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Emerging Pharmacologic Targets in Cerebral Cavernous Malformation and Potential Strategies to Alter the Natural History of a Difficult Disease: A Review
Univ New Mexico, Ctr Comprehens Canc, Albuquerque, NM 87131 USA;Univ New Mexico, Sch Med, Dept Neurosurg, Albuquerque, NM 87131 USA.
Univ New Mexico, Ctr Comprehens Canc, Albuquerque, NM 87131 USA;Univ New Mexico, Sch Med, Dept Neurosurg, Albuquerque, NM 87131 USA;Univ Torino, Dept Oncol, Sch Med, Turin, Italy;Ist Ricovero Cura & Carattere Sci, Fdn Piemonte Oncol, Candiolo Canc Inst, Turin, Italy.
Univ New Mexico, Sch Med, Dept Neurol, Albuquerque, NM 87131 USA.
Harvard Med Sch, Dept Neurol, Boston, MA 02115 USA.
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2019 (English)In: JAMA Neurology, ISSN 2168-6149, E-ISSN 2168-6157, Vol. 76, no 4, p. 492-500Article, review/survey (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
AMER MEDICAL ASSOC , 2019. Vol. 76, no 4, p. 492-500
National Category
Neurology
Identifiers
URN: urn:nbn:se:uu:diva-382769DOI: 10.1001/jamaneurol.2018.3634ISI: 000463873600018PubMedID: 30476961OAI: oai:DiVA.org:uu-382769DiVA, id: diva2:1313336
Available from: 2019-05-03 Created: 2019-05-03 Last updated: 2019-05-03Bibliographically approved

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