A5079993897- Neurofibromatosis and Schwannoma Cases
- Neuroblastoma Research and Treatments
- Meningioma and schwannoma management
- Melanoma and MAPK Pathways
- Neuroendocrine Tumor Research Advances
- Protein Kinase Regulation and GTPase Signaling
- Glioma Diagnosis and Treatment
- Colorectal Cancer Treatments and Studies
- Lung Cancer Treatments and Mutations
- Cancer Genomics and Diagnostics
- Computational Drug Discovery Methods
- Cancer Mechanisms and Therapy
- Inflammatory mediators and NSAID effects
- Receptor Mechanisms and Signaling
- PI3K/AKT/mTOR signaling in cancer
- Cancer therapeutics and mechanisms
- Radiopharmaceutical Chemistry and Applications
- Cellular transport and secretion
- Neuropeptides and Animal Physiology
- Cancer Research and Treatments
- Advanced Breast Cancer Therapies
- Radiomics and Machine Learning in Medical Imaging
- Cancer Treatment and Pharmacology
- Hepatocellular Carcinoma Treatment and Prognosis
- Peptidase Inhibition and Analysis
Loxo Oncology at Lilly (United States)
2022-2024
Eli Lilly (United States)
2012-2023
University of North Carolina at Chapel Hill
2007-2019
Western University
2013
Howard Hughes Medical Institute
2012
Sidney Kimmel Cancer Center
2012
University of Virginia Health System
2012
Case Western Reserve University
2012
Johns Hopkins University
2012
Cancer Genetics (United States)
2012
Hepatocellular carcinoma (HCC) is one of the most deadly cancers worldwide and has no effective treatment, yet molecular basis hepatocarcinogenesis remains largely unknown. Here we report findings from a whole-genome sequencing (WGS) study 88 matched HCC tumor/normal pairs, 81 which are Hepatitis B virus (HBV) positive, seeking to identify genetically altered genes pathways implicated in HBV-associated HCC. We find beta-catenin be frequently mutated oncogene (15.9%) TP53 tumor suppressor...
Mutations in ERK signaling drive a significant percentage of malignancies. LY3009120, pan-RAF and dimer inhibitor, has preclinical activity RAS- BRAF-mutated cell lines including BRAF-mutant melanoma resistant to BRAF inhibitors. This multicenter, open-label, phase I clinical trial (NCT02014116) consisted part A (dose escalation) B confirmation) patients with advanced/metastatic cancer. In A, oral LY3009120 was dose escalated from 50 700 mg twice day on 28-day cycle. B, 300 given day. The...
Abstract Background: Mutations in KRAS are among the most frequent oncogenic drivers with G12C mutation found up to ~13% of NSCLC. LY3537982 is an oral, highly selective, and potent inhibitor G12C, which preclinically delivers >90% sustained target occupancy. We present initial results from LOXO-RAS-20001, a phase 1 study patients (pts) G12C-mutant advanced solid tumors (NCT04956640). Methods: monotherapy dose escalation followed mTPI-2 method. Dose expansion cohorts included...
94 Background: LY3537982 is an oral, potent, and highly selective inhibitor of GDP-bound KRAS G12C with unique pharmacologic properties that achieve high target occupancy at low absolute exposures. Here we present results GI tumors treated on LOXO-RAS-20001, a phase 1 study in patients (pts) mutation. Methods: Dose escalation followed mTPI-2 method. expansion included combination cetuximab colorectal cancer (CRC). All pts were naïve. Key objectives to determine the RP2D, safety, PK,...
8510 Background: While immunotherapy (IO) is established as the cornerstone of first-line treatment for KRAS-mutant NSCLC, outcomes remain suboptimal. Further progress may be achieved with addition targeted therapy to IO, an paradigm in some other cancer types (RCC), but historically challenging NSCLC. Here, we study pembrolizumab plus olomorasib, a potent and highly selective second-generation inhibitor GDP-bound KRAS G12C, NSCLC patients treated on LOXO-RAS-20001, phase 1/2 olomorasib...
3007 Background: Olomorasib is a potent and highly selective second-generation inhibitor of GDP-bound KRAS G12C, which preclinically delivers >90% sustained target occupancy. Here, we report updated results from LOXO-RAS-20001, phase 1/2 study olomorasib in patients with G12C-mutant advanced solid tumors (NCT04956640). Methods: Patients (pts) positive for G12C (tissue or plasma) were eligible. Dose escalation used mTPI-2 method, followed by expansion cohorts NSCLC (with/without prior...
Abstract Anti-EGFR antibodies are effective in therapies for late-stage colorectal cancer (CRC); however, many tumours unresponsive or develop resistance. We performed genomic analysis of intrinsic and acquired resistance to anti-EGFR therapy prospectively collected tumour samples from 25 CRC patients receiving cetuximab (an EGFR inhibitor). Of patients, 13 displayed cetuximab; 12 were intrinsically sensitive. obtained six re-biopsy at the sensitive patients. NCOA4–RET LMNA–NTRK1 fusions...
The phase I study characterized the safety, pharmacokinetics, anti-tumor activity, and recommended II dose/schedule of LY3164530 in patients with advanced or metastatic cancer.Patients received on days 1 15 (Schedule 1: 300, 600, 1000, 1250 mg) Days 1, 8, 15, 22 2: 500 600 each 28 cycle. Dose escalation used a modified toxicity probability interval model.Dose defined maximum tolerated dose (MTD) 1000 mg Schedule 2. Treatment-emergent adverse events related to treatment were consistent...
// Bruce W. Konicek 1 , Andrew R. Capen Kelly M. Credille Philip J. Ebert Beverly L. Falcon Gary Heady Bharvin K.R. Patel Victoria Peek Jennifer Stephens Julie A. Stewart Stephanie Stout David E. Timm Suzane Um Melinda D. Willard Isabella H. Wulur Yi Zeng Yong Wang Richard Walgren and Sau-Chi Betty Yan Lilly Research Laboratories, Eli Company, Indianapolis, IN 46285, USA Correspondence to: Konicek, email: konicek_bruce_w@lilly.com Keywords: NTRK fusion; merestinib; LY2801653; inhibitor; type...
Background Regulator of G-protein signaling (RGS) proteins have been well-described as accelerators Gα-mediated GTP hydrolysis ("GTPase-accelerating proteins" or GAPs). However, RGS with complex domain architectures are now known to regulate much more than Gα GTPase activity. RGS14 contains tandem Ras-binding domains that reported bind Rap- but not Ras GTPases in vitro, leading the suggestion is a Rap-specific effector. recent data from mammals and Drosophila imply that, vivo, may instead be...
Heterotrimeric G-proteins are molecular switches integral to a panoply of different physiological responses that many organisms make environmental cues. The switch from inactive active Gαβγ heterotrimer relies on nucleotide cycling by the Gα subunit: exchange GTP for GDP activates Gα, whereas its intrinsic enzymatic activity catalyzes hydrolysis and inorganic phosphate, thereby reverting state. In several genetic studies filamentous fungi, such as rice blast fungus Magnaporthe oryzae, G42R...
The activity of metabotropic glutamate receptors (mGluRs) is known to be altered as the consequence neurodegenerative diseases such Alzheimer, Parkinson, and Huntington disease. However, little attention has been paid this receptor family's potential link with cancer. Recent reports indicate mGluR signaling in various tumor types, several somatic mutations mGluR1a lung cancer were recently described. Group 1 mGluRs (mGluR1a mGluR5) are coupled primarily G<i>α</i>q, leading activation...
3001 Background: LY3214996 is a selective and potent ERK1/2 inhibitor that has demonstrated tumor growth inhibition in several pre-clinical models with BRAF, RAS, or MAP2K1 mutations. This the first-in-human Phase 1 Study of adv CA pts. Methods: The goals this DE study were to determine recommended 2 dose (RP2D), safety, pharmacokinetic (PK), preliminary efficacy (NCT02857270; I8S-MC-JUAB; Eli Lilly & Co.). Pts CA, ≥18 yrs age, ECOG ≤1, adequate organ function eligible. Pharmacodynamic...
Summary BACKGROUND LY3023414 is a selective, ATP competitive inhibitor of class I PI3K isoforms, mTORC1/2 and DNA-PK. A Phase 1 dose escalation, 200 mg twice daily (BID) was the determined recommended phase 2 (RP2D). We report antitumor activity safety monotherapy in patients with advanced mesothelioma. METHODS Patients enrolled had malignant pleural or peritoneal mesothelioma measurable disease, ECOG PS 0–1, were refractory ineligible to receive standard therapies. received BID. This...
Heterotrimeric G-proteins are a class of signal transduction proteins highly conserved throughout evolution that serve as dynamic molecular switches regulating the intracellular communication initiated by extracellular signals including sensory information. This property is achieved guanine nucleotide cycle wherein inactive, signaling-incompetent Gα subunit normally bound to GDP; activation signaling-competent occurs through exchange GDP for GTP (typically catalyzed via seven-transmembrane...
The roles of cholecystokinin 2 receptor (CCK2R) in numerous physiologic processes the gastrointestinal tract and central nervous system are well documented. There has been some evidence that CCK2R alterations play a role cancers, but functional significance these for tumorigenesis is unknown. We have identified six mutations among panel 140 colorectal cancers 44 gastric cancers. show increase activity, activate multiple downstream signaling pathways, cell migration, promote angiogenesis. Our...
Abstract Purpose: Plexiform neurofibromas (PNF) are peripheral nerve sheath tumors that cause significant morbidity in persons with neurofibromatosis type 1 (NF1), yet treatment options remain limited. To identify novel therapeutic targets for PNF, we applied an integrated multi-omic approach to quantitatively profile kinome enrichment a mouse model has predicted responses clinical trials NF1-associated PNF high fidelity. Experimental Design: Utilizing RNA sequencing combined chemical...
Regulators of G Protein Signaling (RGS proteins) inhibit protein-coupled receptor (GPCR) signaling by accelerating the GTP hydrolysis rate activated Gα subunits. Some RGS proteins exert additional signal modulatory functions, and RGS12 is one such protein, with five additional, functional domains: a PDZ domain, phosphotyrosine-binding two Ras-binding domains, Gα·GDP-binding GoLoco motif. expression temporospatially regulated in developing mouse embryos, notable somites skeletal muscle. We...
ObjectivesMetastatic non–small cell lung cancer (mNSCLC) is characterized by complex genomic alterations. NF1 mutations may confer distinct clinical characteristics within NSCLC, and real-world evidence on concurrent mutations, treatment patterns, health outcomes lacking.Materials MethodsThis retrospective study was performed in patients with mNSCLC treated the Flatiron Health network who underwent FoundationOne tumor-sequencing. Anticancer therapies, progression-free survival (rwPFS),...
2507 Background: LY3009120, a pan-Raf and dimer inhibitor, demonstrates inhibition of phospho-Mek/Erk tumor growth in several non-clinical cancer models with BRAF, NRAS, or KRAS mutations. This is the first-in-human phase 1 study LY3009120 patients (pts) advanced cancer. Methods: The safety tolerability was evaluated pts aged 18 years older who had an ECOG performance status ≤1, at least unidimensionally measurable lesion (RECIST 1.1), adequate organ function (NCT02014116; I6X-MC-JBDA; Eli...
Abstract Background This retrospective, real-world study evaluated the prevalence of brain metastases, clinicodemographic characteristics, systemic treatments, and factors associated with overall survival among patients advanced non–small cell lung cancer (aNSCLC) in US. We also described genomic characterization 180 metastatic specimens frequency clinically actionable genes. Materials Methods De-identified electronic health records-derived data adult diagnosed aNSCLC between 2011 2017 were...
<p>Raw log2LFQ values for kinases profiled by MIB/MS</p>