Targeted medical therapies for vascular anomalies

2.

Queisser

A

,

Seront

E

,

Boon

LM

,

Vikkula

M.

Genetic basis and therapies for vascular anomalies

.

Circ Res

.

2021

;

129

(

1

):

155

-

173

.

3.

Si

Y

,

Chu

H

,

Zhu

W

, et al.

Concentration-dependent effects of rapamycin on proliferation, migration and apoptosis of endothelial cells in human venous malformation

.

Exp Ther Med

.

2018

;

16

(

6

):

4595

-

4601

.

4.

Bissler

JJ

,

Kingswood

JC

,

Radzikowska

E

, et al.

Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebo-controlled trial

.

Lancet

.

2013

;

381

(

9869

):

817

-

824

.

5.

Lane

HA

,

Wood

JM

,

McSheehy

PM

, et al.

mTOR inhibitor RAD001 (everolimus) has antiangiogenic/vascular properties distinct from a VEGFR tyrosine kinase inhibitor

.

Clin Cancer Res

.

2009

;

15

(

5

):

1612

-

1622

.

6.

Hammill

AM

,

Wentzel

M

,

Gupta

A

, et al.

Sirolimus for the treatment of complicated vascular anomalies in children

.

Pediatr Blood Cancer

.

2011

;

57

(

6

):

1018

-

1024

.

7.

Adams

DM

,

Trenor CC

III

,

Hammill

AM

, et al.

Efficacy and safety of sirolimus in the treatment of complicated vascular anomalies

.

Pediatrics

.

2016

;

137

(

2

):

e20153257

.

8.

Seront

E

,

Van Damme

A

,

Legrand

C

, et al.

Preliminary results of the European multicentric phase III trial regarding sirolimus in slow-flow vascular malformations

.

JCI Insight

.

2023

;

8

(

21

):

e173095

.

9.

Ji

Y

,

Chen

S

,

Yang

K

, et al.

A prospective multicenter study of sirolimus for complicated vascular anomalies

.

J Vasc Surg

.

2021

;

74

(

5

):

1673

-

1681.e31681e3

.

10.

Maruani

A

,

Tavernier

E

,

Boccara

O

, et al.

Sirolimus (rapamycin) for slow-flow malformations in children: the observational-phase randomized clinical PERFORMUS trial

.

JAMA Dermatol

.

2021

;

157

(

11

):

1289

-

1298

.

11.

Seront

E

,

Biard

JM

,

Van Damme

A

, et al.

A case report of sirolimus use in early fetal management of lymphatic malformation

.

Nat Cardiovasc Res

.

2023

;

2

(

6

):

595

-

599

.

12.

Mizuno

T

,

Fukuda

T

,

Emoto

C

, et al.

Developmental pharmacokinetics of sirolimus: implications for precision dosing in neonates and infants with complicated vascular anomalies

.

Pediatr Blood Cancer

.

2017

;

64

(

8

).

13.

Badia

P

,

Ricci

K

,

Gurria

JP

,

Dasgupta

R

,

Patel

M

,

Hammill

A.

Topical sirolimus for the treatment of cutaneous manifestations of vascular anomalies: a case series

.

Pediatr Blood Cancer

.

2020

;

67

(

4

):

e28088

.

14.

Teng

JMC

,

Hammill

A

,

Martini

J

,

Treat

J.

Sirolimus in the treatment of microcystic lymphatic malformations: a systematic review

.

Lymphat Res Biol

.

2023

;

21

(

2

):

101

-

110

.

15.

Kalbfell

R

,

Cohen-Cutler

S

,

Grisham

E

, et al.

Infectious complications of vascular anomalies treated with sirolimus: a systematic review

.

Pediatr Blood Cancer

.

2024

;

71

(

1

):

e30758

.

16.

Navarro

M

,

Allemang-Trivalle

A

,

Leducq

S

, et al.

Indication for a pneumocystis prophylaxis therapy in patients with vascular anomalies treated with PIK3/AKT/mTOR pathway inhibitors: experts' opinion and systematic review from the literature

.

Dermatology

.

2023

;

239

(

6

):

942

-

951

.

17.

Russell

TB

,

Rinker

EK

,

Dillingham

CS

,

Givner

LB

,

McLean

TW

.

Pneumocystis jirovecii pneumonia during sirolimus therapy for kaposiform hemangioendothelioma

.

Pediatrics

.

2018

;

141

(

suppl 5

):

S421

-

S424

.

18.

Qiu

T

,

Li

Y

,

Gong

X

, et al.

Oral antibiotic prophylaxis for infection in patients with vascular anomalies receiving sirolimus treatment: a multicenter retrospective study

.

Orphanet J Rare Dis

.

2023

;

18

(

1

):

121

.

19.

Akinleye

A

,

Avvaru

P

,

Furqan

M

,

Song

Y

,

Liu

D.

Phosphatidylinositol 3-kinase (PI3K) inhibitors as cancer therapeutics

.

J Hematol Oncol

.

2013

;

6

(

1

):

88

.

20.

Kurek

KC

,

Luks

VL

,

Ayturk

UM

, et al.

Somatic mosaic activating mutations in PIK3CA cause CLOVES syndrome

.

Am J Hum Genet

.

2012

;

90

(

6

):

1108

-

1115

.

21.

Keppler-Noreuil

KM

,

Rios

JJ

,

Parker

VE

, et al.

PIK3CA-related overgrowth spectrum (PROS): diagnostic and testing eligibility criteria, differential diagnosis, and evaluation

.

Am J Med Genet A

.

2015

;

167A

(

2

):

287

-

295

.

22.

Venot

Q

,

Blanc

T

,

Rabia

SH

, et al.

Targeted therapy in patients with PIK3CA-related overgrowth syndrome

.

Nature

.

2018

;

558

(

7711

):

540

-

546

.

23.

André

F

,

Ciruelos

E

,

Rubovszky

G

, et al;

SOLAR-1 Study Group

.

Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer

.

N Engl J Med

.

2019

;

380

(

20

):

1929

-

1940

.

. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-alpelisib-pik3ca-related-overgrowth-spectrum.

24.

US Food and Drug Administration

.

FDA approves alpelisib for PIK3CA- related overgrowth spectrum

. Published online

6

April

2022

. Accessed

29

February

2024

25.

Canaud

G

,

Lopez Gutierrez

JC

,

Irvine

AD

, et al.

Alpelisib for treatment of patients with PIK3CA-related overgrowth spectrum (PROS)

.

Genet Med

.

2023

;

25

(

12

):

100969

.

26.

Raghavendran

P

,

Albers

SE

,

Phillips

JD

,

Zarnegar-Lumley

S

,

Borst

AJ

.

Clinical response to PI3K-α inhibition in a cohort of children and adults with PIK3CA-related overgrowth spectrum disorders

.

J Vasc Anom (Phila)

.

2022

;

3

(

1

):

e038

.

27.

Sterba

M

,

Pokorna

P

,

Faberova

R

, et al.

Targeted treatment of severe vascular malformations harboring PIK3CA and TEK mutations with alpelisib is highly effective with limited toxicity

.

Sci Rep

.

2023

;

13

(

1

):

10499

.

28.

Remy

A

,

Tran

TH

,

Dubois

J

, et al.

Repurposing alpelisib, an anti-cancer drug, for the treatment of severe TIE2-mutated venous malformations: preliminary pharmacokinetics and pharmacodynamic data

.

Pediatr Blood Cancer

.

2022

;

69

(

10

):

e29897

.

29.

Canaud

G

,

López Gutiérrez

JC

,

Hammill

AM

, et al.

EPIK-P2: a prospective phase 2, double-blind, randomized, placebo-controlled study of alpelisib in pediatric and adult patients (Pts) with PIK3CA-related overgrowth spectrum (PROS)

.

J Clin Oncol

.

2021

;

39

(

suppl 15

):

TPS3160

-

TPS3160

.

30.

Al-Olabi

L

,

Polubothu

S

,

Dowsett

K

, et al.

Mosaic RAS/MAPK variants cause sporadic vascular malformations which respond to targeted therapy

.

J Clin Invest

.

2018

;

128

(

4

):

1496

-

1508

.

31.

Barclay

SF

,

Inman

KW

,

Luks

VL

, et al.

A somatic activating NRAS variant associated with kaposiform lymphangiomatosis

.

Genet Med

.

2019

;

21

(

7

):

1517

-

1524

.

32.

Manevitz-Mendelson

E

,

Leichner

GS

,

Barel

O

, et al.

Somatic NRAS mutation in patient with generalized lymphatic anomaly

.

Angiogenesis

.

2018

;

21

(

2

):

287

-

298

.

33.

Nozawa

A

,

Ozeki

M

,

Niihori

T

,

Suzui

N

,

Miyazaki

T

,

Aoki

Y.

A somatic activating KRAS variant identified in an affected lesion of a patient with G orham-Stout disease

.

J Hum Genet

.

2020

;

65

(

11

):

995

-

1001

.

34.

Nguyen

HL

,

Boon

LM

,

Vikkula

M.

Trametinib as a promising therapeutic option in alleviating vascular defects in an endothelial KRAS-induced mouse model [published online 16 August 2022]

.

Hum Mol Genet

.

35.

Sheppard

SE

,

March

ME

,

Seiler

C

, et al.

Lymphatic disorders caused by mosaic, activating KRAS variants respond to MEK inhibition

.

JCI Insight

.

2023

;

8

(

9

):

e166888

.

36.

Cooke

DL

,

Frieden

IJ

,

Shimano

KA

.

Angiographic evidence of response to trametinib therapy for a spinal cord arteriovenous malformation

.

J Vasc Anom

.

2021

;

2

(

3

):

e018

.

37.

Nicholson

CL

,

Flanagan

S

,

Murati

M

, et al.

Successful management of an arteriovenous malformation with trametinib in a patient with capillary-malformation arteriovenous malformation syndrome and cardiac compromise

.

Pediatr Dermatol

.

2022

;

39

(

2

):

316

-

319

.

38.

Edwards

EA

,

Phelps

AS

,

Cooke

D

, et al.

Monitoring arteriovenous malformation response to genotype-targeted therapy

.

Pediatrics

.

2020

;

146

(

3

):

e20193206

.

39.

Lekwuttikarn

R

,

Lim

YH

,

Admani

S

,

Choate

KA

,

Teng

JMC

.

Genotype-guided medical treatment of an arteriovenous malformation in a child

.

JAMA Dermatol

.

2019

;

155

(

2

):

256

-

257

.

40.

Al-Samkari

H

,

Eng

W.

A precision medicine approach to hereditary hemorrhagic telangiectasia and complex vascular anomalies

.

J Thromb Haemost

.

2022

;

20

(

5

):

1077

-

1088

.

41.

Chowers

G

,

Abebe-Campino

G

,

Golan

H

, et al.

Treatment of severe kaposiform lymphangiomatosis positive for NRAS mutation by MEK inhibition

.

Pediatr Res

.

2023

;

94

(

6

):

1911

-

1915

.

42.

Foster

JB

,

Li

D

,

March

ME

, et al.

Kaposiform lymphangiomatosis effectively treated with MEK inhibition

.

EMBO Mol Med

.

2020

;

12

(

10

):

e12324

.

43.

Dori

Y

,

Smith

C

,

Pinto

E

, et al.

Severe lymphatic disorder resolved with MEK inhibition in a patient with Noonan syndrome and SOS1 mutation

.

Pediatrics

.

2020

;

146

(

6

):

e20200167

.

44.

Rankin

AW

,

Annam

A

,

Chatfield

K

, et al.

Trametinib for refractory chylous effusions in children with Noonan syndrome

.

Blood

.

September

2021

;

138

:

3140

.

45.

Li

D

,

March

ME

,

Gutierrez-Uzquiza

A

, et al.

ARAF recurrent mutation causes central conducting lymphatic anomaly treatable with a MEK inhibitor

.

Nat Med

.

2019

;

25

(

7

):

1116

-

1122

.

46.

McCarter

AL

,

Dellinger

MT

.

Trametinib inhibits lymphatic vessel invasion of bone in a mouse model of Gorham-Stout disease

.

J Vasc Anom (Phila)

.

2023

;

4

(

4

):

e070

.

47.

Nakano

TA

,

Rankin

AW

,

Annam

A

, et al.

Trametinib for refractory chylous effusions and systemic complications in children with Noonan syndrome

.

J Pediatr

.

September

2022

;

248

:

81

-

88.e188e1

.

48.

Jeng-Miller

KW

,

Miller

MA

,

Heier

JS

.

Ocular effects of MEK inhibitor therapy: literature review, clinical presentation, and best practices for mitigation

.

Oncologist

.

2024

;

29

(

5

):

e616

-

e621

.

. http://www.ncbi.nlm.nih.gov/books/NBK99495/.

49.

Biesecker

LG

,

Sapp

JC

.

Proteus Syndrome

. In:

Adam

MP

,

Feldman

J

,

Mirzaa

GM

, et al., eds. GeneReviews.

University of Washington

;

1993

. Accessed

1

May

2024

50.

Ranieri

C

,

Di Tommaso

S

,

Loconte

DC

, et al.

In vitro efficacy of ARQ 092, an allosteric AKT inhibitor, on primary fibroblast cells derived from patients with PIK3CA-related overgrowth spectrum (PROS)

.

Neurogenetics

.

2018

;

19

(

2

):

77

-

91

.

51.

Keppler-Noreuil

KM

,

Sapp

JC

,

Lindhurst

MJ

, et al.

Pharmacodynamic study of miransertib in individuals with Proteus syndrome

.

Am J Hum Genet

.

2019

;

104

(

3

):

484

-

491

.

52.

Forde

K

,

Resta

N

,

Ranieri

C

, et al.

Clinical experience with the AKT1 inhibitor miransertib in two children with PIK3CA-related overgrowth syndrome

.

Orphanet J Rare Dis

.

2021

;

16

(

1

):

109

.

53.

Ola

R

,

Hessels

J

,

Hammill

A

, et al.

Executive summary of the 14th HHT international scientific conference

.

Angiogenesis

.

2023

;

26

(

suppl 1

):

27

-

37

.

54.

Seebauer

CT

,

Wiens

B

,

Hintschich

CA

, et al.

Targeting the microenvironment in the treatment of arteriovenous malformations

.

Angiogenesis

.

2024

;

27

(

1

):

91

-

103

.

55.

Al-Samkari

H

,

Kasthuri

RS

,

Parambil

JG

, et al.

An international, multicenter study of intravenous bevacizumab for bleeding in hereditary hemorrhagic telangiectasia: the InHIBIT-Bleed study

.

Haematologica

.

2021

;

106

(

8

):

2161

-

2169

.

56.

Dmytriw

AA

,

Song

JS

,

Power

S

,

Saliou

G

,

terBrugge

K.

Management of a large diffuse maxillofacial arteriovenous malformation previously treated with ligation of ipsilateral arterial supply

.

Dentomaxillofac Radiol

.

2017

;

46

(

1

):

20160130

.

57.

Léauté-Labrèze

C

,

Dumas de la Roque

E

,

Hubiche

T

,

Boralevi

F

,

Thambo

JB

,

Taïeb

A.

Propranolol for severe hemangiomas of infancy

.

N Engl J Med

.

2008

;

358

(

24

):

2649

-

2651

.

58.

Seebauer

CT

,

Graus

MS

,

Huang

L

, et al.

Non-beta blocker enantiomers of propranolol and atenolol inhibit vasculogenesis in infantile hemangioma

.

J Clin Invest

.

2022

;

132

(

3

):

e151109

.

59.

Schrenk

S

,

Boscolo

E.

A transcription factor is the target of propranolol treatment in infantile hemangioma

.

J Clin Invest

.

2022

;

132

(

3

).

60.

Ji

Y

,

Chen

S

,

Yang

K

, et al.

Efficacy and safety of propranolol vs atenolol in infants with problematic infantile hemangiomas: a randomized clinical trial

.

JAMA Otolaryngol Head Neck Surg

.

2021

;

147

(

7

):

599

-

607

.

61.

Léauté-Labrèze

C.

Medical management of vascular anomalies of the head and neck

.

J Oral Pathol Med

.

2022

;

51

(

10

):

837

-

843

.

62.

Jayson

GC

,

Kerbel

R

,

Ellis

LM

,

Harris

AL

.

Antiangiogenic therapy in oncology: current status and future directions

.

Lancet

.

2016

;

388

(

10043

):

518

-

529

.

63.

Zhu

W

,

Chen

W

,

Zou

D

, et al.

Thalidomide reduces hemorrhage of brain arteriovenous malformations in a mouse model

.

Stroke

.

2018

;

49

(

5

):

1232

-

1240

.

64.

Boon

LM

,

Dekeuleneer

V

,

Coulie

J

, et al.

Case report study of thalidomide therapy in 18 patients with severe arteriovenous malformations

.

Nat Cardiovasc Res

. 10 June

2022

;

1

:

562

-

567

.

65.

Al-Samkari

H

,

Kasthuri

RS

,

Iyer

V

, et al.

PATH-HHT, a double-blind, randomized, placebo-controlled trial in hereditary hemorrhagic telangiectasia demonstrates that pomalidomide reduces epistaxis and improves quality of life

.

Blood

.

2023

;

142

(

suppl 2

):

LBa

-

LB3

.

66.

Triana

P

,

Lopez-Gutierrez

JC

.

Activity of a TIE2 inhibitor (rebastinib) in a patient with a life-threatening cervicofacial venous malformation

.

Pediatr Blood Cancer

.

2023

;

70

(

8

):

e30404

.

67.

Boscolo

E

,

Limaye

N

,

Huang

L

, et al.

Rapamycin improves TIE2-mutated venous malformation in murine model and human subjects

.

J Clin Invest

.

2015

;

125

(

9

):

3491

-

3504

.

. https://clinicaltrials.gov/study/NCT04409145.

68.

Venthera Inc

. Open-label, intra subject, dose escalation (part 1) followed by randomized, double blind, placebo controlled (part 2) trial of topical VT30 in pts with venous, lymphatic or mixed malformations associated with PIK3CA or TEK genetic mutations. Accessed

31

December

2023

69.

Lokhorst

MM

,

Horbach

SER

,

Young-Afat

DA

, et al;

OVAMA Steering Group

.

Development of a condition-specific patient-reported outcome measure for measuring symptoms and appearance in vascular malformations: the OVAMA questionnaire

.

Br J Dermatol

.

2021

;

185

(

4

):

797

-

803

.

70.

Kerr

AM

,

Sisk

BA

.

Unanswered questions and unmet needs: a call for communication research in vascular anomalies

.

Patient Educ Couns

.

2021

;

104

(

11

):

2839

-

2842

.