A5023348910- HER2/EGFR in Cancer Research
- Monoclonal and Polyclonal Antibodies Research
- Prostate Cancer Treatment and Research
- Cancer Treatment and Pharmacology
- Cancer, Lipids, and Metabolism
- Nuclear Structure and Function
- Cell Adhesion Molecules Research
- DNA Repair Mechanisms
- Radiopharmaceutical Chemistry and Applications
- Advanced Biosensing Techniques and Applications
- Glycosylation and Glycoproteins Research
- Cancer-related Molecular Pathways
- Gastric Cancer Management and Outcomes
- Lung Cancer Treatments and Mutations
- Cancer therapeutics and mechanisms
- Microtubule and mitosis dynamics
- Ubiquitin and proteasome pathways
- Estrogen and related hormone effects
- Cancer, Hypoxia, and Metabolism
- Click Chemistry and Applications
- Acute Myeloid Leukemia Research
- Cancer Genomics and Diagnostics
- Caveolin-1 and cellular processes
- PARP inhibition in cancer therapy
- Lung Cancer Research Studies
AstraZeneca (United States)
2023-2025
Kala Pharmaceuticals (United States)
2023
AstraZeneca (United Kingdom)
2023
AstraZeneca (Brazil)
2023
Pfizer (United States)
2015-2020
Cornell University
2010-2014
University of Washington
2014
Geriatric Research Education and Clinical Center
2014
Abstract Prostate cancer growth depends on androgen receptor signaling. Androgen ablation therapy induces expression of constitutively active splice variants that drive disease progression. Taxanes are a standard care in castration-resistant prostate (CRPC); however, mechanisms underlying the clinical activity taxanes poorly understood. Recent work suggests microtubule network cells is critical for nuclear translocation and activity. In this study, we used set deletion mutants to identify...
Antibody-drug conjugates (ADC) are emerging as clinically effective therapy. We hypothesized that cancers treated with ADCs would acquire resistance mechanisms unique to immunoconjugate therapy and changing ADC components may overcome resistance. Breast cancer cell lines were exposed multiple cycles of anti-Her2 trastuzumab-maytansinoid (TM-ADC) at IC80 concentrations followed by recovery. The resistant cells, 361-TM JIMT1-TM, characterized cytotoxicity, proteomic, transcriptional, other...
Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate (ADC) that has demonstrated clinical benefit for patients with HER2+ metastatic breast cancer; however, its activity limited by inherent or acquired drug resistance. The molecular mechanisms drive resistance to T-DM1, especially in tumors, are not well understood. We used cell lines develop models of T-DM1 using a cyclical dosing schema which cells received "on-off" routine until T-DM1-resistant population was generated. N87...
Taxanes are the only chemotherapies used to treat patients with metastatic castration-resistant prostate cancer (CRPC). Despite initial efficacy of taxanes in treating CRPC, all ultimately fail due development drug resistance. In this study, we show that ERG overexpression vitro and vivo models CRPC is associated decreased sensitivity taxanes. affects several parameters microtubule dynamics inhibits effective drug-target engagement docetaxel or cabazitaxel tubulin. Finally, analysis a cohort...
Circulating tumor cells (CTCs) have emerged as a reliable source of cells, and their concentration has prognostic implications. CTC capture offers real-time access to cancer tissue without the need an invasive biopsy, while phenotypic molecular interrogation can provide insight into biological changes that occur during treatment. The majority methods are based on EpCAM expression surface marker tumor-derived cells. However, protein levels be significantly down regulated progression...
Abstract The approval of ado-trastuzumab emtansine (T-DM1) in HER2+ metastatic breast cancer validated HER2 as a target for HER2-specific antibody–drug conjugates (ADC). Despite its demonstrated clinical efficacy, certain inherent properties within T-DM1 hamper this compound from achieving the full potential targeting HER2-expressing solid tumors with ADCs. Here, we detail discovery PF-06804103, an anti-HER2 ADC designed to have widened therapeutic window compared T-DM1. We utilized...
Summary Bimodal protein expression, characterized by the distribution of expression with two modes, is linked to phenotypic variation across various biological systems. Whereas previous studies focused on RNA data, we developed a bimodality model tailored for proteomics enhance identification cancer-associated biomarkers and targets, facilitating precision oncology. We analyzed data from cancer types identified 2401 tumor-associated bimodal proteins. These proteins were evaluated pathway...
Abstract Bimodal protein expression, characterized by a distribution with two modes, is linked to phenotypic variation across various biological systems. While previous studies focused on RNA expression data, we developed bimodality model tailored for proteomics enhance the identification of cancer-associated biomarkers and targets, facilitating precision oncology. We analyzed data from cancer types identified 2,401 tumor-associated bimodal proteins. These proteins were evaluated pathway...
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin with poor patient overall survival rate. While Bruton tyrosine kinase inhibitors (BTKis) have shown benefit in relapsed/refractory MCL (Wang M, et al., 2018; Song Y, al.,2020; Wang ML 2013) portion of patients eventually progress. Here, we explored which biomarkers might be associated resistance to acalabrutinib, second generation BTKi, by analyzing samples from who were on treatment or progressed acalabrutinib the...
Abstract Datopotamab deruxtecan (Dato-DXd) is an antibody drug conjugate (ADC) comprised of a humanized anti-TROP2 IgG1 monoclonal attached to DXd, topoisomerase I inhibitor, via plasma stable cleavable linker. Dato-DXd currently under clinical investigation for the treatment patients with solid tumors including non-small cell lung cancer (NSCLC), hormone receptor positive and triple negative breast cancer. Recently, TROP2 Normalized Membrane Ratio (NMR) was identified as exploratory...
Significance Nicotinamide adenine dinucleotide (NAD + ) is an endogenous small molecule that has effects on diverse processes, including obesity, lifespan, and cancer. A major goal to identify the NAD -regulated cellular pathways may mediate these effects. In this study, we demonstrate regulates microtubule cytoskeleton. We find are mediated by mitochondrial sirtuin-3. Our findings have implications for many clinically used chemotherapeutics target microtubules, as high levels can reduce...
Trastuzumab deruxtecan (T-DXd; DS-8201; ENHERTU®) is a human epithelial growth factor receptor 2 (HER2)-directed antibody drug conjugate (ADC) with demonstrated antitumor activity against range of tumor types. Aiming to understand the relationship between antigen expression and downstream efficacy outcomes, T-DXd was administered in tumor-bearing mice carrying NCI-N87, Capan-1, JIMT-1, MDA-MB-468 xenografts, characterized by varying HER2 levels. Plasma pharmacokinetics (PK) total antibody,...
Abstract A modeling and simulation approach was used for quantitative comparison of a new generation HER2 antibody drug conjugate (ADC, PF-06804103) with trastuzumab-DM1 (T-DM1). To compare preclinical efficacy, the pharmacokinetic (PK)/pharmacodynamic (PD) relationship PF-06804103 T-DM1 determined across range mouse tumor xenograft models, using growth inhibition model. The static concentration assigned as minimal efficacious concentration. concluded to be more potent than cell lines...
The National Cancer Institute's Clinical Proteomic Tumor Analysis Consortium (CPTAC) provides unique opportunities for cancer target discovery using protein expression. Proteomics data from CPTAC tumor types have been primarily generated a multiplex tandem mass tag (TMT) approach, which is designed to provide quantification relative reference samples. However, expression are suboptimal prioritization of targets within tissue type, requires additional reprocessing the original proteomics...
Gemtuzumab ozogamicin (GO) is an anti-CD33 antibody-drug conjugate for the treatment of acute myeloid leukemia (AML). Although GO shows a narrow therapeutic window in early clinical studies, recent reports detailing modified dosing regimen can be safely combined with induction chemotherapy, and combination provides significant survival benefits AML patients. Here we tested whether seen arise from enhanced reduction chemoresidual disease leukemic initiating cells (LICs). Herein, use cell line...
Abstract Background: Dato-DXd is a TROP2-directed antibody drug conjugate comprised of topoisomerase I inhibitor (an exatecan derivative, DXd) conjugated to datopotamab, humanized anti-TROP2 IgG1 antibody, via cleavable plasma-stable tetrapeptide-based linker. Topoisomerase inhibitors stabilize DNA-topoisomerase cleavage complexes (Topo1cc) that lead double-strand breaks and activation DNA damage response (DDR). Poly(ADP-ribose) polymerase 1 (PARP1) mediates signal transduction in the DDR as...
Abstract Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate (ADC) consisting of a humanized anti-TROP2 monoclonal antibody linked to potent DNA topoisomerase I (TOP1) inhibitor payload via plasma-stable, tumor-selective, tetrapeptide-based cleavable linker. Dato-DXd currently under clinical investigation for the treatment patients with solid tumors including non-small cell lung cancer (NSCLC), hormone receptor positive (HR+ BC) and triple negative breast (TNBC). Pharmacotherapy...
Abstract Patient-derived xenografts (PDXs) are resected human tumors engrafted into mice and represent personalized murine ‘avatars' of those tumors. PDXs valuable tumor models for drug development since they recapitulate the complexity microenvironment more extensively than cell line (CLXs). Unlike CLXs, never passaged in vitro, therefore faithfully native biology response to therapeutics. Thus, may accurately predict clinical activity therapeutic compounds traditional CLXs. We developing a...
Abstract Although the recent availability of novel treatment for castration resistant prostate cancer (CRPC) has shown improvements in overall survival, CRPC is incurable and lethal disease. It been recognized that tumor progression despite castrate levels androgens still associated with active signaling from androgen receptor (AR) which affects gene transcription following its nuclear accumulation. Taxanes bind to stabilize cellular microtubules (MTs) perturbing fine intricate organization...
Abstract Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate (ADC) comprised of the HER2-targeting antibody trastuzumab and DM1, a microtubule depolymerizing agent covalently attached via non-cleavable thioether linker. T-DM1 has demonstrated clinical benefit for patients with metastatic breast cancer, however activity may be limited by inherent or acquired resistance during prolonged treatment periods. The molecular mechanisms that drive to T-DM1, especially in HER2 positive tumors,...
Abstract Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate (ADC) consisting of a humanized anti-TROP2 IgG1 monoclonal antibody covalently linked to highly potent topoisomerase I (TOP1) inhibitor payload via stable, tumor-selective, tetrapeptide-based cleavable linker. Despite its promising early clinical signals, drug resistance challenge that may emerge with time. The mechanisms Dato-DXd are currently unknown. Herein, we created and investigated novel models characterize...
Abstract Prostate cancer progression into castration-resistant prostate (CRPC) is driven by continued androgen receptor (AR) signaling despite surgical and chemical ablation. The taxanes represent the only class of chemotherapy that improves overall survival in CRPC patients. Despite their success, patients do progress on taxane treatment rendering taxane-resistant tumors. molecular mechanisms underlying clinical resistance have not been well elucidated due to lack available tumor tissue...
Abstract DNA targeting drugs represent one of cornerstones anti-cancer therapy for both hematologic and solid tumor indications. Low potency anti-DNA compounds (e.g. platins, anthracyclines) are included in many standard-of-care (SOC) regimens, however their modest activity overall toxicity profiles limit therapeutic potential. To increase the window DNA-damaging agents, high with enhanced anti-tumor have been delivered to tumors as payloads modalities such antibody-drug conjugates (ADCs)....