Cavernous angioma future or investigational therapies

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Edzel Lorrraine F. Co, D.M.D., M.D.

Future Investigations

Insights

Several insights on the development of cavernous angioma exist.
Factors other than genetic mutation are considered such as: ^[1]^[2]
- Oxidative stress
- Inflammation
- Alterations in angiogenesis
- Gut microbiome involvement
  - Lipopolysaccharide can stimulate the toll-like receptor 4 (TLR4) found on walls of endothelium ^[3]

Possible Medications that can Reduce Risk of Bleeding

Some drugs have been identified to be able to reduce risk of hemorrhage, and possible development of new lesions. ^[2]^[4]^[5]^[6]^[7]
These include:
- Rapamycin ^[8]
- Sorafenib ^[9]
- Sulindac (NSAID) ^[10]
- TLR4-blocking agents ^[3]
- Fasudil ^[11]^[12]^[13]
- Vitamin D ^[7]
- Tempol ^[7]
- Simvastatin ^[13]
- Bevacizumab ^[14]^[15]^[16]^[17]^[18]
- Propanolol ^[14]^[15]^[16]^[17]^[18]

Advances in Biomarkers

Evolving techniques in identifying the iron content and permeability of vessels:
- Quantitative susceptibility mapping (QSM) ^[19]^[20]^[21]^[22]
- Dynamic contrast-enhanced quantitative perfusion

Serum biomarkers reflect angiogenesis, and inflammatory activity: ^[23]

References

↑ Fischer A, Zalvide J, Faurobert E, Albiges-Rizo C, Tournier-Lasserve E (2013). "Cerebral cavernous malformations: from CCM genes to endothelial cell homeostasis". Trends Mol Med. 19 (5): 302–8. doi:10.1016/j.molmed.2013.02.004. PMID 23506982.
↑ ^2.0 ^2.1 Retta SF, Glading AJ (2016). "Oxidative stress and inflammation in cerebral cavernous malformation disease pathogenesis: Two sides of the same coin". Int J Biochem Cell Biol. 81 (Pt B): 254–270. doi:10.1016/j.biocel.2016.09.011. PMC 5155701. PMID 27639680.
↑ ^3.0 ^3.1 Tang AT, Choi JP, Kotzin JJ, Yang Y, Hong CC, Hobson N; et al. (2017). "Endothelial TLR4 and the microbiome drive cerebral cavernous malformations". Nature. 545 (7654): 305–310. doi:10.1038/nature22075. PMC 5757866. PMID 28489816.
↑ Zafar A, Quadri SA, Farooqui M, Ikram A, Robinson M, Hart BL; et al. (2019). "Familial Cerebral Cavernous Malformations". Stroke. 50 (5): 1294–1301. doi:10.1161/STROKEAHA.118.022314. PMC 6924279 Check |pmc= value (help). PMID 30909834.
↑ Witiw CD, Abou-Hamden A, Kulkarni AV, Silvaggio JA, Schneider C, Wallace MC (2012). "Cerebral cavernous malformations and pregnancy: hemorrhage risk and influence on obstetrical management". Neurosurgery. 71 (3): 626–30, discussion 631. doi:10.1227/NEU.0b013e31825fd0dc. PMID 22710379.
↑ Chohan MO, Marchiò S, Morrison LA, Sidman RL, Cavenee WK, Dejana E; et al. (2019). "Emerging Pharmacologic Targets in Cerebral Cavernous Malformation and Potential Strategies to Alter the Natural History of a Difficult Disease: A Review". JAMA Neurol. 76 (4): 492–500. doi:10.1001/jamaneurol.2018.3634. PMID 30476961.
↑ ^7.0 ^7.1 ^7.2 Gibson CC, Zhu W, Davis CT, Bowman-Kirigin JA, Chan AC, Ling J; et al. (2015). "Strategy for identifying repurposed drugs for the treatment of cerebral cavernous malformation". Circulation. 131 (3): 289–99. doi:10.1161/CIRCULATIONAHA.114.010403. PMC 4356181. PMID 25486933.
↑ De Luca E, Pedone D, Moglianetti M, Pulcini D, Perrelli A, Retta SF; et al. (2018). "Multifunctional Platinum@BSA-Rapamycin Nanocarriers for the Combinatorial Therapy of Cerebral Cavernous Malformation". ACS Omega. 3 (11): 15389–15398. doi:10.1021/acsomega.8b01653. PMC 6288776. PMID 30556006.
↑ Wüstehube J, Bartol A, Liebler SS, Brütsch R, Zhu Y, Felbor U; et al. (2010). "Cerebral cavernous malformation protein CCM1 inhibits sprouting angiogenesis by activating DELTA-NOTCH signaling". Proc Natl Acad Sci U S A. 107 (28): 12640–5. doi:10.1073/pnas.1000132107. PMC 2906569. PMID 20616044.
↑ Bravi L, Rudini N, Cuttano R, Giampietro C, Maddaluno L, Ferrarini L; et al. (2015). "Sulindac metabolites decrease cerebrovascular malformations in CCM3-knockout mice". Proc Natl Acad Sci U S A. 112 (27): 8421–6. doi:10.1073/pnas.1501352112. PMC 4500248. PMID 26109568.
↑ McDonald DA, Shi C, Shenkar R, Stockton RA, Liu F, Ginsberg MH; et al. (2012). "Fasudil decreases lesion burden in a murine model of cerebral cavernous malformation disease". Stroke. 43 (2): 571–4. doi:10.1161/STROKEAHA.111.625467. PMC 3265629. PMID 22034008.
↑ Shenkar R, Shi C, Austin C, Moore T, Lightle R, Cao Y; et al. (2017). "RhoA Kinase Inhibition With Fasudil Versus Simvastatin in Murine Models of Cerebral Cavernous Malformations". Stroke. 48 (1): 187–194. doi:10.1161/STROKEAHA.116.015013. PMC 5183488. PMID 27879448.
↑ ^13.0 ^13.1 Weiner GM, Ducruet AF (2017). "Fasudil Slows Development of Cavernous Malformations". Neurosurgery. 80 (5): N25–N27. doi:10.1093/neuros/nyx100. PMID 28586486.
↑ ^14.0 ^14.1 Apra C, Dumot C, Bourdillon P, Pelissou-Guyotat I (2019). "Could propranolol be beneficial in adult cerebral cavernous malformations?". Neurosurg Rev. 42 (2): 403–408. doi:10.1007/s10143-018-01074-0. PMID 30610500.
↑ ^15.0 ^15.1 Berti I, Marchetti F, Skabar A, Zennaro F, Zanon D, Ventura A (2014). "Propranolol for cerebral cavernous angiomatosis: a magic bullet". Clin Pediatr (Phila). 53 (2): 189–90. doi:10.1177/0009922813492885. PMID 23804539.
↑ ^16.0 ^16.1 Reinhard M, Schuchardt F, Meckel S, Heinz J, Felbor U, Sure U; et al. (2016). "Propranolol stops progressive multiple cerebral cavernoma in an adult patient". J Neurol Sci. 367: 15–7. doi:10.1016/j.jns.2016.04.053. PMID 27423555.
↑ ^17.0 ^17.1 Schmoldt A, Benthe HF, Haberland G (1975). "Digitoxin metabolism by rat liver microsomes". Biochem Pharmacol. 24 (17): 1639–41. PMID 2017.12.JNS172404. https://doi.org/10.3171/ 2017.12.JNS172404. Check |pmid= value (help).
↑ ^18.0 ^18.1 Zabramski JM, Kalani MYS, Filippidis AS, Spetzler RF (2016). "Propranolol Treatment of Cavernous Malformations with Symptomatic Hemorrhage". World Neurosurg. 88: 631–639. doi:10.1016/j.wneu.2015.11.003. PMID 26578351.
↑ Girard R, Fam MD, Zeineddine HA, Tan H, Mikati AG, Shi C; et al. (2017). "Vascular permeability and iron deposition biomarkers in longitudinal follow-up of cerebral cavernous malformations". J Neurosurg. 127 (1): 102–110. doi:10.3171/2016.5.JNS16687. PMC 6421857. PMID 27494817.
↑ Mikati AG, Khanna O, Zhang L, Girard R, Shenkar R, Guo X; et al. (2015). "Vascular permeability in cerebral cavernous malformations". J Cereb Blood Flow Metab. 35 (10): 1632–9. doi:10.1038/jcbfm.2015.98. PMC 4640319. PMID 25966944.
↑ Mikati AG, Tan H, Shenkar R, Li L, Zhang L, Guo X; et al. (2014). "Dynamic permeability and quantitative susceptibility: related imaging biomarkers in cerebral cavernous malformations". Stroke. 45 (2): 598–601. doi:10.1161/STROKEAHA.113.003548. PMC 4351041. PMID 24302484.
↑ Hart BL, Taheri S, Rosenberg GA, Morrison LA (2013). "Dynamic contrast-enhanced MRI evaluation of cerebral cavernous malformations". Transl Stroke Res. 4 (5): 500–6. doi:10.1007/s12975-013-0285-y. PMC 3939060. PMID 24323376.
↑ Girard R, Zeineddine HA, Koskimäki J, Fam MD, Cao Y, Shi C; et al. (2018). "Plasma Biomarkers of Inflammation and Angiogenesis Predict Cerebral Cavernous Malformation Symptomatic Hemorrhage or Lesional Growth". Circ Res. 122 (12): 1716–1721. doi:10.1161/CIRCRESAHA.118.312680. PMC 5993629. PMID 29720384.

[pmid23506982-1] Fischer A, Zalvide J, Faurobert E, Albiges-Rizo C, Tournier-Lasserve E (2013). "Cerebral cavernous malformations: from CCM genes to endothelial cell homeostasis". Trends Mol Med. 19 (5): 302–8. doi:10.1016/j.molmed.2013.02.004. PMID 23506982.

[pmid27639680-2] 2.0 ^2.1 Retta SF, Glading AJ (2016). "Oxidative stress and inflammation in cerebral cavernous malformation disease pathogenesis: Two sides of the same coin". Int J Biochem Cell Biol. 81 (Pt B): 254–270. doi:10.1016/j.biocel.2016.09.011. PMC 5155701. PMID 27639680.

[pmid28489816-3] 3.0 ^3.1 Tang AT, Choi JP, Kotzin JJ, Yang Y, Hong CC, Hobson N; et al. (2017). "Endothelial TLR4 and the microbiome drive cerebral cavernous malformations". Nature. 545 (7654): 305–310. doi:10.1038/nature22075. PMC 5757866. PMID 28489816.

[pmid30909834-4] Zafar A, Quadri SA, Farooqui M, Ikram A, Robinson M, Hart BL; et al. (2019). "Familial Cerebral Cavernous Malformations". Stroke. 50 (5): 1294–1301. doi:10.1161/STROKEAHA.118.022314. PMC 6924279 Check |pmc= value (help). PMID 30909834.

[pmid22710379-5] Witiw CD, Abou-Hamden A, Kulkarni AV, Silvaggio JA, Schneider C, Wallace MC (2012). "Cerebral cavernous malformations and pregnancy: hemorrhage risk and influence on obstetrical management". Neurosurgery. 71 (3): 626–30, discussion 631. doi:10.1227/NEU.0b013e31825fd0dc. PMID 22710379.

[pmid30476961-6] Chohan MO, Marchiò S, Morrison LA, Sidman RL, Cavenee WK, Dejana E; et al. (2019). "Emerging Pharmacologic Targets in Cerebral Cavernous Malformation and Potential Strategies to Alter the Natural History of a Difficult Disease: A Review". JAMA Neurol. 76 (4): 492–500. doi:10.1001/jamaneurol.2018.3634. PMID 30476961.

[pmid25486933-7] 7.0 ^7.1 ^7.2 Gibson CC, Zhu W, Davis CT, Bowman-Kirigin JA, Chan AC, Ling J; et al. (2015). "Strategy for identifying repurposed drugs for the treatment of cerebral cavernous malformation". Circulation. 131 (3): 289–99. doi:10.1161/CIRCULATIONAHA.114.010403. PMC 4356181. PMID 25486933.

[pmid30556006-8] De Luca E, Pedone D, Moglianetti M, Pulcini D, Perrelli A, Retta SF; et al. (2018). "Multifunctional Platinum@BSA-Rapamycin Nanocarriers for the Combinatorial Therapy of Cerebral Cavernous Malformation". ACS Omega. 3 (11): 15389–15398. doi:10.1021/acsomega.8b01653. PMC 6288776. PMID 30556006.

[pmid20616044-9] Wüstehube J, Bartol A, Liebler SS, Brütsch R, Zhu Y, Felbor U; et al. (2010). "Cerebral cavernous malformation protein CCM1 inhibits sprouting angiogenesis by activating DELTA-NOTCH signaling". Proc Natl Acad Sci U S A. 107 (28): 12640–5. doi:10.1073/pnas.1000132107. PMC 2906569. PMID 20616044.

[pmid26109568-10] Bravi L, Rudini N, Cuttano R, Giampietro C, Maddaluno L, Ferrarini L; et al. (2015). "Sulindac metabolites decrease cerebrovascular malformations in CCM3-knockout mice". Proc Natl Acad Sci U S A. 112 (27): 8421–6. doi:10.1073/pnas.1501352112. PMC 4500248. PMID 26109568.

[pmid22034008-11] McDonald DA, Shi C, Shenkar R, Stockton RA, Liu F, Ginsberg MH; et al. (2012). "Fasudil decreases lesion burden in a murine model of cerebral cavernous malformation disease". Stroke. 43 (2): 571–4. doi:10.1161/STROKEAHA.111.625467. PMC 3265629. PMID 22034008.

[pmid27879448-12] Shenkar R, Shi C, Austin C, Moore T, Lightle R, Cao Y; et al. (2017). "RhoA Kinase Inhibition With Fasudil Versus Simvastatin in Murine Models of Cerebral Cavernous Malformations". Stroke. 48 (1): 187–194. doi:10.1161/STROKEAHA.116.015013. PMC 5183488. PMID 27879448.

[pmid28586486-13] 13.0 ^13.1 Weiner GM, Ducruet AF (2017). "Fasudil Slows Development of Cavernous Malformations". Neurosurgery. 80 (5): N25–N27. doi:10.1093/neuros/nyx100. PMID 28586486.

[pmid30610500-14] 14.0 ^14.1 Apra C, Dumot C, Bourdillon P, Pelissou-Guyotat I (2019). "Could propranolol be beneficial in adult cerebral cavernous malformations?". Neurosurg Rev. 42 (2): 403–408. doi:10.1007/s10143-018-01074-0. PMID 30610500.

[pmid23804539-15] 15.0 ^15.1 Berti I, Marchetti F, Skabar A, Zennaro F, Zanon D, Ventura A (2014). "Propranolol for cerebral cavernous angiomatosis: a magic bullet". Clin Pediatr (Phila). 53 (2): 189–90. doi:10.1177/0009922813492885. PMID 23804539.

[pmid27423555-16] 16.0 ^16.1 Reinhard M, Schuchardt F, Meckel S, Heinz J, Felbor U, Sure U; et al. (2016). "Propranolol stops progressive multiple cerebral cavernoma in an adult patient". J Neurol Sci. 367: 15–7. doi:10.1016/j.jns.2016.04.053. PMID 27423555.

[pmidhttps://doi.org/10.3171/_2017.12.JNS172404.-17] 17.0 ^17.1 Schmoldt A, Benthe HF, Haberland G (1975). "Digitoxin metabolism by rat liver microsomes". Biochem Pharmacol. 24 (17): 1639–41. PMID 2017.12.JNS172404. https://doi.org/10.3171/ 2017.12.JNS172404. Check |pmid= value (help).

[pmid26578351-18] 18.0 ^18.1 Zabramski JM, Kalani MYS, Filippidis AS, Spetzler RF (2016). "Propranolol Treatment of Cavernous Malformations with Symptomatic Hemorrhage". World Neurosurg. 88: 631–639. doi:10.1016/j.wneu.2015.11.003. PMID 26578351.

[pmid27494817-19] Girard R, Fam MD, Zeineddine HA, Tan H, Mikati AG, Shi C; et al. (2017). "Vascular permeability and iron deposition biomarkers in longitudinal follow-up of cerebral cavernous malformations". J Neurosurg. 127 (1): 102–110. doi:10.3171/2016.5.JNS16687. PMC 6421857. PMID 27494817.

[pmid25966944-20] Mikati AG, Khanna O, Zhang L, Girard R, Shenkar R, Guo X; et al. (2015). "Vascular permeability in cerebral cavernous malformations". J Cereb Blood Flow Metab. 35 (10): 1632–9. doi:10.1038/jcbfm.2015.98. PMC 4640319. PMID 25966944.

[pmid24302484-21] Mikati AG, Tan H, Shenkar R, Li L, Zhang L, Guo X; et al. (2014). "Dynamic permeability and quantitative susceptibility: related imaging biomarkers in cerebral cavernous malformations". Stroke. 45 (2): 598–601. doi:10.1161/STROKEAHA.113.003548. PMC 4351041. PMID 24302484.

[pmid24323376-22] Hart BL, Taheri S, Rosenberg GA, Morrison LA (2013). "Dynamic contrast-enhanced MRI evaluation of cerebral cavernous malformations". Transl Stroke Res. 4 (5): 500–6. doi:10.1007/s12975-013-0285-y. PMC 3939060. PMID 24323376.

[pmid29720384-23] Girard R, Zeineddine HA, Koskimäki J, Fam MD, Cao Y, Shi C; et al. (2018). "Plasma Biomarkers of Inflammation and Angiogenesis Predict Cerebral Cavernous Malformation Symptomatic Hemorrhage or Lesional Growth". Circ Res. 122 (12): 1716–1721. doi:10.1161/CIRCRESAHA.118.312680. PMC 5993629. PMID 29720384.

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Cavernous angioma future or investigational therapies

Future Investigations

Insights

Possible Medications that can Reduce Risk of Bleeding

Advances in Biomarkers

References

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