Kaposiform lymphangiomatosis effectively treated with
            <scp>MEK</scp>
            inhibition

Foster, Jessica; Liu, Dong; March, Michael; Sheppard, Sarah E.; Adams, Denise M.; Hákonarson, Hákon; Dori, Yoav

doi:10.15252/emmm.202012324

Cited by 63 publications

(65 citation statements)

References 8 publications

(11 reference statements)

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“…Importantly, the health of these two patients improved in response to trametinib, but not to sirolimus (28,31). The precise mechanism by which trametinib improved lymphatic function in these patients was not determined.…”

Section: Discussionmentioning

confidence: 93%

“…There is growing evidence that other complex lymphatic anomalies are associated with RAS pathway–activating mutations. Mutations in RASA1 ( 26 ), EPHB4 ( 27 ), ARAF ( 28 ), NRAS ( 29 , 30 ), and CBL ( 31 ) have been identified in complex lymphatic anomaly patients. Additionally, patients with Noonan syndrome with RAS signaling pathway mutations can have lymphatic dysplasia, lymphedema, and retrograde lymph flow ( 32 – 34 ).…”

Section: Discussionmentioning

confidence: 99%

“…Trametinib is an FDA-approved MEK inhibitor that has been used to treat diseases caused by excessive RAS/MAPK signaling. To our knowledge, there are only 2 case reports of complex lymphatic anomaly patients with a RAS pathway–activating mutation being treated with trametinib ( 28 , 31 ). Importantly, the health of these 2 patients improved in response to trametinib but not to sirolimus ( 28 , 31 ).…”

Section: Discussionmentioning

confidence: 99%

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KRAS-driven model of Gorham-Stout disease effectively treated with trametinib

et al. 2021

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Gorham-Stout disease (GSD) is a sporadically occurring lymphatic disorder. Patients with GSD develop ectopic lymphatics in bone, gradually lose bone, and can have life-threatening complications such as chylothorax. The etiology of GSD is poorly understood and current treatments for this disease are inadequate for most patients. To explore the pathogenesis of GSD, we performed targeted high-throughput sequencing with samples from a GSD patient and identified an activating somatic mutation in KRAS (p.G12V). To characterize the effect of hyperactive KRAS signaling on lymphatic development, we expressed an active form of KRAS (p.G12D) in murine lymphatics (iLEC Kras mice). We found that iLEC Kras mice developed lymphatics in bone, which is a hallmark of GSD. We also found that lymphatic valve development and maintenance was altered in iLEC Kras mice. Because most iLEC Kras mice developed chylothorax and died before they had significant bone disease, we analyzed the effect of trametinib (an FDAapproved MEK1/2 inhibitor) on lymphatic valve regression in iLEC Kras mice. Notably, we found that trametinib suppressed this phenotype in iLEC Kras mice. Together, our results demonstrate that somatic activating mutations in KRAS can be associated with GSD and reveal that hyperactive KRAS signaling stimulates the formation of lymphatics in bone and impairs the development of lymphatic valves. These findings provide insight into the pathogenesis of GSD and suggest that trametinib could be an effective treatment for GSD.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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KRAS-driven model of Gorham-Stout disease effectively treated with trametinib

et al. 2021

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“…There is evidence suggesting that MEK inhibitors may be effective in patients with KLA after NRAS mutations are detected, but there are currently no clinical trials. Furthermore, trametinib has been reported to be effective in the treatment of KLA patients without NRAS mutations [ 20 ].…”

Section: Discussionmentioning

confidence: 99%

Sirolimus in the treatment of kaposiform lymphangiomatosis

Zhou

Yang

Chen

et al. 2021

Orphanet J Rare Dis

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Background Kaposiform lymphangiomatosis (KLA), which is a new subtype of generalized lymphatic anomaly, is a rare disease with a poor prognosis. Currently, there is no standard treatment due to the poor understanding of KLA. Sirolimus, which is an inhibitor of mammalian target of rapamycin, has been shown to have promising potential in the treatment of complicated vascular anomalies. The aim of this study was to introduce the use of sirolimus for the treatment of KLA and to highlight the challenges of managing this refractory disease. Results We reported seven patients with KLA who received sirolimus therapy in our center. Combined with previously reported cases, 58.3% achieved a partial response, 25.0% had stable disease, and 16.7% experienced disease progression. No severe sirolimus-related adverse events occurred during treatment. Conclusions This study suggests that sirolimus is currently an option for the treatment of KLA, and it is hoped that more specific therapies will be developed in the future. Rapid advances in basic science and clinical practice may facilitate the development of important new treatments for KLA.

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“…Finally, in recent years, somatic mutations underlying pathogenesis of vascular anomalies have been identified, including mutations in the phosphoinositide 3‐kinase (PI3K)/Akt/mTOR and RAS viral oncogene homolog (Ras)/mitogen‐activated protein kinase (MAPK) signaling pathways 29–32 . A Phase II study demonstrated that sirolimus is effective and safe for complicated vascular anomalies, 14 and other novel targeted therapies, including PI3K and mitogen‐activated protein kinase kinase (MEK) inhibitors are being evaluated in the clinical and preclinical setting 29–32 . In our cohort, only one patient received a targeted therapy, sirolimus, prior to radiotherapy.…”

Section: Discussionmentioning

confidence: 99%

Long‐term outcomes of pediatric and young adult patients receiving radiotherapy for nonmalignant vascular anomalies

Liu

Lamba

Marcus

et al. 2021

Pediatric Blood & Cancer

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Background Nonmalignant vascular anomalies (VA) comprise a heterogeneous spectrum of conditions characterized by aberrant growth or development of blood and/or lymphatic vessels and can cause significant morbidity. Little is known about outcomes after radiotherapy in pediatric and young adult patients with nonmalignant VA. Methods Thirty patients who were diagnosed with nonmalignant VA and treated with radiotherapy prior to 2017 and before the age of 30 were identified. Clinical and treatment characteristics and outcomes were recorded. Results Median age at first radiotherapy was 15 years (range 0.02–27). Median follow‐up from completion of first radiotherapy was 9.8 years (range 0.02–67.4). Lymphatic malformations (33%), kaposiform hemangioendothelioma (17%), and venous malformations (17%) were the most common diagnoses. The most common indication for first radiotherapy was progression despite standard therapy and/or urgent palliation for symptoms (57%). After first radiotherapy, 14 patients (47%) had a complete response or partial response, defined as decrease in size of treated lesion or symptomatic improvement. After first radiotherapy, 27 (90%) required additional treatment for progression or recurrence. Long‐term complications included telangiectasias, fibrosis, xerophthalmia, radiation pneumonitis, ovarian failure, and central hypothyroidism. No patient developed secondary malignancies. At last follow‐up, three patients (10%) were without evidence of disease, 26 (87%) with disease, and one died of complications (3.3%). Conclusions A small group of pediatric and young adult patients with nonmalignant, high‐risk VA experienced clinical benefit from radiotherapy with expected toxicity; however, most experienced progression. Prospective studies are needed to characterize indications for radiotherapy in VA refractory to medical therapy, including targeted inhibitors.

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Kaposiform lymphangiomatosis effectively treated with MEK inhibition

Cited by 63 publications

References 8 publications

KRAS-driven model of Gorham-Stout disease effectively treated with trametinib

KRAS-driven model of Gorham-Stout disease effectively treated with trametinib

Sirolimus in the treatment of kaposiform lymphangiomatosis

Long‐term outcomes of pediatric and young adult patients receiving radiotherapy for nonmalignant vascular anomalies

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