Publications by authors named "Matthew Lastrapes"

4 Publications

  • Page 1 of 1

Genomic characterization of human brain metastases identifies drivers of metastatic lung adenocarcinoma.

Nat Genet 2020 04 23;52(4):371-377. Epub 2020 Mar 23.

Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.

Brain metastases from lung adenocarcinoma (BM-LUAD) frequently cause patient mortality. To identify genomic alterations that promote brain metastases, we performed whole-exome sequencing of 73 BM-LUAD cases. Using case-control analyses, we discovered candidate drivers of brain metastasis by identifying genes with more frequent copy-number aberrations in BM-LUAD compared to 503 primary LUADs. We identified three regions with significantly higher amplification frequencies in BM-LUAD, including MYC (12 versus 6%), YAP1 (7 versus 0.8%) and MMP13 (10 versus 0.6%), and significantly more frequent deletions in CDKN2A/B (27 versus 13%). We confirmed that the amplification frequencies of MYC, YAP1 and MMP13 were elevated in an independent cohort of 105 patients with BM-LUAD. Functional assessment in patient-derived xenograft mouse models validated the notion that MYC, YAP1 or MMP13 overexpression increased the incidence of brain metastasis. These results demonstrate that somatic alterations contribute to brain metastases and that genomic sequencing of a sufficient number of metastatic tumors can reveal previously unknown metastatic drivers.
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http://dx.doi.org/10.1038/s41588-020-0592-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136154PMC
April 2020

The Dual PI3K/mTOR Pathway Inhibitor GDC-0084 Achieves Antitumor Activity in -Mutant Breast Cancer Brain Metastases.

Clin Cancer Res 2019 06 22;25(11):3374-3383. Epub 2019 Feb 22.

Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.

Purpose: Previous studies have shown that the PI3K/Akt/mTOR pathway is activated in up to 70% of breast cancer brain metastases, but there are no approved agents for affected patients. GDC-0084 is a brain penetrant, dual PI3K/mTOR inhibitor that has shown promising activity in a preclinical model of glioblastoma. The aim of this study was to analyze the efficacy of PI3K/mTOR blockade in breast cancer brain metastases models. The efficacy of GDC-0084 was evaluated in -mutant and wild-type breast cancer cell lines and the isogenic pairs of wild-type and mutant (H1047R/+) MCF10A cells . studies included cell viability and apoptosis assays, cell-cycle analysis, and Western blots. , the effect of GDC-0084 was investigated in breast cancer brain metastasis xenograft mouse models and assessed by bioluminescent imaging and IHC.

Results: , GDC-0084 considerably decreased cell viability, induced apoptosis, and inhibited phosphorylation of Akt and p70 S6 kinase in a dose-dependent manner in -mutant breast cancer brain metastatic cell lines. In contrast, GDC-0084 led only to growth inhibition in wild-type cell lines . , treatment with GDC-0084 markedly inhibited the growth of -mutant, with accompanying signaling changes, and not wild-type brain tumors.

Conclusions: The results of this study suggest that the brain-penetrant PI3K/mTOR targeting GDC-0084 is a promising treatment option for breast cancer brain metastases with dysregulated PI3K/mTOR signaling pathway conferred by activating mutations. A national clinical trial is planned to further investigate the role of this compound in patients with brain metastases.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-3049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6685218PMC
June 2019

L265P mutation and loss are early mutational events in primary central nervous system diffuse large B-cell lymphomas.

Blood Adv 2019 02;3(3):375-383

Division of Hematology/Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA.

The genetic alterations that define primary central nervous system lymphoma (PCNSL) are incompletely elucidated, and the genomic evolution from diagnosis to relapse is poorly understood. We performed whole-exome sequencing (WES) on 36 PCNSL patients and targeted sequencing on a validation cohort of 27 PCNSL patients. We also performed WES and phylogenetic analysis of 3 matched newly diagnosed and relapsed tumor specimens and 1 synchronous intracranial and extracranial relapse. Immunohistochemistry (IHC) for programmed death-1 ligand (PD-L1) was performed on 43 patient specimens. Combined WES and targeted sequencing identified mutation in 67% (42 of 63) of patients, biallelic loss in 44% (16 of 36), and mutation in 61% (22 of 36). Copy-number analysis demonstrated frequent regions of copy loss (ie, ), with few areas of amplification. mutations were associated with improved progression-free and overall survival. We did not identify amplification at the / loci. IHC for PD-L1 revealed membranous expression in 30% (13 of 43) of specimens. Phylogenetic analysis of paired primary and relapsed specimens identified mutation and loss as early clonal events. PCNSL is characterized by frequent mutations within the B-cell receptor and NF-κB pathways. The lack of amplifications, along with membranous PD-L1 expression in 30% of our cohort, suggests that PD-1/PD-L1 inhibitors may be useful in a subset of PCNSL. WES of PCNSL provides insight into the genomic landscape and evolution of this rare lymphoma subtype and potentially informs more rational treatment decisions.
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http://dx.doi.org/10.1182/bloodadvances.2018027672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6373750PMC
February 2019

DMD genomic deletions characterize a subset of progressive/higher-grade meningiomas with poor outcome.

Acta Neuropathol 2018 11 19;136(5):779-792. Epub 2018 Aug 19.

Stephen E. and Catherine Pappas Center for Neuro-Oncology, Divisions of Hematology/Oncology and Neuro-Oncology, Departments of Medicine and Neurology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA, 02114, USA.

Progressive meningiomas that have failed surgery and radiation have a poor prognosis and no standard therapy. While meningiomas are more common in females overall, progressive meningiomas are enriched in males. We performed a comprehensive molecular characterization of 169 meningiomas from 53 patients with progressive/high-grade tumors, including matched primary and recurrent samples. Exome sequencing in an initial cohort (n = 24) detected frequent alterations in genes residing on the X chromosome, with somatic intragenic deletions of the dystrophin-encoding and muscular dystrophy-associated DMD gene as the most common alteration (n = 5, 20.8%), along with alterations of other known X-linked cancer-related genes KDM6A (n =2, 8.3%), DDX3X, RBM10 and STAG2 (n = 1, 4.1% each). DMD inactivation (by genomic deletion or loss of protein expression) was ultimately detected in 17/53 progressive meningioma patients (32%). Importantly, patients with tumors harboring DMD inactivation had a shorter overall survival (OS) than their wild-type counterparts [5.1 years (95% CI 1.3-9.0) vs. median not reached (95% CI 2.9-not reached, p = 0.006)]. Given the known poor prognostic association of TERT alterations in these tumors, we also assessed for these events, and found seven patients with TERT promoter mutations and three with TERT rearrangements in this cohort (n = 10, 18.8%), including a recurrent novel RETREG1-TERT rearrangement that was present in two patients. In a multivariate model, DMD inactivation (p = 0.033, HR = 2.6, 95% CI 1.0-6.6) and TERT alterations (p = 0.005, HR = 3.8, 95% CI 1.5-9.9) were mutually independent in predicting unfavorable outcomes. Thus, DMD alterations identify a subset of progressive/high-grade meningiomas with worse outcomes.
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http://dx.doi.org/10.1007/s00401-018-1899-7DOI Listing
November 2018