Dismantling drug resistance in colorectal cancer

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Researchers at the Ludwig Institute for Cancer Research Lausanne in collaboration with the Swiss Federal Institute for Technology in Lausanne have developed a potentially new treatment modality for colorectal cancers (CRCs) that are resistant to standard chemotherapy. Their study appears in the current issue of the Journal of Clinical Investigation.

A subset of drug resistant colorectal cancers known as desmoplastic CRCs contain a dense stroma characterized by fibroblasts, a thick matrix and chaotic blood vessels, all of which contribute to their drug resistance. Led by Tatiana Petrova of Ludwig Lausanne, the scientists investigated the genetic features of these and other types of CRC tumours obtained from patients and mouse models of the disease. They discovered that one gene, known as PROX1, was dysfunctional in the desmoplastic tumours and helped make tumours desmoplastic and resistant to chemotherapy.

To disrupt the desmoplasia, the researchers treated experimental CRCs with a drug (A2V) that modifies the blood vessels of the tumour and facilitates the arrival of potentially tumour-targeting immune cells. When A2V was combined with an experimental immune-modulating drug (an agonist anti-CD40 antibody), the treatment unleashed a potent immune response against desmoplastic tumours, achieving remarkable benefits in preclinical models.

“After treatment, the tumours became highly infiltrated by anti-tumoural T cells, which normally cannot penetrate these tumours, owing to the very dense stroma,” said Petrova. Notably, both A2V and the anti-CD40 antibody have already been tested in clinical trials, making an evaluation of their combination feasible relatively soon in patients with desmoplastic CRC.

Petrova is also a professor in the department of oncology at the University of Lausanne.

This summary is derived from a UNIL release that can be found here.

Source: University of Lausanne



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