Countering therapy resistance in colorectal cancer
A new treatment modality for colorectal cancers that do not respond to standard chemotherapy has been identified by Tatiana Petrova of the Lausanne Branch of the Ludwig Institute for Cancer Research and Michele De Palma of the EPFL.
Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality. Current treatments include a combination of surgery and systemic chemotherapy. Although chemotherapy is generally effective, many tumors do not respond or relapse after treatment. This is especially true for a subset of CRCs – called desmoplastic – that contain a dense stroma made of fibroblasts, a thick matrix, and chaotic blood vessels. These features make the desmoplastic CRCs resistant to chemotherapy.
Scientists led by Pr Tatiana Petrova from the Department of oncology of the University of Lausanne (UNIL) and the Ludwig Institute for Cancer Research Lausanne have investigated the genetic features of both desmoplastic and normal CRCs obtained from patients and mouse models of the disease. They discovered that one gene, known as PROX1, was dysfunctional in the desmoplastic tumors. Genetic studies further indicated that the impairment of PROX1 was responsible for making the tumors desmoplastic and resistant to chemotherapy.
In order to tackle these resistant tumors, the UNIL/Ludwig scientists collaborated with researchers based at EPFL in Lausanne and Roche in Zurich. They reasoned that reversing the desmoplastic properties of the tumors was key to make them more tractable. To achieve this goal, they treated experimental CRCs with a drug(A2V), which can modify the blood vessels of the tumor and facilitate the arrival of immune cells that can potentially destroy the tumor and its dense stroma.
When combined with another drug that potentates the immune cells (called agonist anti-CD40), A2V was able to unleash a potent immune response against the tumor and its desmoplatic stroma, achieving remarkable benefits in the experimental models. “After treatment, the tumors became highly infiltrated by anti-tumoral T cells, which normally cannot penetrate these tumors owing to the very dense stroma”, noted Pr Petrova.
Importantly, both A2V and the agonist anti-CD40 have already been tested in clinical trails, making their combination feasible in patients with desmoplastic CRC. “These drugs have been used in other contexts, but have not yet been investigated for the treatment of desmoplastic CRC. Our promising results should encourage new clinical trials in patients who have to live with this challenging disease”, added Pr Petrova.
The study is published in The Journal of Clinical Investigation. The work was the result of a broad collaborative effort between UNIL/Ludwig Institute for Cancer Research Lausanne (T. Petrova), EPFL (M. De Palma and M. Lutolf), CHUV (J. Perentes), Swiss Institute of Bioinformatics (M.Delorenzi), University of Zurich (G. Marra), Northwestern University (G. Oliver) and Pharma Research and Early Development of Roche (E. Corse and R. Bianchi).
par Diane De Saab