CNIO will study how to improve cancer treatments according to time of day, in a project funded with 1.5 million euros by the European Research Council

One way to increase effectiveness in cancer therapies may be to simply change the time at which they are given. This is suggested by recent results by María Casanova-Acebes, from the Spanish National Cancer Research Centre (CNIO). The researcher has just been awarded 1.5 million euros to further advance her work towards discovering how to adjust treatments to the time at which they can prove most effective, according to the body’s physiology.

Her project is called INN-TIME, and the funding comes from the European Research Council (ERC), the European institution managing the most prestigious and competitive projects in the European Union.

Casanova-Acebes, head of the Cancer Immunity Group at CNIO, has spent years studying the relationship between cancer, the body’s immune system –our natural defence against cancer– and biorhythms, that is, the biochemical mechanisms that allow the body to know the time. These biorhythms play an important role in the synchronization of physiological processes with the Earth’s day/night cycle –he so-called circadian rhythms–.

Cancer alters the rhythms in the immune system

One of the CNIO researcher’s findings is that tumour cells alter the circadian rhythm of the immune system in an attempt to evade its attack.

“In mice, we have observed an increased activity of the immune system at night, which means there are more opportunities to prevent the tumour from growing,” says the researcher. “But tumour cells manage to override this advantage by emitting signals that distort the immune system’s circadian rhythm. Thus, the immune system ceases to recognise them as tumour cells,” says Casanova-Acebes.

Througout INN-TIME’s next five years, Casanova-Acebes and her team will analyse the activity cycles of tumour cells, of the immune system and of fibroblasts, cells in the tumour microenvironment that regulate when to attract cells from the immune system and when to activate them.

Resulting data will be integrated into a model that, as Casanova-Acebes explains, “will allow to understand time-related messages in each of the three blocks involved –tumour cells, the immune system and fibroblasts–.”

Best timing for treatment

The ultimate goal is to identify “time windows with the best treatment outcome”, in order to be able to adjust treatment scheduling to these times, so as to increase their effectiveness.

“In mice, a nocturnal species, we have observed that the response to immunotherapy against lung cancer is 10 times stronger when given at night,” says Casanova-Acebes. “In humans, this effect has already been verified in patients with advanced stages of melanoma, and in people vaccinated against COVID. Both treatments were more effective when given in the morning than in the evening”, according to our most active time.

Her vision is “to be able to tell oncologists which treatments to administer –or which operations to perform– at different times of day or night, in order to achieve better results. In addition, this would help to alleviate bottlenecks in the health care system and make much more efficient use of resources.”

Donations from lung cancer patients and from the Spanish Association of Airline Cabin Crew Members

The studies will be carried out on animal models and lung tumour tissues. Through CNIO’s Biobank coordination, the researcher will have access to samples donated by more than 300 lung cancer patients from biobanks at both Ramón y Cajal Hospital in Madrid and the Lleida Hospital.

The project will also analyse blood samples from a professional group whose work activity is out of sync with circadian rhythms: airline cabin crew members.

Thanks to an agreement with its professional association, AETCP, signed in collaboration with CNIO Biobank, both short-haul and long-haul flight crew members will be monitored for five years, to compare how biorhythms in the cells of the immune systems are modified when subject to circadian rhythms alterations experienced in transatlantic flights.

Alongside this research a bioinformatics tool will be developed in collaboration with CNIO’s Bioinformatics Unit, under Fátima Al-Shahrour’s lead. The tool will be public and open source and will make resulting data and information available to researchers and society at large. “In addition to oncology, our research will be useful for pathologists, allergists, and any specialist focused on lung physiology and the immune system, because it will also include information on the healthy cells of this organ,” says Casanova-Acebes.

Beside those already mentioned, collaborations will be established with José Javier Bravo Cordero from Mount Sinai Hospital, with Julio Aguirre-Ghiso, from the Albert College of Medicine in New York (United States) and with Roser Vento-Tormo, from the Wellcome Sanger Institute in Cambridge (United Kingdom).

About European Research Council Starting Grants

Starting Grants are part of the European Union’s Horizon Europe programme. They are awarded to cutting-edge research proposals and intend to encourage early-career researchers to launch projects based on their best ideas and form research groups with a solid foundation.

For María Casanova-Acebes, “their main advantage is that they allow you to hire very competitive staff, with good salaries. We will hire two postdoctoral researchers, a bioinformatician and also senior staff specialised in the complex experiments we are going to carry out. The leap for those of us who are just starting out is a qualitative one.”

In this last call, 2,696 proposals were submitted and 400 grants –worth up to 1.5 million euros each–, awarded, which will cover work over five years. Casanova-Acebes’s proposal is one of the 43% awarded to women, 39% more than in 2022. Among the selected applications, 23 came from Spanish institutions and 20 were submitted by Spanish nationals.