A5029970520- PI3K/AKT/mTOR signaling in cancer
- Cancer Genomics and Diagnostics
- Monoclonal and Polyclonal Antibodies Research
- Metabolism, Diabetes, and Cancer
- Biochemical and Molecular Research
- HER2/EGFR in Cancer Research
- Radiopharmaceutical Chemistry and Applications
- Molecular Biology Techniques and Applications
- Immunotherapy and Immune Responses
- Genetics, Bioinformatics, and Biomedical Research
- Glycosylation and Glycoproteins Research
- Advanced Biosensing Techniques and Applications
- Genetic factors in colorectal cancer
- Advanced Breast Cancer Therapies
- Gastrointestinal Tumor Research and Treatment
- Cancer Cells and Metastasis
- Gastric Cancer Management and Outcomes
- Genomics and Phylogenetic Studies
- BRCA gene mutations in cancer
- Inflammatory Bowel Disease
- Eosinophilic Esophagitis
- Cancer Treatment and Pharmacology
- Cancer Immunotherapy and Biomarkers
- Microscopic Colitis
- Pancreatic and Hepatic Oncology Research
Broad Institute
2019-2024
Virginia Commonwealth University
2017
Centre Hospitalier Universitaire de Rouen
1968
Hôpital Bichat-Claude-Bernard
1968
Sacituzumab govitecan (SG), the first antibody-drug conjugate (ADC) approved for triple-negative breast cancer, incorporates anti-TROP2 antibody hRS7 conjugated to a topoisomerase-1 (TOP1) inhibitor payload. We sought identify mechanisms of SG resistance through RNA and whole-exome sequencing pretreatment postprogression specimens. One patient exhibiting de novo progression lacked TROP2 expression, in contrast robust expression focal genomic amplification TACSTD2/TROP2 observed with deep,...
PIK3CA mutations occur in ∼8% of cancers, including ∼40% HR-positive breast where the PI3K-alpha (PI3Kα)-selective inhibitor alpelisib is FDA approved combination with fulvestrant. Although prior studies have identified resistance mechanisms, such as PTEN loss, clinically acquired to PI3Kα inhibitors remains poorly understood. Through serial liquid biopsies and rapid autopsies 39 patients advanced cancer developing inhibitors, we observe that 50% acquire genomic alterations within PI3K...
Microphthalmia transcription factor (MiT)–family translocation renal cell carcinomas (RCCs) are an unusual but increasingly recognized group of RCC defined by recurrent gene rearrangements involving the TFE3 or TFEB loci. These genes belong to MiT family, imparting a unique expression melanocytic markers seen in these tumors. The Xp11 RCCs more common and better studied than their t(6;11) counterpart, newly emerging entity TFEB-amplified (technically falling under unclassified category RCC)...
<div>Abstract<p><i>PIK3CA</i> mutations occur in ∼8% of cancers, including ∼40% HR-positive breast where the PI3K-alpha (PI3Kα)-selective inhibitor alpelisib is FDA approved combination with fulvestrant. Although prior studies have identified resistance mechanisms, such as <i>PTEN</i> loss, clinically acquired to PI3Kα inhibitors remains poorly understood. Through serial liquid biopsies and rapid autopsies 39 patients advanced cancer developing inhibitors,...
<p>Supplementary Figure S1: PI3K pathway activity in selected cases with acquired PTEN alteration. Supplementary S2. Validation of AKT constructs expression T47D cells. S3. activating mutations confer resistance to PI3Ka inhibitors. S4: Free energy calculations predict orthosteric inhibitors due specific double PIK3CA mutants. S5: perturbation predicts reduced binding S6. Expression S7. MCF7 cells expressing W780R or Q859H mutants show differential response S8: Chemical structure...
<div>Abstract<p><i>PIK3CA</i> mutations occur in ∼8% of cancers, including ∼40% HR-positive breast where the PI3K-alpha (PI3Kα)-selective inhibitor alpelisib is FDA approved combination with fulvestrant. Although prior studies have identified resistance mechanisms, such as <i>PTEN</i> loss, clinically acquired to PI3Kα inhibitors remains poorly understood. Through serial liquid biopsies and rapid autopsies 39 patients advanced cancer developing inhibitors,...
<p>Supplementary Figure S1: PI3K pathway activity in selected cases with acquired PTEN alteration. Supplementary S2. Validation of AKT constructs expression T47D cells. S3. activating mutations confer resistance to PI3Ka inhibitors. S4: Free energy calculations predict orthosteric inhibitors due specific double PIK3CA mutants. S5: perturbation predicts reduced binding S6. Expression S7. MCF7 cells expressing W780R or Q859H mutants show differential response S8: Chemical structure...
<div>Abstract<p><i>PIK3CA</i> mutations occur in ∼8% of cancers, including ∼40% HR-positive breast where the PI3K-alpha (PI3Kα)-selective inhibitor alpelisib is FDA approved combination with fulvestrant. Although prior studies have identified resistance mechanisms, such as <i>PTEN</i> loss, clinically acquired to PI3Kα inhibitors remains poorly understood. Through serial liquid biopsies and rapid autopsies 39 patients advanced cancer developing inhibitors,...
<p>Supplementary Figure S1: PI3K pathway activity in selected cases with acquired PTEN alteration. Supplementary S2. Validation of AKT constructs expression T47D cells. S3. activating mutations confer resistance to PI3Ka inhibitors. S4: Free energy calculations predict orthosteric inhibitors due specific double PIK3CA mutants. S5: perturbation predicts reduced binding S6. Expression S7. MCF7 cells expressing W780R or Q859H mutants show differential response S8: Chemical structure...
<p>Supplementary Figure S1: PI3K pathway activity in selected cases with acquired PTEN alteration. Supplementary S2. Validation of AKT constructs expression T47D cells. S3. activating mutations confer resistance to PI3Ka inhibitors. S4: Free energy calculations predict orthosteric inhibitors due specific double PIK3CA mutants. S5: perturbation predicts reduced binding S6. Expression S7. MCF7 cells expressing W780R or Q859H mutants show differential response S8: Chemical structure...
Abstract PIK3CA is among the most frequently mutated kinases in multiple types of cancer, including 40% hormone receptor-positive, HER2-negative breast cancers. The PI3Kα-selective orthosteric inhibitor alpelisib only drug targeting currently approved this patient population, combination with fulvestrant. As commonly observed other targeted therapies, resistance often develops during treatment inhibitors. In one largest cohorts to date, serial liquid biopsies and rapid autopsies 39 patients,...
Abstract Background: PIK3CA mutations occur in ~40% of HR-positive breast cancers, where alpelisib, an orthosteric PI3Kα inhibitor, is FDA-approved combination with fulvestrant. Although prior studies have identified potential resistance mechanisms, such as PTEN loss, clinical acquired to inhibitors and the role next-generation allosteric remain poorly understood. Methods: To identify on-target off-target alterations potentially mediating inhibitors, we used a targeted sequencing assay...
Abstract Detecting cancer at early stages or upon recurrence is critical to decreasing morbidity and mortality. We developed TuFEst (Tumor Fraction Estimator), a cost-effective computational approach for pan-cancer detection tumor burden estimation from ultra-low coverage whole genome sequencing (~0.1x, ULP-WGS) of minimally invasive cell-free DNA (cfDNA). Current state-of-the-art methods estimate fraction (TF) ULP-WGS depending exclusively on total copy number variation, which loses signal...
Abstract Determining patterns and mechanisms of drug resistance is fundamentally required for improving clinical outcome cancer treatments. The ability to study multiple samples from different metastatic sites the same patient a clinically challenging task, which has become possible with advent “rapid” autopsy procedures (&lt;6 hours death) conducted on patients deceased cancer. We have obtained analyzed whole-exome, whole genome transcriptome sequencing data advanced breast derived...
<div>Abstract<p>Sacituzumab govitecan (SG), the first antibody–drug conjugate (ADC) approved for triple-negative breast cancer, incorporates anti-TROP2 antibody hRS7 conjugated to a topoisomerase-1 (TOP1) inhibitor payload. We sought identify mechanisms of SG resistance through RNA and whole-exome sequencing pretreatment postprogression specimens. One patient exhibiting <i>de novo</i> progression lacked TROP2 expression, in contrast robust expression focal genomic...
Abstract Comprehensive characterization of tumor evolution is essential for understanding the drivers metastasis and treatment resistance, which are still largely unknown. Studying resistance requires large cohorts patients; each patient, a comprehensive phylogenetic tree used to follow clones over time space. Deep whole-genome sequencing (WGS) enables creation more robust phylogenies, since (i) clone characterized by far clone-specific mutations (compared whole-exome or panel sequencing);...