A5008479799- Cancer Immunotherapy and Biomarkers
- Melanoma and MAPK Pathways
- Immunotherapy and Immune Responses
- CAR-T cell therapy research
- Immune cells in cancer
- Cutaneous Melanoma Detection and Management
- Colorectal Cancer Treatments and Studies
- PI3K/AKT/mTOR signaling in cancer
- Cancer Genomics and Diagnostics
- Brain Metastases and Treatment
- Chronic Lymphocytic Leukemia Research
- Lung Cancer Treatments and Mutations
- Advanced Breast Cancer Therapies
- Ocular Oncology and Treatments
- Cancer Mechanisms and Therapy
- Computational Drug Discovery Methods
- HER2/EGFR in Cancer Research
- Synthesis and biological activity
- Glioma Diagnosis and Treatment
- Immune Cell Function and Interaction
- Click Chemistry and Applications
- Nanoplatforms for cancer theranostics
- Pancreatic and Hepatic Oncology Research
- Lung Cancer Research Studies
- Protein Degradation and Inhibitors
Massachusetts General Hospital
2016-2025
Harvard University
2016-2025
Center for Cancer Research
2021-2025
Cooper University Hospital
2025
Novartis (United States)
2024
Alphora Research (Canada)
2024
Harvard University Press
2012-2023
Dana-Farber Cancer Institute
2009-2023
Naval Postgraduate School
2011-2023
Boston University
2021-2023
To explore the distinct genotypic and phenotypic states of melanoma tumors, we applied single-cell RNA sequencing (RNA-seq) to 4645 single cells isolated from 19 patients, profiling malignant, immune, stromal, endothelial cells. Malignant within same tumor displayed transcriptional heterogeneity associated with cell cycle, spatial context, a drug-resistance program. In particular, all tumors harbored malignant two states, such that characterized by high levels MITF transcription factor also...
PD-1 inhibitors are established agents in the management of non-small cell lung cancer (NSCLC); however, only a subset patients derives clinical benefit. To determine activity PD-1/PD-L1 within clinically relevant molecular subgroups, we retrospectively evaluated response patterns among EGFR-mutant, anaplastic lymphoma kinase (ALK)-positive, and EGFR wild-type/ALK-negative patients.We identified 58 treated with inhibitors. Objective rates (ORR) were assessed using RECIST v1.1. PD-L1...
To evaluate the effects of BRAF inhibition on tumor microenvironment in patients with metastatic melanoma.Thirty-five biopsies were collected from 16 melanoma pretreatment (day 0) and at 10 to 14 days after initiation treatment either inhibitor alone (vemurafenib) or + MEK (dabrafenib trametinib) also taken time progression. Biopsies analyzed for antigens, T-cell markers, immunomodulatory cytokines.Treatment was associated an increased expression antigens increase CD8+ infiltrate. This a...
Abstract Treatment with immune checkpoint blockade (CPB) therapies often leads to prolonged responses in patients metastatic melanoma, but the common mechanisms of primary and acquired resistance these agents remain incompletely characterized have yet be validated large cohorts. By analyzing longitudinal tumor biopsies from 17 melanoma treated CPB therapies, we observed point mutations, deletions or loss heterozygosity (LOH) beta-2-microglobulin ( B2M ), an essential component MHC class I...
Oncogenic TACC-tics Human cancers exhibit many types of genomic rearrangements—including some that juxtapose sequences from two unrelated genes—thereby creating fusion proteins with oncogenic activity. Functional analysis these genes can provide mechanistic insights into tumorigenesis and potentially lead to effective drugs, as famously illustrated by the BCR-ABL gene in chronic myelogenous leukemia. Singh et al. (p. 1231 , published online 26 July) identify characterize a present 3% human...
Uveal melanoma is a disease that distinct from cutaneous melanoma, with low tumor mutational burden and 1-year overall survival of approximately 50% in patients metastatic uveal melanoma. Data showing proven benefit systemic treatment are lacking. Tebentafusp bispecific protein consisting an affinity-enhanced T-cell receptor fused to anti-CD3 effector can redirect T cells target glycoprotein 100-positive cells.In this open-label, phase 3 trial, we randomly assigned previously untreated...
Ipilimumab and other immune therapies are effective treatment options for patients with advanced melanoma but cause frequent immune-related toxic effects. Autoimmune diseases common, the safety efficacy of ipilimumab therapy in preexisting autoimmune disorders is not known.To determine disorders.Retrospective review who received at 9 academic tertiary referral centers from January 1, 2012, through August 2015. The data analysis was performed on 24, 2015.Ipilimumab therapy.Safety, terms...
Anti-PD-1 therapy yields objective clinical responses in 30-40% of advanced melanoma patients. Since most patients do not respond, predictive biomarkers to guide treatment selection are needed. We hypothesize that MHC-I/II expression is required for tumour antigen presentation and may predict anti-PD-1 response. In this study, across 60 cell lines, we find bimodal patterns MHC-II, while MHC-I was ubiquitous. A unique subset melanomas capable expressing MHC-II under basal or IFNγ-stimulated...
Treatment of BRAF-mutant melanoma with combined dabrafenib and trametinib, which target RAF the downstream MAP-ERK kinase (MEK)1 MEK2 kinases, respectively, improves progression-free survival response rates compared monotherapy. Mechanisms clinical resistance to RAF/MEK inhibition are unknown. We performed whole-exome sequencing (WES) whole-transcriptome (RNA-seq) on pretreatment drug-resistant tumors from five patients acquired dabrafenib/trametinib. In three these patients, we identified...
Therapeutic antibodies blocking programmed death-1 and its ligand (PD-1/PD-L1) induce durable responses in a substantial fraction of melanoma patients. We sought to determine whether the number and/or type mutations identified using next-generation sequencing (NGS) panel available clinic was correlated with response anti-PD-1 melanoma. Using archival samples from anti-PD-1/PD-L1-treated patients, we performed hybrid capture-based NGS on 236-315 genes T-cell receptor (TCR) initial validation...
Significance Metastasis is responsible for 90% of cancer-related deaths and driven by tumor cells circulating in blood. However, it believed that only individual can reach distant organs because multicellular clusters are too large to pass through narrow capillaries. Here, we collected evidence examining microscale devices, computational simulations, animals, which suggest this assumption incorrect, may transit capillaries unfolding into single-file chains. This previously unidentified cell...
Ipilimumab (Ipi) is approved by the Food and Drug Administration for treatment of unresectable or metastatic melanoma. Little known about Ipi-induced hypophysitis (IH), an important complication.The objectives study were as follows: 1) to examine prevalence IH, 2) characterize clinical course outcomes in 3) identify risk factors development 4) determine optimal strategies management IH.This was a retrospective review.The conducted at tertiary referral center.One hundred fifty-four adult...
It remains unclear whether high doses of glucocorticoids have a negative impact on the efficacy checkpoint inhibitors. To control for potential association between immune-related adverse events (irAEs) and improved survival, this study examined unique cohort patients who had same irAE treated with varying glucocorticoid doses.In total, 98 melanoma ipilimumab-induced hypophysitis were identified retrospectively in Partners Healthcare system using an automated electronic medical record query...
Immune checkpoint inhibitors (ICIs) treat an expanding range of cancers. Consistent basic data suggest that these same checkpoints are critical negative regulators atherosclerosis. Therefore, our objectives were to test whether ICIs associated with accelerated atherosclerosis and a higher risk atherosclerosis-related cardiovascular events.
Ulixertinib (BVD-523) is an ERK1/2 kinase inhibitor with potent preclinical activity in BRAF- and RAS-mutant cell lines. In this multicenter phase I trial (NCT01781429), 135 patients were enrolled to accelerated 3 + dose-escalation cohort six distinct dose-expansion cohorts. Dose escalation included 27 patients, dosed from 10 900 mg twice daily established the recommended II dose (RP2D) of 600 daily. exposure was proportional RP2D, which provided near-complete inhibition ERK whole blood....
Prognostically relevant RNA expression states exist in pancreatic ductal adenocarcinoma (PDAC), but our understanding of their drivers, stability, and relationship to therapeutic response is limited.To examine these attributes systematically, we profiled metastatic biopsies matched organoid models at single-cell resolution.In vivo, identify a new intermediate PDAC transcriptional cell state uncover distinct site-and state-specific tumor microenvironments (TMEs).Benchmarking against this...
Antibodies inhibiting the programmed death receptor 1 (PD-1) have demonstrated significant activity in treatment of advanced cutaneous melanoma. The efficacy and safety PD-1 blockade patients with uveal melanoma has not been well characterized.Fifty-eight stage IV received or ligand (PD-L1) antibodies between 2009 2015 at 9 academic centers. Patients who were evaluable for response eligible analysis. Imaging was performed every 12 weeks investigators' discretion. Safety clinical outcomes,...