Part of CNIO Breast Cancer Unit. From left: Manuel Muñoz, María José Bueno, Miguel Quintela, Verónica Jiménez and Leonardo Garma. / MadMoviex. CNIO
The CNIO team has identified a new target that could be acted on to make tumours respond to antiangiogenic treatment: the protein osteopontin
Blocking this target could also enhance immunotherapy
The study, conducted by CNIO’s Breast Cancer Clinical Research Unit, is published in 'The Journal of Clinical Investigation'.
CNIO’s Breast Cancer Clinical Research Unit has identified a new cancer-related target in mice: the protein osteopontin.
The new finding opens up a way to increase the effectiveness of antiangiogenic treatments by blocking this target. Targeting osteopontin could also help enhance immunotherapy.
Strategies aimed at blocking osteopontin in the future are already being developed, in collaboration with several CNIO groups.
Starving the tumour
Antiangiogenic drugs starve tumours by preventing them from forming new blood vessels, thereby slowing their growth. In some patients these treatments work as expected, but not in all. Indeed, resistance to antiangiogenic drugs remains a challenge in cancer therapy, and the mechanisms responsible for this resistance are still not fully understood.
The CNIO team provides an explanation: in response to a lack of oxygen (hypoxia), tumour cells produce the protein osteopontin, which can reprogramme immune-system cells so that, instead of attacking the tumour, they protect it.
In other words, the treatment itself triggers an adaptation by the tumour, causing the therapy to lose some of its effectiveness.
The CNIO group, led by Miguel Quintela, also found that osteopontin production makes the tumour respond less effectively to immunotherapy.
Osteopontin as a new therapeutic target
“We found that osteopontin could be a target for preventing the development of resistance to antiangiogenic drugs, and also for enhancing immunotherapy,” says Quintela.
The researcher highlights the length and complexity of the study, which began more than six years ago. The group experimentally blocked osteopontin in mice and observed a reduction in hypoxia as well as a restoration of the immune system’s ability to kill tumour cells: immunotherapy became effective again.
“Our results identified osteopontin as a central mediator of resistance to hypoxia-inducing antiangiogenic treatments; helped establish a comprehensive model of resistance to antiangiogenic therapy; and supported the development of strategies targeting osteopontin to personalise immunotherapy and antiangiogenic therapy according to tumour hypoxia,” the authors state.
Reference article
Osteopontin mediates acquired resistance to hypoxia-inducing antiangiogenics and promotes anti–PD-L1 refractoriness in breast cancer models. DOI 10.1172/JCI174092