A5043836989- Cell Adhesion Molecules Research
- Protein Tyrosine Phosphatases
- Prostate Cancer Treatment and Research
- Synthesis and biological activity
- Bioactive Compounds and Antitumor Agents
- Melanoma and MAPK Pathways
- Galectins and Cancer Biology
- Pharmacological Effects of Natural Compounds
- Immune cells in cancer
- HER2/EGFR in Cancer Research
- Extracellular vesicles in disease
- PI3K/AKT/mTOR signaling in cancer
- Immunotherapy and Immune Responses
- interferon and immune responses
- Cancer therapeutics and mechanisms
- Monoclonal and Polyclonal Antibodies Research
- Cancer-related molecular mechanisms research
- Atherosclerosis and Cardiovascular Diseases
- Chemokine receptors and signaling
- Ubiquitin and proteasome pathways
- Biochemical and Molecular Research
- Radiopharmaceutical Chemistry and Applications
- Cancer Immunotherapy and Biomarkers
- Caveolin-1 and cellular processes
- Colorectal Cancer Screening and Detection
Novartis (United States)
2023
NYU Langone Health
2018-2021
New York University
2020-2021
Thomas Jefferson University
2013-2018
Sidney Kimmel Cancer Center
2015-2018
Prostate Cancer UK
2015
University of Naples Federico II
2009-2013
Federico II University Hospital
2011-2012
Sapienza University of Rome
1994
Adaptive resistance to MEK inhibitors (MEKi) typically occurs via induction of genes for different receptor tyrosine kinases (RTK) and/or their ligands, even in tumors the same histotype, making combination strategies challenging. SHP2 (PTPN11) is required RAS/ERK pathway activation by most RTKs and might provide a common node. We found that combining inhibitor SHP099 with MEKi inhibited proliferation multiple cancer cell lines vitroPTPN11 knockdown/MEKi treatment had similar effects,...
KRAS is the most frequently mutated human oncogene, and inhibition has been a longtime goal. Recently, inhibitors were developed that bind KRASG12C-GDP react with Cys-12 (G12C-Is). Using new affinity reagents to monitor KRASG12C activation inhibitor engagement, we found an SHP2 (SHP2-I) increases KRAS-GDP occupancy, enhancing G12C-I efficacy. The SHP2-I abrogated RTK feedback signaling adaptive resistance G12C-Is in vitro, xenografts, syngeneic KRASG12C-mutant pancreatic ductal...
Covalent inhibitors of KRASG12C have shown antitumor activity against advanced/metastatic KRASG12C-mutated cancers, though resistance emerges and additional strategies are needed to improve outcomes. JDQ443 is a structurally unique covalent inhibitor GDP-bound that forms novel interactions with the switch II pocket. potently inhibits KRASG12C-driven cellular signaling demonstrates selective antiproliferative in cell lines, including those G12C/H95 double mutations. In vivo, induces AUC...
The αvβ3 integrin is known to be highly upregulated during cancer progression and promotes a migratory metastatic phenotype in many types of tumors. We hypothesized that the transferred through exosomes and, upon transfer, has ability support functional aberrations recipient cells. Here, for first time, it demonstrated present released from PC3 CWR22Pc prostate Exosomal β3 as protein donor nontumorigenic tumorigenic cells or mRNA levels remain unaffected transcription translation inhibition...
Activating mutants of RAS are commonly found in human cancers, but to date selective targeting the clinic has been limited KRAS(G12C) through covalent inhibitors. Here, we report a monobody, termed 12VC1, that recognizes active state both KRAS(G12V) and up 400-times more tightly than wild-type KRAS. The crystal structures reveal 12VC1 mutations shallow pocket, competes against RAS-effector interaction. When expressed intracellularly, potently inhibits ERK activation proliferation RAS-driven...
// Marco Trerotola 1,2,6 , Kirat K. Ganguly 1,2 Ladan Fazli 3 Carmine Fedele Huimin Lu Anindita Dutta Qin Liu 1,4 Tiziana De Angelis Luke W. Riddell Natalia A. Riobo 5 Martin E. Gleave Amina Zoubeidi Richard G. Pestell 2 Dario C. Altieri and Lucia R. Languino 1 Prostate Cancer Discovery Development Program, Thomas Jefferson University, Philadelphia, PA, USA Department of Biology, Sidney Kimmel Center, The Vancouver Centre, University British Columbia, Vancouver, Canada 4 Tumor...
Abstract SHP2 inhibitors (SHP2i) alone and in various combinations are being tested multiple tumors with overactivation of the RAS/ERK pathway. plays critical roles normal cell signaling; hence, SHP2is could influence tumor microenvironment. We found that SHP2i treatment depleted alveolar M2-like macrophages, induced tumor-intrinsic CCL5/CXCL10 secretion, promoted B T lymphocyte infiltration Kras- Egfr-mutant non–small lung cancer (NSCLC). However, also increased intratumor granulocytic...
Abstract Although KRASG12C inhibitors show clinical activity in patients with KRAS G12C mutated non–small cell lung cancer (NSCLC) and other solid tumor malignancies, response is limited by multiple mechanisms of resistance. The inhibitor JDQ443 shows enhanced preclinical antitumor combined the SHP2 TNO155, combination currently under evaluation. To identify rational strategies that could help overcome or prevent some types resistance, we evaluated duration responses to ± alone PI3Kα...
Abstract Androgen receptor signaling fuels prostate cancer and is a major therapeutic target. However, mechanisms of resistance to androgen ablation are not well understood. Here, using mouse model, Ptenpc−/−, carrying epithelial-specific Pten deletion, we show that the αvβ6 integrin required for tumor growth in vivo castrated as noncastrated mice. We describe novel pathway couples cell surface via activation JNK1 causes increased nuclear localization activity receptor. This downstream...
Dynamic crosstalk between growth factor receptors, cell adhesion molecules and extracellular matrix is essential for cancer migration invasion. Integrins are transmembrane receptors that bind proteins enable cytoskeletal organization. They also mediate signal transduction to regulate proliferation survival. The type 1 insulin-like receptor (IGF-IR) mediates tumor growth, inhibition of apoptosis in several types cancer. We have previously demonstrated β1 integrins anchorage-independent...
Transforming growth factor (TGF) β1 activity depends on a complex signalling cascade that controls expression of several genes. Among others, TGFβ1 regulates matrix metalloproteinases (MMPs) through activation Smads. In the present study, we demonstrate for first time αvβ6 integrin interacts with TGFβ receptor II (TβRII) β6 cytoplasmic domain and promotes Smad3 in prostate cancer (PrCa) cells. Another related αv integrin, αvβ5, as well αvβ6/3 which contains chimeric form β3 domain, do not...
Two novel human antitumor immunoconjugates, engineered by fusion of a single‐chain antibody fragment against ErbB2 receptor, termed Erbicin, with either RNase or the Fc region IgG 1 , are selectively cytotoxic for ErbB2‐positive cancer cells in vitro and vivo . These Erbicin‐derived immunoagents (EDIAs) do not show most negative properties Herceptin, only humanized mAb used therapy breast carcinoma: cardiotoxicity inability to act on resistant tumors. differences probably attributable...
Abstract Clinical trials of SHP2 inhibitors (SHP2i) alone and in various combinations are ongoing for multiple tumors with over-activation the RAS/ERK pathway. plays critical roles normal cell signaling; hence, SHP2is could influence tumor microenvironment. We found that SHP2i treatment depleted alveolar M2-like macrophages promoted B T lymphocyte infiltration Kras - Egfr -mutant non-small lung cancer (NSCLC). However, also increased intratumor gMDSCs via tumor-intrinsic, NF-kB-dependent...
e11054 Background: Herceptin (H), an anti-ErbB2 humanized antibody prescribed for treatment of ErbB2-positive breast cancer, has proved to be essential tool in immunotherapy. However, large-scale clinical studies with H have shown that it engenders cardiomyopathy, particularly patients treated either concurrently or previously anthracyclines. Two novel human antitumor immunoconjugates were engineered our laboratory by fusion a scFv, Erbicin, RNase the Fc region IgG1, and thus called Erb-...
Adaptive resistance to MEK inhibitors (MEK-Is) typically occurs via induction of genes for different receptor tyrosine kinases (RTKs) and/or their ligands, even in tumors the same histotype, making combination strategies challenging. SHP2 (PTPN11) is required RAS/ERK pathway activation by most RTKs, and might provide a common node. We found that combining inhibitor SHP099 with MEK-I inhibits proliferation multiple cancer cells vitro. PTPN11 knockdown/MEK-I had similar effects, while...
Abstract Intercellular communications have been recently shown to be mediated by exosomes, exocytosed vesicles of endosomal origin, which are thought involved in cancer progression. We investigated whether integrins, transmembrane receptors that known deregulated progression, transferred among different subsets prostate cells through exosomes and the ability support functional aberrations recipient cells. Recent studies characterized integrin expression but not integrins actually shuttled...
AimsAnaemia and hematochezia are common symptoms in patients (pts) aged 70 years or older.Colonoscopy is strongly recommended these elderly pts to investigate an underlying disease.Our study evaluates role, safety utility of colonoscopy older with anaemia and/or hematochezia.