Improving radiation-induced DNA damage effect on cancer cells using chronotherapy

Description

Cancer arises from the accumulation of mutations in specific genes due to the inherent genomic instability of cancer cells. This trait, interestingly, has become a target in oncological treatments. Cancer cells exhibit sensitivity to DNA-damaging agents such as ionizing radiation and various chemotherapeutic drugs. Our recent research revealed that the circadian protein CRY1 plays a crucial role in regulating the repair of DNA damage caused by these genotoxic agents, as observed in cellular models and mouse xenografts. Remarkably, cancer cell lines lacking CRY1 exhibit reduced sensitivity to these treatments, which correlates with a poorer prognosis for the host according to analyses of patient databases. Additionally, our analysis of data from the University Hospital Virgen Macarena revealed differential responses to radiotherapy at different times of the day in certain cancer types, including breast cancer. This variability may be attributed to circadian oscillation of CRY1 expression.

Our current research has, therefore, linked the circadian clock with the response to radiation therapy at two levels that are quite far away: cellular systems vs patient-derived survival analysis. Thus, this project aims to bridge that gap to fully understand how our molecular knowledge could truly be translated into clinical outcomes. Our main ideas focus on the specific role of CRY1, a circadian oscillator, in the repair of radiation-induced DNA breaks. To challenge this hypothesis, we plan to investigate the impact of CRY1 levels in various advanced breast cancer models. We will combine cellular models reflecting the differential status of cancer progression but also organoids derived from those cellular models. Additionally, we will study the role of CRY1 specifically in recombination-defective cancer. Our study will encompass an analysis of cancer progression in these models under normal conditions, considering the presence of CRY1. Furthermore, we will assess their responses to DNA damage mimicking radiotherapy. Additionally, we will explore the influence of the circadian cycle by administering treatments at different times of day or night. In addition to exploring the toxic effect of radiotherapy on cancer cells, our project aims to study the relevance of chronoradiotherapy on normal, noncancerous, surrounding tissue too, as a means to minimize the secondary effects of radiotherapy on patients.

This research aims to elucidate the intricate relationships among circadian rhythms, CRY1 expression, and cancer response to therapy, potentially paving the way for more effective treatment strategies. Specifically, we would like to explore in detail whether we can harness these observations and use CRY1 levels as a cell stratification method to determine differential sensitivities to radiation in healthy versus tumour cellular models. In this project, we will focus on breast cancer due to its inherent connection with recombination and radiotherapy. However, our global aim is that this research acts as a proof of concept that could be expanded to other cancer models and other oncological treatments in the future.

Project investigators

• Pablo Huertas Sánchez – Principal Investigator
• Candela Caballero Fernández
• Natalia Quesada Lechón

Funding entities

Fundación Científica Asociación Española Contra el Cáncer (AECC)