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

A Review

Muhammad O. Chohan, Serena Marchiò, Leslie A. Morrison, Richard L. Sidman, Webster K. Cavenee, Elisabetta Dejana, Howard Yonas, Renata Pasqualini, Wadih Arap

Research output: Contribution to journalReview article

1 Citation (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)492-500
Number of pages9
JournalJAMA Neurology
Volume76
Issue number4
DOIs
StatePublished - Apr 1 2019

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Central Nervous System Cavernous Hemangioma
Drug Repositioning
Penetrance
Germ-Line Mutation
Radiosurgery
Neurologic Manifestations
Blood Vessels
Seizures
Cardiovascular Diseases
Therapeutics
Hemorrhage
Morbidity
Mutation
Mortality
Brain
Research
Genes
Neoplasms

All Science Journal Classification (ASJC) codes

  • Clinical Neurology

Cite this

Chohan, Muhammad O. ; Marchiò, Serena ; Morrison, Leslie A. ; Sidman, Richard L. ; Cavenee, Webster K. ; Dejana, Elisabetta ; Yonas, Howard ; Pasqualini, Renata ; Arap, Wadih. / Emerging Pharmacologic Targets in Cerebral Cavernous Malformation and Potential Strategies to Alter the Natural History of a Difficult Disease : A Review. In: JAMA Neurology. 2019 ; Vol. 76, No. 4. pp. 492-500.
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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. / Chohan, Muhammad O.; Marchiò, Serena; Morrison, Leslie A.; Sidman, Richard L.; Cavenee, Webster K.; Dejana, Elisabetta; Yonas, Howard; Pasqualini, Renata; Arap, Wadih.

In: JAMA Neurology, Vol. 76, No. 4, 01.04.2019, p. 492-500.

Research output: Contribution to journalReview article

TY - JOUR

T1 - Emerging Pharmacologic Targets in Cerebral Cavernous Malformation and Potential Strategies to Alter the Natural History of a Difficult Disease

T2 - A Review

AU - Chohan, Muhammad O.

AU - Marchiò, Serena

AU - Morrison, Leslie A.

AU - Sidman, Richard L.

AU - Cavenee, Webster K.

AU - Dejana, Elisabetta

AU - Yonas, Howard

AU - Pasqualini, Renata

AU - Arap, Wadih

PY - 2019/4/1

Y1 - 2019/4/1

N2 - 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.

AB - 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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