A5088111017- Mechanisms of cancer metastasis
- Cell death mechanisms and regulation
- Melanoma and MAPK Pathways
- Peptidase Inhibition and Analysis
- Protease and Inhibitor Mechanisms
- Cancer Mechanisms and Therapy
- Graphene and Nanomaterials Applications
- Cancer-related Molecular Pathways
- PI3K/AKT/mTOR signaling in cancer
- Ubiquitin and proteasome pathways
- Protein Degradation and Inhibitors
- Cancer, Lipids, and Metabolism
- Microtubule and mitosis dynamics
- interferon and immune responses
- Protein Kinase Regulation and GTPase Signaling
- CAR-T cell therapy research
- Hippo pathway signaling and YAP/TAZ
- Cancer Genomics and Diagnostics
- Click Chemistry and Applications
- Metabolism, Diabetes, and Cancer
- T-cell and B-cell Immunology
- Phagocytosis and Immune Regulation
- Endoplasmic Reticulum Stress and Disease
- Lipid metabolism and biosynthesis
- Advanced biosensing and bioanalysis techniques
Temple University
2023-2025
Fox Chase Cancer Center
2025
Philadelphia University
2023-2024
National Cancer Institute
2017-2023
Center for Cancer Research
2018-2022
Office of Extramural Research
2019-2021
Universidad Complutense de Madrid
2007-2020
Cancer Research UK Manchester Institute
2016-2018
University of Manchester
2016-2018
Frederick National Laboratory for Cancer Research
2017
Abstract Idiopathic pulmonary fibrosis (IPF) is an aggressive interstitial lung disease with a high mortality rate. Putative drug targets in IPF have failed to translate into effective therapies at the clinical level. We identify TRAF2- and NCK-interacting kinase (TNIK) as anti-fibrotic target using predictive artificial intelligence (AI) approach. Using AI-driven methodology, we generated INS018_055, small-molecule TNIK inhibitor, which exhibits desirable drug-like properties activity...
Lung squamous cell carcinoma (LSCC) is the second most prevalent type of lung cancer. Despite extensive genomic characterization, no targeted therapies are approved for treatment LSCC. Distal amplification 3q chromosome frequent alteration in LSCC, and there an urgent need to identify efficacious druggable targets within this amplicon. We protein kinase TNIK as a therapeutic target amplified approximately 50% LSCC cases. genetic depletion or pharmacologic inhibition reduces growth cells...
Abstract Mixed-lineage kinase 3 (MLK3) is a member of the MLK family serine/threonine kinases. MLK3 well-known to regulate MAPK signaling by acting upstream ERK, JNK, and p38 pathways. In addition its canonical role in activating cascades, regulates activity various proteins pathways, including NF-κB, Wnt/β-catenin, PAK1. Previous studies demonstrated that can promote proliferation, invasive growth, metastatic potential human cancers. Triple-negative breast cancer (TNBC) subtype...
Abstract Cholangiocarcinoma (CCA) is a highly aggressive malignancy that arises from the biliary tree, and often presents with advanced stage disease. For patients disease arising intrahepatic bile ducts, genomic analyses have revealed targetable mutations. Unfortunately, these mutations are exceedingly rare in extrahepatic (eCCA), limiting therapeutic options. It therefore necessary to investigate functional crosstalk resulting different signal transduction pathways identify new treatment...
Diacylglycerol (DAG) generation at the T cell immunological synapse (IS) determines correct activation of antigen-specific immune responses. DAG kinases (DGKs) α and ζ act as negative regulators DAG-mediated signals by catalyzing conversion to phosphatidic acid (PA). Nonetheless, specific input each enzyme their spatial regulation during IS formation remain uncharacterized. Here we report recruitment endogenous DGKα DGKζ receptor (TCR) complex following TCR/CD28 engagement. Specific DGK gene...
// Pedro Torres-Ayuso 1 , Manuel Daza-Martín Jorge Martín-Pérez 2 Antonia Ávila-Flores and Isabel Mérida Department of Immunology Oncology, Centro Nacional de Biotecnología/CSIC, Madrid, Spain Cancer Biology, Instituto Investigaciones Biomédicas Alberto Sols/CSIC, Universidad Autónoma Correspondence: Ávila-Flores, email: Mérida, Keywords : Diacylglycerol kinase, Src, 3D tumor growth, chemotherapy resistance, PI3K/Akt...
Abstract Most patients with lung squamous cell carcinoma (LSCC) undergo chemotherapy, radiotherapy, and adjuvant immunotherapy for locally advanced disease. The efficacy of these treatments is still limited because dose-limiting toxicity or locoregional recurrence. New combination approaches targets such as actionable oncogenic drivers are needed to advance treatment options LSCC. Moreover, other chemotherapy-ineligible limited. As such, there a critical need the development selective potent...
Triple-negative breast cancer (TNBC) is associated with poor prognosis because of the lack effective therapies. Mixed-lineage protein kinase 3 (MLK3) a that often upregulated in TNBC and involved driving tumorigenic potential cells. Here, we present selective MLK3 degrader, CEP1347-VHL-02, based on pan-MLK inhibitor CEP1347 ligand for E3 ligase von Hippel–Lindau (VHL) by employing proteolysis-targeting chimera (PROTAC) technology. Our compound effectively targeted degradation via...
Diacylglycerol kinases (DGKs) transform diacylglycerol (DAG) into phosphatidic acid (PA), balancing the levels of these key metabolic and signaling lipids. We previously showed that PA derived from DGKζ isoform promotes mammalian target rapamycin complex 1 (mTORC1) activation. This function might be crucial for growth survival cancer cells, especially those resistant to allosteric mTOR inhibitor rapamycin. How this positive coordinates with DAG metabolism is unknown. In study, we used a...
Abstract Head and neck squamous cell carcinoma (HNSCC) includes epithelial cancers of the oral nasal cavity, larynx, pharynx accounts for ∼350,000 deaths per year worldwide. Smoking-related HNSCC is associated with few targetable mutations but defined by frequent copy-number alteration, most common which gain at 3q. Critical 3q target genes have not been conclusively determined HNSCC. Here, we present data indicating that MAP3K13 (encoding LZK) an amplified driver gene in Copy-number...
Diacylglycerol kinase α (DGKα) regulates diacylglycerol levels, catalyzing its conversion into phosphatidic acid. The isoform is central to immune response regulation; it downmodulates Ras-dependent pathways and necessary for establishment of the unresponsive state termed anergy. DGKα functions are regulated in part at transcriptional level although mechanisms involved remain poorly understood. Here, we analyzed 5' end structure mouse gene detected three binding sites forkhead box O (FoxO)...
Abstract The lack of actionable mutations in patients with non‐small cell lung cancer ( NSCLC ) presents a significant hurdle the design targeted therapies for this disease. Here, we identify somatically mutated ABL 1 as genetic dependency that is required to maintain survival. We demonstrate cells are sensitive inhibitors and verify drug‐induced effects on viability specific pharmacological inhibition kinase. Furthermore, confirm imatinib suppresses tumor growth vivo , specifically...
Identifying additional mitogen-activated protein kinase (MAPK) pathway regulators is invaluable in aiding our understanding of the complex signaling networks that regulate cellular processes, including cell proliferation and survival. Here, using vitro assays by expressing WT or kinase-dead MAPK 19 (MAP3K19) HEK293T line assessing activation extracellular signal-regulated (ERK) JUN N-terminal (JNK) pathways, we defined MAP3K19 as a novel regulator signaling. We also observed overexpression...
Many Gram-negative bacteria produce N-acyl-homoserine lactones (AHLs), quorum sensing (QS) molecules that can be enzymatically inactivated by quenching (QQ) processes; this approach is considered an emerging antimicrobial alternative. In study, kinetic parameters of several AHLs hydrolyzed penicillin acylase from Streptomyces lavendulae (SlPA) and aculeacin A Actinoplanes utahensis (AuAAC) have been determined. Both enzymes catalyze efficiently the amide bond hydrolysis in with different...
PIM kinases have important pro-tumorigenic roles and mediate several oncogenic traits, including cell proliferation, survival, chemotherapeutic resistance. As a result, multiple inhibitors been pursued as investigational new drugs in cancer; however, response to solid tumors has fallen short of expectations. We found that inhibition kinase activity stabilizes protein levels all three isoforms (PIM1/2/3), this can promote resistance chemotherapy. To overcome effect, we designed proteolysis...
ABSTRACT Aculeacin A acylase from Actinoplanes utahensis produced by Streptomyces lividans revealed activities that are able to hydrolyze penicillin V and several natural aliphatic penicillins. Penicillin K was the best substrate, showing a catalytic efficiency of 34.79 mM −1 s . Furthermore, aculeacin highly thermostable, with midpoint transition temperature 81.5°C.
Precision medicine aims to tailor cancer therapies target specific tumor-promoting aberrations. For tumors that lack actionable drivers, which occurs frequently in the clinic, extensive molecular characterization and pre-clinical drug efficacy studies will be required. A cell line maintained at low passage a patient- derived xenograft model (PDX) were generated using fresh biopsy from patient with poorly-differentiated neuroendocrine tumor of unknown primary origin. Next-generation...
Abstract Lung squamous cell carcinoma (LSCC) is the second most prevalent type of lung cancer with no FDA-approved targeted therapies. Platinum-based chemotherapy and immunotherapy remain cornerstone current treatments for advanced LSCC, 5-year survival rate less than 10%. Despite abundant knowledge mutational landscape there a paucity effective Amplification chromosome 3q26 common genomic alteration in LSCC this leads to overexpression oncogenic kinases like TNIK. TNIK amplification occurs...