A5061790056- Cancer Genomics and Diagnostics
- Prostate Cancer Treatment and Research
- Prostate Cancer Diagnosis and Treatment
- Genetic factors in colorectal cancer
- Lung Cancer Treatments and Mutations
- Microtubule and mitosis dynamics
- Polyomavirus and related diseases
- Science, Research, and Medicine
- Cancer Immunotherapy and Biomarkers
- Bladder and Urothelial Cancer Treatments
- Cancer-related Molecular Pathways
- Ubiquitin and proteasome pathways
- Renal cell carcinoma treatment
- Radiomics and Machine Learning in Medical Imaging
- DNA Repair Mechanisms
- Full-Duplex Wireless Communications
- Pancreatic and Hepatic Oncology Research
- RNA modifications and cancer
- Plant Virus Research Studies
- Cancer-related molecular mechanisms research
- PARP inhibition in cancer therapy
- Cancer-related gene regulation
- Hippo pathway signaling and YAP/TAZ
- Virus-based gene therapy research
- Colorectal Cancer Treatments and Studies
Foundation Medicine (United States)
2020-2025
Editas Medicine (United States)
2023
Dana-Farber Cancer Institute
2003-2022
Harvard University
1999-2022
Cambridge Scientific (United States)
2022
Broad Institute
2017-2022
Boston Foundation
2022
The Medical Foundation
2022
Brigham and Women's Hospital
2022
Boston University
2020
Merkel cell polyomavirus (MCV) is a virus discovered in our laboratory at the University of Pittsburgh that monoclonally integrated into genome approximately 80% human carcinomas (MCCs). Transcript mapping was performed to show MCV expresses transcripts MCCs similar large T (LT), small (ST), and 17kT SV40. Nine MCC tumor-derived LT genomic sequences have been examined, all were found harbor mutations prematurely truncating helicase. In contrast, four presumed episomal viruses from nontumor...
Merkel cell polyomavirus (MCV) is a recently discovered human virus closely related to African green monkey lymphotropic polyomavirus. MCV DNA integrated in approximately 80% of carcinomas (MCC), neuroendocrine skin cancer linked lymphoid malignancies such as chronic lymphocytic leukemia (CLL). To assess infection and its association with diseases, we developed monoclonal antibody that specifically recognizes endogenous transfected large T (LT) antigen. We show expression LT protein...
FoundationOne®CDx (F1CDx) is a United States (US) Food and Drug Administration (FDA)-approved companion diagnostic test to identify patients who may benefit from treatment in accordance with the approved therapeutic product labeling for 28 drug therapies. F1CDx utilizes next-generation sequencing (NGS)-based comprehensive genomic profiling (CGP) technology examine 324 cancer genes solid tumors. reports known likely pathogenic short variants (SVs), copy number alterations (CNAs), select...
Comprehensive genomic profiling (CGP) is of increasing value for patients with metastatic castration-resistant prostate cancer (mCRPC). mCRPC tends to metastasize bone, making tissue biopsies challenging obtain. We hypothesized CGP cell-free circulating tumor DNA (ctDNA) could offer a minimally invasive alternative detect targetable alterations (GA) that inform clinical care.Using plasma from 3,334 (including 1,674 screening samples TRITON2/3), we evaluated the landscape GAs detected in...
Recent clinical development of KRAS inhibitors has heightened interest in the genomic landscape KRAS-altered cancers. We performed a pan-cancer analysis samples from 426,706 adult patients with solid or hematologic malignancies using comprehensive profiling; additional analyses included 62,369 liquid biopsy and 7241 pediatric samples. 23% had alterations; 88% were mutations, most commonly G12D/G12V/G12C/G13D/G12R, prevalence was similar biopsies. Co-alteration landscapes largely across...
Growth factor signaling is mediated through Class IA phosphatidylinositol 3-kinases (PI3Ks). Among this class of enzymes, only p110alpha, encoded by the PIK3CA gene, has been found to be mutant in human cancers. To determine specific functions we generated mice carrying a conditionally targeted allele gene. Here, report that PIK3CA-knockout mouse embryonic fibroblasts are deficient cellular response various growth factors, unable differentiate into adipocytes, and resistant oncogenic...
Resistance to anoikis, the subtype of apoptosis triggered by lack adhesion, contributes malignant transformation and development metastasis. Although several lines evidence suggest that p53 plays a critical role in pathway(s) connect cell detachment remain undefined. Here, through use kinome-wide loss-of-function screen, we identify serine-threonine kinase SIK1 (salt-inducible 1) as regulator p53-dependent anoikis. Inactivation compromised function anoikis allowed cells grow an...
Merkel cell polyomavirus (MCV), a previously unrecognized component of the human viral skin flora, was discovered as mutated and clonally-integrated virus inserted into carcinoma (MCC) genomes. We reconstructed replicating MCV clone (MCV-HF), then sites required for replication or interaction with cellular proteins to examine efficiency gene expression. Three days after MCV-HF transfection 293 cells, although is not robust, encapsidated DNA protein can be readily isolated by density gradient...
Alternative splicing of mRNA precursors represents a key gene expression regulatory step and permits the generation distinct protein products with diverse functions. In genome-scale screen for inducers epithelial-to-mesenchymal transition (EMT), we found striking enrichment RNA-binding proteins. We validated that QKI RBFOX1 were necessary sufficient to induce an intermediate mesenchymal cell state increased tumorigenicity. Using RNA-seq eCLIP analysis, coordinately regulated function...
The most useful biomarkers for clinical decision-making identify patients likely to have improved outcomes with one treatment vs another.To evaluate class-specific of receiving immune checkpoint inhibitor (ICI) taxane chemotherapy by tumor mutational burden (TMB).This comparative effectiveness analysis variables and used prospectively defined biomarker-stratified genomic data from a deidentified clinicogenomic database. Data included men previously treated metastatic castration-resistant...
Profiling of circulating tumor DNA (ctDNA) is increasingly adopted in the management solid tumors, concurrent with increased availability more comprehensive ctDNA panels. However, variable shed can result assay sensitivity. We studied relationship between fraction (TF) and detection actionable alterations across cancer types.A total 23,482 liquid biopsies (LBx) submitted September 2020 October 2021 were sequenced using a hybrid capture panel that reports genomic (GAs) biomarkers 324...
Abstract Purpose: Chemoimmunotherapy (chemoIO) is a prevalent first-line treatment for advanced driver-negative non–small cell lung cancer (NSCLC), with maintenance therapy given after induction. However, there significant clinical variability in the duration, dosing, and timing of induction chemoIO. We used circulating tumor DNA (ctDNA) monitoring to inform outcomes patients NSCLC receiving Experimental Design: This retrospective study included 221 from phase III trial...
Simian virus 40 (SV40) large T antigen (LT) is a multifunctional protein that important for viral replication and oncogenic transformation. Previously, infection of monkey or human cells with SV40 was shown to lead the induction DNA damage response signaling, which required efficient replication. However, it not clear if LT sufficient induce and, so, what genetic requirements functional consequences might be. Here, we show expression alone, without origin, can key markers including...
Here, we show how targeting protein phosphatase 2A (PP2A), a key regulator of cellular phosphorylation, can either induce or prevent apoptosis depending on what other signals the cell is receiving. The oncoprotein polyoma small T interacts with PP2A to regulate survival. In presence growth factors, induces apoptosis. Akt activity, which usually promotes survival, required for this death response, because inhibitors PI3 kinase protect cells from death. activation under these conditions...
We demonstrated previously that expression of simian virus 40 (SV40) large T antigen (LT), without a viral origin, is sufficient to induce the hallmarks cellular DNA damage response (DDR), such as focal accumulation gamma-H2AX and 53BP1, via Bub1 binding. Here we expand our characterization LT effects on DDR. Using comet assays, demonstrate induces overt damage. The Fanconi anemia pathway, associated with replication stress, becomes activated, since FancD2 accumulates in foci,...
Androgen-receptor (AR) inhibitors, including enzalutamide, are used for treatment of all metastatic castration-resistant prostate cancers (mCRPCs). However, some patients develop resistance or never respond. We find that the transcription factor CREB5 confers enzalutamide in an open reading frame (ORF) expression screen and tumor xenografts. overexpression is essential enzalutamide-resistant patient-derived organoid. In AR-expressing cancer cells, interactions enhance AR activity at a subset...
Alterations involving serine-threonine phosphatase PP2A subunits occur in a range of human cancers, and partial loss function contributes to cell transformation. Displacement regulatory B by the SV40 Small T antigen (ST) or mutation/deletion alters abundance types complexes cells, leading Here, we show that ST not only displaces common but also promotes A-C subunit interactions with alternative (B’’’, striatins) are components Striatin-interacting kinase (STRIPAK) complex. We found STRN4,...
The mitotic spindle checkpoint protein Bub1 has been found to be mutated at low frequency in certain human cancers characterized by aneuploidy. Simian virus 40 large T antigen efficiently immortalizes rodent cells and occasionally transforms them tumorigenicity. can also cause genomic instability, inducing chromosomal aberrations Here, we report an interaction between antigen. coimmunoprecipitates with endogenous Bub3, another component of the complex. Genetic analysis demonstrates that is...
MET exon 14 (METex14) skipping alterations are oncogenic drivers in non-small-cell lung cancer (NSCLC). We present a comprehensive overview of METex14 samples from 1,592 patients with NSCLC, associated clinicogenomic characteristics, potential mechanisms acquired resistance, treatment patterns, and outcomes to inhibitors.Hybrid capture-based genomic profiling (CGP) was performed on 69,219 NSCLC. For patterns analysis, advanced METex14-altered NSCLC were selected the Flatiron...
At diagnosis, the majority of patients with intrahepatic cholangiocarcinoma (IHCC) present advanced disease and a poor prognosis. Comprehensive genomic profiling (CGP) early in course may increase access to targeted therapies clinical trials; however, unresolved issues remain surrounding optimal biopsy type submit for CGP.Mutational frequencies between primary tumor biopsies (Pbx), metastatic (Mbx), liquid (Lbx) 1,632 IHCC were compared.Potentially actionable alterations found 52%, 34%, 35%...
Metastasis is a complex and poorly understood process. In pancreatic cancer, loss of the transforming growth factor (TGF)-β/BMP effector SMAD4 correlated with changes in altered histopathological transitions, metastatic disease, poor prognosis. this study, we use isogenic cancer cell lines to identify regulated genes that contribute development colonization. We perform an vivo screen identifying FOSL1 as both target sufficient drive colonization lung. The targeting these early treatment may...