A5069522876- Cancer Genomics and Diagnostics
- Sarcoma Diagnosis and Treatment
- Protein Degradation and Inhibitors
- CRISPR and Genetic Engineering
- Health Systems, Economic Evaluations, Quality of Life
- Bone Tumor Diagnosis and Treatments
- Musculoskeletal synovial abnormalities and treatments
- Cancer, Hypoxia, and Metabolism
- Bioinformatics and Genomic Networks
- Lung Cancer Treatments and Mutations
- Neuroblastoma Research and Treatments
- Computational Drug Discovery Methods
- Epigenetics and DNA Methylation
- Biochemical and Molecular Research
- Glioma Diagnosis and Treatment
- Cancer-related gene regulation
- Renal and related cancers
- Neuroendocrine Tumor Research Advances
- Acute Myeloid Leukemia Research
- Single-cell and spatial transcriptomics
- CAR-T cell therapy research
- Amino Acid Enzymes and Metabolism
- Gastric Cancer Management and Outcomes
- Enzyme Structure and Function
- PI3K/AKT/mTOR signaling in cancer
Kettering University
2010-2025
Memorial Sloan Kettering Cancer Center
2016-2025
Molecular Oncology (United States)
2018-2021
Cornell University
2016
Medical University of Vienna
2016
The University of Texas MD Anderson Cancer Center
2016
Columbia University
2006
Rockefeller University
2004
Estrogen receptor α (ESR1) mutations found in metastatic breast cancer (MBC) promote ligand-independent activation and resistance to estrogen-deprivation therapy laboratory models. The prevalence of these their potential impact on clinical outcomes has not been established.To determine the ESR1 (Y537S D538G) estrogen (ER)-positive MBC whether mutation is associated with inferior outcomes.From December 16, 2014, August 26, 2015, we analyzed cell-free DNA (cfDNA) from baseline plasma samples...
Cancer spread to the central nervous system (CNS) often is diagnosed late and unresponsive therapy. Mechanisms of tumor dissemination evolution within CNS are largely unknown because limited access tissue.We sequenced 341 cancer-associated genes in cell-free DNA from cerebrospinal fluid (CSF) obtained through routine lumbar puncture 53 patients with suspected or known involvement by cancer.We detected high-confidence somatic alterations 63% (20 32) metastases solid tumors, 50% (six 12)...
Abstract Somatic mutations in cytosolic or mitochondrial isoforms of isocitrate dehydrogenase (IDH1 IDH2, respectively) contribute to oncogenesis via production the metabolite 2-hydroxyglutarate (2HG). Isoform-selective IDH inhibitors suppress 2HG and induce clinical responses patients with IDH1- IDH2-mutant malignancies. Despite promising activity inhibitors, mechanisms that mediate resistance inhibition are poorly understood. Here, we describe four cases identify mutant isoform switching,...
The current analysis was performed to evaluate the impact of PIK3CA hotspot mutations on everolimus efficacy in BOLERO-2 participants, using cell-free DNA (cfDNA) from plasma samples collected at time patient randomisation. H1047R, E545K, and E542K plasma-derived cfDNA were analysed by droplet digital PCR (ddPCR). Median PFS estimated for subgroups defined each treatment arm. Among 550 patients included analysis, median vs placebo arms similar with tumours that had wild-type or mutant...
Abstract Predicting in vivo response to antineoplastics remains an elusive challenge. We performed a first-of-kind evaluation of two transcriptome-based precision cancer medicine methodologies predict tumor sensitivity comprehensive repertoire clinically relevant oncology drugs, whose mechanism action we experimentally assessed cognate cell lines. enrolled patients with histologically distinct, poor-prognosis malignancies who had progressed on multiple therapies, and developed low-passage,...
Using total internal reflection fluorescence microscopy, we have developed an assay to monitor individual fusion events between proteoliposomes containing vesicle soluble N -ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) and a supported planar bilayer cognate target SNAREs. Approach, docking, of vesicles the membrane were quantified by delivery subsequent lateral spread fluorescent phospholipids from into bilayer. Fusion probability was increased raising divalent...
Using a cell fusion assay, we show here that in addition to complete SNAREs also promote hemifusion as an alternative outcome. Approximately 65% of events resulted full fusion, and the remaining 35% hemifusion; those, approximately two thirds were permanent one third reversible. We predict this relatively close balance among outcomes could be tipped by binding regulatory proteins SNAREs, allowing for dynamic physiological regulation between reversible kiss-and-run-like events.
Tumor-derived cell free DNA (cfDNA) can be detected in plasma. We hypothesized that mutated BRAF V600 cfDNA could quantified the cerebrospinal fluid (CSF) of patients with central nervous system (CNS) metastases. collected CSF from V600E or K-mutated melanoma (N=8) Erdheim-Chester Disease (ECD) (N=3) suspected involvement on basis neurological symptoms (10/11), MRI imaging (8/11), both. was by digital PCR 6/11 (range 0.15-10.56 copies/μL). Conventional cytology negative all except two...
High-risk neuroblastoma, a pediatric tumor originating from the sympathetic nervous system, has low mutation load but highly recurrent somatic DNA copy number variants. Previously, segmental gains and/or amplifications allowed identification of drivers for neuroblastoma development. Using this approach, combined with gene dosage impact on expression and survival, we identified ribonucleotide reductase subunit M2 (RRM2) as candidate dependency factor further supported by growth inhibition...
Abstract Purpose: Epigenetic silencing of tumor suppressor genes (TSG) is an acquired abnormality observed in cancer and prototypically linked to DNA methylation. We postulated that pretreatment (priming) with 5-azacitidine would increase the efficacy chemotherapy by reactivating TSGs. This study was conducted identify a tolerable dose prior EOX (epirubicin, oxaliplatin, capecitabine) neoadjuvant patients locally advanced esophageal/gastric adenocarcinoma (EGC). Experimental Design: Eligible...
Abstract Multiple large-scale genomic profiling efforts have been undertaken in osteosarcoma to define the drivers of tumorigenesis, therapeutic response, and disease recurrence. The spatial temporal intratumor heterogeneity could also play a role promoting tumor growth treatment resistance. We conducted longitudinal whole-genome sequencing 37 samples from 8 patients with relapsed or refractory osteosarcoma. Each patient had at least one sample primary site metastatic relapse site. Subclonal...
Ewing Sarcoma (ES) and Desmoplastic Small Round Cell Tumors (DSRCT) are aggressive sarcomas molecularly characterized by EWSR1 gene fusions. As pathognomonic genomic events in these respective tumor types, fusions represent robust potential biomarkers for disease monitoring.To investigate the feasibility of identifying plasma derived cell-free DNA (cfDNA) from ES DSRCT patients, we evaluated two complementary approaches samples 17 patients with radiographic evidence disease. The first...
Desmoplastic small round cell tumor (DSRCT) is characterized by the EWSR1-WT1 t(11;22) (p13:q12) translocation. Few additional putative drivers have been identified, and research has suffered from a lack of model systems. Next-generation sequencing (NGS) data 68 matched tumor-normal samples, whole-genome 10 transcriptomic affymetrix array data, bank DSRCT patient-derived xenograft (PDX) are presented. fusions were noted to be simple, balanced events. Recurrent mutations uncommon, but in TERT...
Abstract PAX3-FOXO1, an oncogenic transcription factor, drives a particularly aggressive subtype of rhabdomyosarcoma (RMS) by enforcing gene expression programs that support malignant cell states. Here we show PAX3-FOXO1 + RMS cells exhibit altered pyrimidine metabolism and increased dependence on enzymes involved in de novo synthesis, including dihydrofolate reductase (DHFR). Consequently, display sensitivity to inhibition DHFR the chemotherapeutic drug methotrexate, this is rescued...
Abstract Cholangiocarcinoma is an aggressive biliary adenocarcinoma with limited treatment options. Stromal infiltration and intratumoral heterogeneity in this tumor type prevents identification of actionable dependencies from bulk-tissue profiles. While cholangiocarcinoma illustrates these challenges, they are common across many other tumors.To address we introduce a single-cell RNA-Sequencing (scRNA-Seq) framework for prioritization drugs to treat heterogeneous cell subpopulations....
Abstract Introduction: OBI-3424 is a DNA alkylating prodrug activated by aldo-keto reductase family 1 member C3 (AKR1C3). Elevated AKR1C3 expression observed in variety of tumors including prostate cancer, T-cell acute lymphoblastic leukemia (T-ALL), hepatocellular carcinoma (HCC) and hepatoblastoma. Interim Phase 2 data advanced HCC patients showed encouraging survival benefit good safety profile. Evaluation across spectrum pediatric highest T-ALL Prior preclinical testing patient-derived...
Malignant transformation requires the interaction of cancer cells with their microenvironment, including infiltrating leukocytes. However, somatic mutational studies have focused on alterations in cells, assuming that microenvironment is genetically normal. Because we hypothesized this might not be a valid assumption, performed exome sequencing and targeted to investigate for presence pathogenic mutations tumor-associated leukocytes breast cancers.We used evaluate sorted tumor-infiltrating...
Abstract Despite advances in multi-modal treatment approaches, clinical outcomes of patients suffering from PAX3-FOXO1 fusion oncogene-expressing alveolar rhabdomyosarcoma (ARMS) remain dismal. Here we show that PAX3-FOXO1-expressing ARMS cells are sensitive to pharmacological ataxia telangiectasia and Rad3 related protein (ATR) inhibition. Expression muscle progenitor is not only sufficient increase sensitivity ATR inhibition, but also exhibit increased structurally diverse inhibitors ATR....
SNARE proteins mediate the fusion of lipid bilayers by directed assembly coiled-coil domains arising from apposing membranes. We have utilized inverted cone-shaped lipids, antagonists necessary membrane deformation during to characterize extent and range up moment stalk formation between bilayers. The family acyl-CoAs specifically inhibits completion in an acyl-chain length-dependent manner. Removal acyl-CoA relieves inhibition initiates a burst with rates exceeding any point control curves...