Brain metastases, increasingly prevalent and fatal with a 90% mortality rate within one year of diagnosis, may have a new therapeutic approach on the horizon. Sheila Singh and Jakob Magolan have identified a critical vulnerability in metastatic brain cancer: the enzyme IMPDH. Their research, published in Cell Reports Medicine, suggests that inhibiting this enzyme with novel drugs could prevent the spread of cancer to the brain.
Targeting IMPDH to Prevent Metastasis
Lung cancer, breast cancer, and melanoma are the primary sources of brain metastases. According to Singh, even after successful treatment of these primary cancers, a small percentage of cancer cells can escape and spread to the brain, leading to treatment-resistant, end-stage cancer. The team's approach targets the rare cancer cells capable of metastasizing to other organs by inhibiting IMPDH, an enzyme essential for their survival and proliferation.
Development of IMPDH Inhibitors
Magolan's team has synthesized and evaluated over 500 candidate molecules, a substantial effort for academic laboratories. This extensive screening has identified dozens of molecules with potent activity against IMPDH. These lead molecules are now undergoing further optimization in preparation for evaluation in animal models. The goal is to establish a foundation for eventual human clinical trials.
Clinical Implications and Future Directions
Agata Kieliszek, the lead author of the study, emphasizes that brain metastases are the most common brain tumors in adults, and the current standard of care is largely palliative. Slowing brain metastasis outgrowth by targeting IMPDH could offer an alternative treatment option for patients currently limited to palliative care.
The research team is optimistic about the broader implications of their findings. Magolan suggests that the principles of metastasis may be similar across other organs, and this program could open a gateway to anti-metastasis therapies that prevent other types of cancer spread. The team intends to form a start-up company to translate this research into a first-in-class precision medicine against brain metastasis.
