Detection and pharmacological disruption of CXCR4 oligomerization in lymphoid neoplasms
Research opens door to more effective treatment of lymphoma cancer
Simon Mobach discovered a possible new way to make lymphoid cancers more sensitive to existing therapies. The study shows that disrupting so-called CXCR4 clusters on cancer cells causes these cells to be less protected from drugs. This could lead to more effective treatments in the future for patients in whom the disease recurs.
Lymphoid cancers arise from lymphocytes, a type of white blood cell that is part of the immune system. Although treatment for these cancers has improved greatly in recent years, a proportion of patients still experience recurrence of the disease. A major cause is that cancer cells can hide in protective places in the body, such as the bone marrow and lymph nodes. There, they receive signals that stimulate their growth and survival and make them less sensitive to therapy.
Central to the study was the protein CXCR4. This protein is located on the surface of cancer cells and helps cells move through the body. Mobach discovered that CXCR4 not only acts as a separate protein, but often comes together in small groups called clusters. Using newly developed nanobody technology, these clusters could be accurately visualized for the first time in both cancer cells and patient material.
The study shows that these CXCR4 clusters play an important role in properties that make cancer cells stronger, such as their ability to move and resist therapies. When Mobach took apart the clusters containing small molecules, nanobodies and antibodies, the behavior of the cancer cells changed. They moved less well and became more sensitive to existing drugs.
Notable was the effect on venetoclax, a drug already used in certain blood cancers. In the study, this drug worked better after the CXCR4 clusters were disrupted. Mobach: This suggests that combination therapies may be more successful in the future."
For patients with lymphoid cancer, this approach could contribute to treatments that are more successful and remain effective longer. In addition, the research has developed new antibody-like molecules that can target CXCR4. These could be further tested in future preclinical studies and clinical trials.
The findings are in line with a broader development within oncology: making treatments increasingly targeted and personalized. By better understanding how cancer cells protect themselves from therapy, researchers hope to develop new strategies to break through that protection.
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