Ricerc@Sapienza

BACKGROUND: More than 7 million new cases of cancer diagnosed each year benefit from radiation therapy (RT) but recurrences still occur, suggesting an intrinsic tumor radioresistance. Furthermore RT has been shown to sustain Cancer Stem Cells (CSCs) and cancer-associated fibroblasts (CAF) populations that actively participate in RT resistance. Whether high dose of RT (HDR) could kill CSCs and CAF cells, the risk of inducing acute/late side effects strongly recommend the use of low doses of RT (LDR) that, in combination with radiosensitizing agents, could kill tumor and tumor-derived cells without side effects. Microtubule Targeting Agents (MTAs) are important chemotherapeutics and radiosensitizers agents. This project wants to exploit and optimize a focused library of MTAs based on a proprietary scaffold (PBOX) and innovative radiosensitizers identified from marketed drugs to explore pioneering radiosensitizing therapeutic strategies.
MATERIALS and METHODS: Patient-derived primary tumor and CAF cells will be generated from prostate, endometrium, cervical, rectal, breast and head and neck tumors. A library of optimized PBOXs will be designed in silico using specific software, focusing on affinity for tubulin and drug-like properties. In vitro and in vivo RT will be performed using Helical Tomotherapy (HT) coupled with an in-house phantom that will permit us to deliver at the same time different radiation doses to several flasks or xenografted mice. Several in vitro and in vivo assays will be performed.
RELEVANCE OF THE PROJECT: The public health implications of this study are substantial. Testing our hypothesis is of pivotal importance. The investigation of PBOXs in combination with LDR, the analysis of their effects at the molecular leve will offer the possibility to better undestand the molecular mechanisms of radioresistance and to known drugs as radiosensitizers for a direct translation to clinic.