Genomic landscape of lymphatic malformations: a case series and response to the PI3Kα inhibitor alpelisib in an N-of-1 clinical trial

Medientyp: E-Artikel
Titel: Genomic landscape of lymphatic malformations: a case series and response to the PI3Kα inhibitor alpelisib in an N-of-1 clinical trial
Beteiligte: Shaheen, Montaser F; Tse, Julie Y; Sokol, Ethan S; Masterson, Margaret; Bansal, Pranshu; Rabinowitz, Ian; Tarleton, Christy A; Dobroff, Andrey S; Smith, Tracey L; Bocklage, Thèrése J; Mannakee, Brian K; Gutenkunst, Ryan N; Bischoff, Joyce; Ness, Scott A; Riedlinger, Gregory M; Groisberg, Roman; Pasqualini, Renata; Ganesan, Shridar; Arap, Wadih
Erschienen: eLife Sciences Publications, Ltd, 2022
Erschienen in: eLife
Sprache: Englisch
DOI: 10.7554/elife.74510
ISSN: 2050-084X
Schlagwörter: General Immunology and Microbiology ; General Biochemistry, Genetics and Molecular Biology ; General Medicine ; General Neuroscience
Entstehung:
Anmerkungen:
Beschreibung: <jats:sec id="abs1"><jats:title>Background:</jats:title><jats:p>Lymphatic malformations (LMs) often pose treatment challenges due to a large size or a critical location that could lead to disfigurement, and there are no standardized treatment approaches for either refractory or unresectable cases.</jats:p></jats:sec><jats:sec id="abs2"><jats:title>Methods:</jats:title><jats:p>We examined the genomic landscape of a patient cohort of LMs (<jats:italic>n</jats:italic> = 30 cases) that underwent comprehensive genomic profiling using a large-panel next-generation sequencing assay. Immunohistochemical analyses were completed in parallel.</jats:p></jats:sec><jats:sec id="abs3"><jats:title>Results:</jats:title><jats:p>These LMs had low mutational burden with hotspot <jats:italic>PIK3CA</jats:italic> mutations (<jats:italic>n</jats:italic> = 20) and <jats:italic>NRAS</jats:italic> (<jats:italic>n</jats:italic> = 5) mutations being most frequent, and mutually exclusive. All LM cases with Kaposi sarcoma-like (kaposiform) histology had <jats:italic>NRAS</jats:italic> mutations. One index patient presented with subacute abdominal pain and was diagnosed with a large retroperitoneal LM harboring a somatic <jats:italic>PIK3CA</jats:italic> gain-of-function mutation (H1047R). The patient achieved a rapid and durable radiologic complete response, as defined in RECIST1.1, to the PI3Kα inhibitor alpelisib within the context of a personalized <jats:italic>N</jats:italic>-of-1 clinical trial (NCT03941782). In translational correlative studies, canonical PI3Kα pathway activation was confirmed by immunohistochemistry and human LM-derived lymphatic endothelial cells carrying an allele with an activating mutation at the same locus were sensitive to alpelisib treatment in vitro, which was demonstrated by a concentration-dependent drop in measurable impedance, an assessment of cell status.</jats:p></jats:sec><jats:sec id="abs4"><jats:title>Conclusions:</jats:title><jats:p>Our findings establish that LM patients with conventional or kaposiform histology have distinct, yet targetable, driver mutations.</jats:p></jats:sec><jats:sec id="abs5"><jats:title>Funding:</jats:title><jats:p>R.P. and W.A. are supported by awards from the Levy-Longenbaugh Fund. S.G. is supported by awards from the Hugs for Brady Foundation. This work has been funded in part by the NCI Cancer Center Support Grants (CCSG; P30) to the University of Arizona Cancer Center (CA023074), the University of New Mexico Comprehensive Cancer Center (CA118100), and the Rutgers Cancer Institute of New Jersey (CA072720). B.K.M. was supported by National Science Foundation via Graduate Research Fellowship DGE-1143953.</jats:p></jats:sec><jats:sec id="abs6"><jats:title>Clinical trial number:</jats:title><jats:p>NCT03941782</jats:p></jats:sec>
Zugangsstatus: Freier Zugang

Nur in Feld suchen:

Zuletzt gesuchte Begriffe: