A5080311196- Lung Cancer Treatments and Mutations
- Lung Cancer Research Studies
- Cancer Genomics and Diagnostics
- Colorectal Cancer Treatments and Studies
- Cancer therapeutics and mechanisms
- Lung Cancer Diagnosis and Treatment
- RNA modifications and cancer
- Cancer Immunotherapy and Biomarkers
- PI3K/AKT/mTOR signaling in cancer
- Cancer Mechanisms and Therapy
- Gastric Cancer Management and Outcomes
- Chromatin Remodeling and Cancer
- Pancreatic and Hepatic Oncology Research
- HER2/EGFR in Cancer Research
- Brain Metastases and Treatment
- Peptidase Inhibition and Analysis
- Mechanisms of cancer metastasis
- Multiple and Secondary Primary Cancers
- Genetic factors in colorectal cancer
- Lymphoma Diagnosis and Treatment
- Cholangiocarcinoma and Gallbladder Cancer Studies
- Chronic Lymphocytic Leukemia Research
- Genetics and Neurodevelopmental Disorders
- Heat shock proteins research
- Melanoma and MAPK Pathways
Harvard University
2015-2025
Novartis (United States)
2020-2025
Dana-Farber Cancer Institute
2004-2025
Massachusetts General Hospital
2015-2024
Boston Biomedical Research Institute
2020-2024
University of Sunderland
2023
University Hospitals Bristol and Weston NHS Foundation Trust
2022
Global Cancer Institute
2022
University Hospitals Bristol NHS Foundation Trust
2022
Broad Institute
2006-2021
Oncogenic fusion genes consisting of EML4 and anaplastic lymphoma kinase (ALK) are present in a subgroup non-small-cell lung cancers, representing 2 to 7% such tumors. We explored the therapeutic efficacy inhibiting ALK tumors an early-phase clinical trial crizotinib (PF-02341066), orally available small-molecule inhibitor tyrosine kinase.After screening tumor samples from approximately 1500 patients with cancer for presence rearrangements, we identified 82 advanced ALK-positive disease who...
Lung cancers undergo dynamic genetic and histological changes upon developing resistance to EGFR inhibitors.
In single-group studies, chromosomal rearrangements of the anaplastic lymphoma kinase gene (ALK) have been associated with marked clinical responses to crizotinib, an oral tyrosine inhibitor targeting ALK. Whether crizotinib is superior standard chemotherapy respect efficacy unknown.
Alectinib, a highly selective inhibitor of anaplastic lymphoma kinase (ALK), has shown systemic and central nervous system (CNS) efficacy in the treatment ALK-positive non-small-cell lung cancer (NSCLC). We investigated alectinib as compared with crizotinib patients previously untreated, advanced NSCLC, including those asymptomatic CNS disease.In randomized, open-label, phase 3 trial, we randomly assigned 303 NSCLC to receive either (600 mg twice daily) or (250 daily). The primary end point...
The EML4-ALK fusion oncogene represents a novel molecular target in small subset of non-small-cell lung cancers (NSCLC). To aid identification and treatment these patients, we examined the clinical characteristics outcomes patients who had NSCLC with without EML4-ALK.Patients were selected for genetic screening on basis two or more following characteristics: female sex, Asian ethnicity, never/light smoking history, adenocarcinoma histology. was identified by using fluorescent situ...
Chromosomal rearrangements of the gene encoding ROS1 proto-oncogene receptor tyrosine kinase (ROS1) define a distinct molecular subgroup non-small-cell lung cancers (NSCLCs) that may be susceptible to therapeutic inhibition. Crizotinib is small-molecule inhibitor anaplastic lymphoma (ALK), ROS1, and another kinase, MET.
Purpose Chromosomal rearrangements involving the ROS1 receptor tyrosine kinase gene have recently been described in a subset of non–small-cell lung cancers (NSCLCs). Because little is known about these tumors, we examined clinical characteristics and treatment outcomes patients with NSCLC rearrangement. Patients Methods Using fluorescent situ hybridization (FISH) assay, screened 1,073 correlated rearrangement status characteristics, overall survival, when available, ALK status. In vitro...
Non-small-cell lung cancer (NSCLC) harboring the anaplastic lymphoma kinase gene (ALK) rearrangement is sensitive to ALK inhibitor crizotinib, but resistance invariably develops. Ceritinib (LDK378) a new that has shown greater antitumor potency than crizotinib in preclinical studies.In this phase 1 study, we administered oral ceritinib doses of 50 750 mg once daily patients with advanced cancers genetic alterations ALK. In an expansion received maximum tolerated dose. Patients were assessed...
Abstract KRAS is the most common oncogenic driver in lung adenocarcinoma (LUAC). We previously reported that STK11/LKB1 (KL) or TP53 (KP) comutations define distinct subgroups of KRAS-mutant LUAC. Here, we examine efficacy PD-1 inhibitors these subgroups. Objective response rates to blockade differed significantly among KL (7.4%), KP (35.7%), and K-only (28.6%) (P < 0.001) Stand Up To Cancer (SU2C) cohort (174 patients) with LUAC patients treated nivolumab CheckMate-057 phase III...
Multiple mechanisms of crizotinib resistance were identified in lung cancer patients including new secondary ALK mutations and activation receptor tyrosine kinases.
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...
A multistage microfluidic chip is capable of sorting rare EpCAM + and − CTCs from cancer patients’ whole blood.
Advanced, anaplastic lymphoma kinase (ALK)-positive lung cancer is currently treated with the first-generation ALK inhibitor crizotinib followed by more potent, second-generation inhibitors (e.g., ceritinib and alectinib) upon progression. Second-generation are generally effective even in absence of crizotinib-resistant mutations, likely reflecting incomplete inhibition many cases. Herein, we analyzed 103 repeat biopsies from ALK-positive patients progressing on various inhibitors. We find...
Lorlatinib, a third-generation inhibitor of anaplastic lymphoma kinase (ALK), has antitumor activity in previously treated patients with ALK-positive non–small-cell lung cancer (NSCLC). The efficacy lorlatinib, as compared that crizotinib, first-line treatment for advanced NSCLC is unclear.
Non-small cell lung cancers (NSCLC) harboring anaplastic lymphoma kinase (ALK) gene rearrangements invariably develop resistance to the ALK tyrosine inhibitor (TKI) crizotinib. Herein, we report first preclinical evaluation of next-generation TKI, ceritinib (LDK378), in setting crizotinib resistance. An interrogation vitro and vivo models acquired crizotinib, including lines established from biopsies patients with crizotinib-resistant NSCLC, revealed that potently overcomes mutations. In...
Entrectinib, a potent oral inhibitor of the tyrosine kinases TRKA/B/C, ROS1, and ALK, was evaluated in two phase I studies patients with advanced or metastatic solid tumors, including active central nervous system (CNS) disease. Here, we summarize overall safety report antitumor activity entrectinib cohort tumors harboring NTRK1/2/3, ALK gene fusions, naïve to prior TKI treatment targeting specific gene, who were treated at doses that achieved therapeutic exposures consistent recommended II...
Targeted cancer therapies have produced substantial clinical responses, but most tumors develop resistance to these drugs. Here, we describe a pharmacogenomic platform that facilitates rapid discovery of drug combinations can overcome resistance. We established cell culture models derived from biopsy samples lung patients whose disease had progressed while on treatment with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) tyrosine inhibitors and then subjected...
The anaplastic large cell kinase gene (ALK) is rearranged in approximately 5% of lung adenocarcinomas within the Asian population. We evaluated incidence and characteristics ALK-rearranged western population optimal diagnostic modality to detect ALK rearrangements routine clinical practice.We tested 358 from three institutions for by fluorescent situ hybridization (FISH) immunohistochemistry with without tyramide amplification. clinicopathologic tumors were compared.We identified 20 (5.6%)...