse model.