Maeva Bavoux1, Yuji Kamio2, Emmanuelle Vigneux-Foley3, Julie Lafontaine4, Ouafa Najyb4, Elena Refet-Mollof5, Jean-François Carrier6, Thomas Gervais7, Philip Wong8. 1. Department of Pharmacology and Physiology, Université de Montréal, Canada; Institut du Cancer de Montréal, Canada; Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Canada. 2. Department of Pharmacology and Physiology, Université de Montréal, Canada; Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Canada; Department of Radiation Oncology, Centre Hospitalier de l'Université de Montréal (CHUM), Canada. 3. Department of Engineering Physics, École Polytechnique de Montréal, Canada. 4. Institut du Cancer de Montréal, Canada; Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Canada. 5. Institut du Cancer de Montréal, Canada; Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Canada; Institute of Biomedical Engineering, École Polytechnique de Montréal, Canada. 6. Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Canada; Department of Radiation Oncology, Centre Hospitalier de l'Université de Montréal (CHUM), Canada; Department of Physics, Université de Montréal, Canada. 7. Institut du Cancer de Montréal, Canada; Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Canada; Department of Engineering Physics, École Polytechnique de Montréal, Canada; Institute of Biomedical Engineering, École Polytechnique de Montréal, Canada. Electronic address: thomas.gervais@polymtl.ca. 8. Institut du Cancer de Montréal, Canada; Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Canada; Department of Radiation Oncology, Centre Hospitalier de l'Université de Montréal (CHUM), Canada; Department of Radiation Oncology, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada. Electronic address: philip.wong@rmp.uhn.ca.
Abstract
PURPOSE: Radioresistance, tumor microenvironment, and normal tissue toxicity from radiation limit the efficacy of radiotherapy in treating cancers. These challenges can be tackled by the discovery of new radiosensitizing and radioprotecting agents aimed at increasing the therapeutic efficacy of radiotherapy. The goal of this work was to develop a miniaturized microfluidic platform for the discovery of drugs that could be used in combination with radiotherapy. The microfluidic system will allow the toxicity testing of cancer spheroids to different combinations of radiotherapy and molecular agents. MATERIALS AND METHODS: An orthovoltage-based technique was used to expose the devices to multiple X-ray radiation doses simultaneously. Radiation dose-dependent DNA double-strand breaks in soft tissue sarcoma (STS) spheroids were quantified using comet assays. Analysis of proliferative death using clonogenic assays was also performed, and synergy between treatments with Talazoparib, Pazopanib, AZD7762, and radiotherapy was quantified using dedicated statistical tests. RESULTS: The developed microfluidic system with simple magnetic valves was capable of growing 336 homogeneous STS spheroids. The irradiation of the microfluidic system with an orthovoltage-based technique enabled the screening of sixteen drug-radiotherapy combinations with minimal reagent consumption. Using this framework, we predicted a therapeutic synergy between a novel anticancer drug Talazoparib and radiotherapy for STS. No synergy was found between RT and either Pazopanib or AZD7762, as the combinations were found to be additive. CONCLUSION: This methodology lays the basis for the systemic search for molecular agent/radiotherapy synergies among preexisting pharmaceutical compounds libraries, in the hope to identify failed drug candidates in monotherapy that, in the presence of radiotherapy, would make it through clinical trials.
PURPOSE: Radioresistance, tumor microenvironment, and normal tissue toxicity from radiation limit the efficacy of radiotherapy in treating cancers. These challenges can be tackled by the discovery of new radiosensitizing and radioprotecting agents aimed at increasing the therapeutic efficacy of radiotherapy. The goal of this work was to develop a miniaturized microfluidic platform for the discovery of drugs that could be used in combination with radiotherapy. The microfluidic system will allow the toxicity testing of cancer spheroids to different combinations of radiotherapy and molecular agents. MATERIALS AND METHODS: An orthovoltage-based technique was used to expose the devices to multiple X-ray radiation doses simultaneously. Radiation dose-dependent DNA double-strand breaks in soft tissue sarcoma (STS) spheroids were quantified using comet assays. Analysis of proliferative death using clonogenic assays was also performed, and synergy between treatments with Talazoparib, Pazopanib, AZD7762, and radiotherapy was quantified using dedicated statistical tests. RESULTS: The developed microfluidic system with simple magnetic valves was capable of growing 336 homogeneous STS spheroids. The irradiation of the microfluidic system with an orthovoltage-based technique enabled the screening of sixteen drug-radiotherapy combinations with minimal reagent consumption. Using this framework, we predicted a therapeutic synergy between a novel anticancer drug Talazoparib and radiotherapy for STS. No synergy was found between RT and either Pazopanib or AZD7762, as the combinations were found to be additive. CONCLUSION: This methodology lays the basis for the systemic search for molecular agent/radiotherapy synergies among preexisting pharmaceutical compounds libraries, in the hope to identify failed drug candidates in monotherapy that, in the presence of radiotherapy, would make it through clinical trials.