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November 26, 2018

Emerging Pharmacologic Targets in Cerebral Cavernous Malformation and Potential Strategies to Alter the Natural History of a Difficult Disease: A Review

Author Affiliations
  • 1The University of New Mexico Comprehensive Cancer Center, Albuquerque
  • 2Department of Neurosurgery, University of New Mexico School of Medicine, Albuquerque
  • 3Department of Oncology, University of Torino School of Medicine, Candiolo, Torino, Italy
  • 4Candiolo Cancer Institute-Fondazione del Piemonte per l’Oncologia, Istituto di Ricovero e Cura a Carattere Scientifico, Candiolo, Torino, Italy
  • 5Department of Neurology, University of New Mexico School of Medicine, Albuquerque
  • 6Department of Neurology, Harvard Medical School, Boston, Massachusetts
  • 7Ludwig Institute for Cancer Research, University of California, San Diego
  • 8Fondazione Italiana per la Ricerca sul Cancro Institute of Molecular Oncology Fondazione, Milan, Italy
  • 9Mario Negri Institute for Pharmacological Research, Milan, Italy
  • 10Department of Biosciences, School of Sciences and Department of Oncology, School of Medicine, Milano University, Milan, Italy
  • 11Department of Immunology, Genetics and Pathology, University of Uppsala, Uppsala, Sweden
  • 12Rutgers Cancer Institute of New Jersey at University Hospital, Newark
  • 13Division of Cancer Biology, Department of Radiation Oncology, Rutgers New Jersey Medical School, Newark
  • 14Division of Hematology/Oncology, Department of Medicine, Rutgers New Jersey Medical School, Newark
JAMA Neurol. 2019;76(4):492-500. doi:10.1001/jamaneurol.2018.3634

Importance  Cerebral cavernous malformations (CCMs) are vascular lesions of the brain that may lead to hemorrhage, seizures, and neurologic deficits. Most are linked to loss-of-function mutations in 1 of 3 genes, namely CCM1 (originally called KRIT1), CCM2 (MGC4607), or CCM3 (PDCD10), that can either occur as sporadic events or are inherited in an autosomal dominant pattern with incomplete penetrance. Familial forms originate from germline mutations, often have multiple intracranial lesions that grow in size and number over time, and cause an earlier and more severe presentation. Despite active preclinical research on a few pharmacologic agents, clinical translation has been slow. Open surgery and, in some cases, stereotactic radiosurgery remain the only effective treatments, but these options are limited by lesion accessibility and are associated with nonnegligible rates of morbidity and mortality.

Observations  We discuss the limits of CCM management and introduce findings from in vitro and in vivo studies that provide insight into CCM pathogenesis and indicate molecular mechanisms as potential therapeutic targets. These studies report dysregulated cellular pathways shared between CCM, cardiovascular diseases, and cancer. They also suggest the potential effectiveness of proper drug repurposing in association with, or as an alternative to, targeted interventions.

Conclusions and Relevance  We propose methods to exploit specific molecular pathways to design patient-tailored therapeutic approaches in CCM, with the aim to alter its natural progression. In this scenario, the lack of effective pharmacologic options remains a critical barrier that poses an unfulfilled and urgent medical need.

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