Sirolimus for Angiomyolipoma in Tuberous Sclerosis Complex or Lymphangioleiomyomatosis

Bissler, John J.; McCormack, Francis X.; Young, Lisa R.; Elwing, Jean M.; Chuck, Gail; Leonard, Jennifer; Schmithorst, Vincent J.; Laor, Tal; Brody, Alan S.; Bean, Judy A.; Salisbury, Shelia; Franz, David Neal

doi:10.1056/nejmoa063564

Cited by 1,147 publications

(1,043 citation statements)

References 32 publications

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“…As mentioned previously, limited data suggest that mTOR inhibitors may require continuous use to maintain reductions in TSC‐associated tumors 11, 12. In our study, regrowth of SEGA was observed in 1 patient who had previously met the criteria for treatment success (75% reduction in SEGA volume) at 18 months and then discontinued everolimus.…”

Section: Discussionsupporting

confidence: 62%

“…Patients with TSC typically have comorbidities that reflect the involvement of multiple organs. Unlike a neurosurgical procedure, mTOR inhibitor therapy may cause regression of other lesions, such as angiomyolipomas (kidney), angiofibromas (skin), and lymphangioleiomyomatosis (lung) 12, 22, 23, 24, 25…”

Section: Discussionmentioning

confidence: 99%

“…In some cases discontinuation of mTOR inhibition has resulted in regrowth of TSC‐associated lesions 11, 12. For example, a study evaluating an mTOR inhibitor in treating angiomyolipomas, the renal tumors associated with TSC, demonstrated regrowth of lesions in several patients nearly to baseline 1 year after cessation of mTOR treatment 12.…”

mentioning

confidence: 99%

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Everolimus for subependymal giant cell astrocytoma: 5‐year final analysis

Franz

Agricola

Mays

et al. 2015

Annals of Neurology

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143

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ObjectiveTo analyze the cumulative efficacy and safety of everolimus in treating subependymal giant cell astrocytomas (SEGA) associated with tuberous sclerosis complex (TSC) from an open‐label phase II study (NCT00411619). Updated data became available from the conclusion of the extension phase and are presented in this ≥5‐year analysis.MethodsPatients aged ≥ 3 years with a definite diagnosis of TSC and increasing SEGA lesion size (≥2 magnetic resonance imaging scans) received everolimus starting at 3mg/m2/day (titrated to target blood trough levels of 5–15ng/ml). The primary efficacy endpoint was reduction from baseline in primary SEGA volume.ResultsAs of the study completion date (January 28, 2014), 22 of 28 (78.6%) initially enrolled patients finished the study per protocol. Median (range) duration of exposure to everolimus was 67.8 (4.7–83.2) months; 12 (52.2%) and 14 (60.9%) of 23 patients experienced SEGA volume reductions of ≥50% and ≥30% relative to baseline, respectively, after 60 months of treatment. The proportion of patients experiencing daily seizures was reduced from 7 of 26 (26.9%) patients at baseline to 2 of 18 (11.1%) patients at month 60. Most commonly reported adverse events (AEs) were upper respiratory tract infection and stomatitis of mostly grade 1 or 2 severity. No patient discontinued treatment due to AEs. The frequency of emergence of most AEs decreased over the course of the study.InterpretationEverolimus continues to demonstrate a sustained effect on SEGA tumor reduction over ≥5 years of treatment. Everolimus remained well‐tolerated, and no new safety concerns were noted. Ann Neurol 2015;78:929–938

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Section: Discussionsupporting

confidence: 62%

Section: Discussionmentioning

confidence: 99%

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Everolimus for subependymal giant cell astrocytoma: 5‐year final analysis

Franz

Agricola

Mays

et al. 2015

Annals of Neurology

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143

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“…The results of the first formal prospective phase I/II open-label clinical trial of sirolimus therapy for patients with TSC or sporadic LAM, in which both are associated with AML development, were published in 2008 (Bissler et al, 2008). A cohort of 25 adult patients, 19 with TSC (of who 12 had LAM) and 6 with sporadic LAM, were treated with sirolimus (5-15 ng/ml) for 1 year, followed by a 12-month follow-up period.…”

Section: The Mtorc1 Inhibitors As Treatment For Tscmentioning

confidence: 99%

“…Total regression of lesions due to rapamycin therapy has never been observed, except for facial angiofibromas and erythema treated with topical administration of sirolimus (Kaufman McNamara et al, 2010). In fact, tumor regrowth occurred following cessation of therapy (Franz et al, 2006;Wienecke et al, 2006;Bissler et al, 2008). These observations would implicate a life-long treatment with rapamycin, but little is known yet about long-term effects or complications of the drug.…”

Section: The Mtorc1 Inhibitors As Treatment For Tscmentioning

confidence: 99%

The long and winding road to rational treatment of cancer associated with LKB1/AMPK/TSC/mTORC1 signaling

et al. 2011

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The liver kinase B1 (LKB1)/adenosine mono-phosphateactivated protein kinase (AMPK)/tuberous sclerosis complex (TSC)/mammalian target of rapamycin (mTOR) complex (mTORC1) cassette constitutes a canonical signaling pathway that integrates information on the metabolic and nutrient status and translates this into regulation of cell growth. Alterations in this pathway are associated with a wide variety of cancers and hereditary hamartoma syndromes, diseases in which hyperactivation of mTORC1 has been described. Specific mTORC1 inhibitors have been developed for clinical use, and these drugs have been anticipated to provide efficient treatment for these diseases. In the present review, we provide an overview of the metabolic LKB1/AMPK/TSC/mTORC1 pathway, describe how its aberrant signaling associates with cancer development, and indicate the difficulties encountered when biochemical data are extrapolated to provide avenues for rational treatment of disease when targeting this signaling pathway. A careful examination of preclinical and clinical studies performed with rapamycin or derivatives thereof shows that although results are encouraging, we are only half way in the long and winding road to design rationale treatment targeted at the LKB1/ AMPK/TSC/mTORC1 pathway. Inherited cancer syndromes associated with this pathway such as the PeutzJeghers syndrome and TSC, provide perfect models to study the relationship between genetics and disease phenotype, and to delineate the complexities that underlie translation of biochemical and genetical information to clinical management, and thus provide important clues for devising novel rational medicine for cancerous diseases in general.

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