A5029616157- HER2/EGFR in Cancer Research
- Advanced Breast Cancer Therapies
- Lung Cancer Treatments and Mutations
- Monoclonal and Polyclonal Antibodies Research
- Colorectal Cancer Treatments and Studies
- PI3K/AKT/mTOR signaling in cancer
- RNA modifications and cancer
- Chronic Lymphocytic Leukemia Research
- Histone Deacetylase Inhibitors Research
- Ubiquitin and proteasome pathways
- Autophagy in Disease and Therapy
- Computational Drug Discovery Methods
- Estrogen and related hormone effects
- Peptidase Inhibition and Analysis
- Gastric Cancer Management and Outcomes
- Cancer, Lipids, and Metabolism
- Cancer Treatment and Pharmacology
- Hepatocellular Carcinoma Treatment and Prognosis
- Cancer Genomics and Diagnostics
- Cancer-related gene regulation
- Epigenetics and DNA Methylation
- Click Chemistry and Applications
- PARP inhibition in cancer therapy
- Protein Degradation and Inhibitors
- CAR-T cell therapy research
QED Technologies (United States)
2020
Puma Biotechnology (United States)
2017-2019
Cardiff University
2018
University Hospital Llandough
2018
Vanderbilt University Medical Center
2018
Swim Across America
2012
Harnessing the adaptive immune response to treat malignancy is now a clinical reality. Several strategies are used melanoma; however, very few result in complete response. CD4+ T cells important and potent mediators of anti-tumor immunity adoptive transfer specific can promote tumor regression mice patients. OX40, costimulatory molecule expressed primarily on activated cells, promotes enhances with limited success large tumors mice. We show that OX40 engagement, context chemotherapy-induced...
Mutations in ERBB2, the gene encoding epidermal growth factor receptor (EGFR) family member HER2, are common and drive of "HER2-negative" (not ERBB2 amplified) tumors but rare "HER2-positive" (ERBB2 breast cancer. We analyzed DNA-sequencing data from HER2-positive patients used cell lines a patient-derived xenograft model to test consequence HER2 mutations on efficacy anti-HER2 agents such as trastuzumab, lapatinib, neratinib, an irreversible pan-EGFR inhibitor. were present ~7% tumors, all...
// Laurence Booth 1 , Jane L. Roberts Andrew Poklepovic 2 Francesca Avogadri-Connors 3 Richard E. Cutler Alshad S. Lalani and Paul Dent Department of Biochemistry Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298, USA Medicine, Puma Biotechnology Inc., Los Angeles, CA 90024, Correspondence to: Dent, email: paul.dent@vcuhealth.org Keywords: autophagy, HDAC, receptor tyrosine kinase, neratinib Received: August 21, 2017 Accepted: September 13, Published: October 09,...
The phase III ExteNET trial showed improved invasive disease-free survival in patients with HER2+ breast cancer treated neratinib versus placebo after trastuzumab-based adjuvant therapy. benefit from appeared to be greater ER+/HER2+ tumors. We thus sought discover mechanisms that may explain the extended therapy neratinib.Experimental Design: Mice established MDA-MB-361 tumors were paclitaxel plus trastuzumab ± pertuzumab for 4 weeks, and then randomized fulvestrant treatment. was evaluated...
The FDA approved irreversible inhibitor of ERBB1/2/4, neratinib, was recently shown to rapidly down-regulate the expression ERBB1/2/4 as well levels c-MET and mutant K-RAS via autophagic degradation. In present studies, in a dose-dependent fashion, neratinib reduced or N-RAS, which augmented an additive greater than fashion by HDAC inhibitors sodium valproate AR42. Neratinib could reduce PDGFRα GBM cells, that enhanced valproate. Knock down Beclin1 ATG5 prevented combined with / AR42 from...
The irreversible ERBB1/2/4 inhibitor neratinib has been shown to rapidly down-regulate the expression of as well levels c-MET, PDGFRα and mutant RAS proteins via autophagic degradation. Neratinib interacted in an additive synergistic fashion with approved PARP1 niraparib kill ovarian cancer cells. caused ATM-dependent activation AMPK which turn was required cause mTOR inactivation, ULK-1 ATG13 phosphorylation. drug combination initially increased autophagosome followed later by autolysosome...
The irreversible ERBB1/2/4 inhibitor neratinib has been shown in vitro to rapidly reduce the expression of and RAS proteins via autophagic/lysosomal degradation. We have recently demonstrated that valproate interact suppress growth 4T1 mammary tumors but had not defined whether [neratinib + valproate] drug combination, a mouse, altered biology cells. Exposure for three days resulted, two weeks later, expressed less ERBB1, K-RAS, N-RAS, indoleamine-pyrrole 2,3-dioxygenase (IDO-1), ornithine...
Endocrine therapies are the mainstay of treatment for oestrogen receptor (ER)-positive (ER+) breast cancer (BC). However, resistance remains problematic largely due to enhanced cross-talk between ER and growth factor pathways, circumventing need steroid hormones. Previously, we reported anti-proliferative effect everolimus (RAD001-mTORC1 inhibitor) with endocrine therapy in models; however, potential routes escape from via ERBB2/3 signalling were observed. We hypothesised that combined...
The irreversible ERBB1/2/4 inhibitor, neratinib, down-regulates the expression of as well levels MCL-1 and BCL-XL. Venetoclax (ABT199) is a BCL-2 inhibitor. At physiologic concentrations neratinib interacted in synergistic fashion with venetoclax to kill HER2 + TNBC mammary carcinoma cells. This was associated drug-combination: reducing phosphorylation ERBB1/2/3; an eIF2α-dependent BCL-XL increasing Beclin1 ATG5; activity ATM-AMPKα-ULK1 S317 pathway which causal formation toxic...
Abstract Background: Neratinib is a potent, irreversible pan-HER tyrosine kinase inhibitor. The phase III trial ExteNET showed improved disease-free survival of neratinib vs placebo in early-stage HER2+ breast cancer patients (pts) after trastuzumab-based adjuvant therapy. This benefit from was greater pts with hormone receptor (HR)+ tumors. Based on these findings, we sought to establish human-in-mouse model that would simulate this clinical and outcome, thus providing platform for...
Abstract Activation by amplification or overexpression of the proto-oncogene HER2 (also known as ERBB2) is associated with development and progression breast cancer. Neratinib a novel, irreversible, pan-HER tyrosine kinase inhibitor which selectively inhibits EGFR, HER4. In this preclinical study, we explored efficacy neratinib in combination other clinically relevant targeted agents for optimal treatment HER2-positive cancer vitro vivo models. Western blot (WB) analysis panel cell lines...
Abstract Background: Cholangiocarcinoma (CCA) is the most common biliary tract malignancy with up to 10,000 new cases annually in US. The absence of approved molecular therapies restricts CCA patients chemotherapy options limited clinical benefit. Recognizing that actionable genomic alterations occur tumors, NCCN guidelines state testing should be considered before initiation primary therapy. In this study, catalog genetic abnormalities was analyzed determine prevalence tumors and quantify...
Abstract Background: Tumor genomic profiling has identified patients with cancers harboring activating ERBB2 (HER2) mutations that are sensitive to HER2 targeted therapies. In the SUMMIT phase II ‘basket' trial, a subset of mutant have exhibited significant clinical benefit from treatment pan-HER irreversible tyrosine kinase inhibitor (TKI) neratinib. However, durable responses neratinib few, suggesting mechanisms de novo and acquired drug resistance. Thus, we sought identify druggable...
Abstract Background: Neratinib is a potent, irreversible pan-HER tyrosine kinase inhibitor. The phase III trial ExteNET showed improved disease-free survival in patients (pts) with HER2+ breast cancer treated neratinib vs placebo after trastuzumab-based adjuvant therapy. benefit from appeared to be greater pts ER+ tumors. Thus, we sought elucidate mechanisms that may explain the extended therapy ER+/HER2+ using human-in-mouse model simulates clinical outcomes seen ExteNET. Results: Mice...
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<div>AbstractPurpose:<p>The phase III ExteNET trial showed improved invasive disease-free survival in patients with HER2<sup>+</sup> breast cancer treated neratinib versus placebo after trastuzumab-based adjuvant therapy. The benefit from appeared to be greater ER<sup>+</sup>/HER2<sup>+</sup> tumors. We thus sought discover mechanisms that may explain the extended therapy neratinib.</p><p><b>Experimental Design:</b> Mice...
<div>AbstractPurpose:<p>The phase III ExteNET trial showed improved invasive disease-free survival in patients with HER2<sup>+</sup> breast cancer treated neratinib versus placebo after trastuzumab-based adjuvant therapy. The benefit from appeared to be greater ER<sup>+</sup>/HER2<sup>+</sup> tumors. We thus sought discover mechanisms that may explain the extended therapy neratinib.</p><p><b>Experimental Design:</b> Mice...
Abstract Introduction The majority of breast cancers (BC) are estrogen (E) receptor positive (ER+). Endocrine therapies target E stimulation tumour growth but resistance remains problematic, often a result enhanced crosstalk between ER and factor pathways. Previously we reported the antiproliferative efficacy combining everolimus (RAD001, mTORC1 inhibitor) with endocrine therapy in models, potential routes escape from treatment via ERBB2/3 signalling were observed. We hypothesised that...
Abstract Overexpression/amplification of HER2/ERBB2 occurs in 20% breast cancers. Thanks to specific anti-HER2 agents, the prognosis HER2-positive cancer has improved considerably. However, acquired resistance inevitably emerges over time and tumors escape pharmacologic pressure. In this work, we propose that acquisition activating somatic mutations HER2 upon therapy may be more frequent than commonly reported can reduce sensitivity these agents. Moreover, tested whether neratinib, an...
Abstract Background. Neratinib is an orally available tyrosine kinase inhibitor that irreversibly binds and inhibits EGFR, HER2 HER4 receptor kinases. has been shown to have clinical activity in HER2-amplified or overexpressed breast cancers those with mutations. However, there are indications it may also work on other subtypes not strongly positive for the receptors. The present study first screened effects of neratinib a range targets identified Wnt signalling components key factors allow...