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1.
Ann Hematol ; 101(8): 1689-1701, 2022 Aug.
Article de Anglais | MEDLINE | ID: mdl-35488900

RÉSUMÉ

This phase 1b study evaluated glasdegib (100 mg once daily) + azacitidine in adults with newly diagnosed acute myeloid leukemia (AML), higher-risk myelodysplastic syndromes (MDS), or chronic myelomonocytic leukemia (CMML) who were ineligible for intensive chemotherapy. Of 72 patients enrolled, 12 were in a lead-in safety cohort (LIC) and 60 were in the AML and MDS (including CMML) expansion cohorts. In the LIC, the safety profile of glasdegib + azacitidine was determined to be consistent with those of glasdegib or azacitidine alone, with no evidence of drug-drug interaction. In the expansion cohort, the most frequently (≥ 10%) reported non-hematologic Grade ≥ 3 treatment-emergent adverse events were decreased appetite, electrocardiogram QT prolongation, and hypertension in the AML cohort and sepsis, diarrhea, hypotension, pneumonia, and hyperglycemia in the MDS cohort. Overall response rates in the AML and MDS cohorts were 30.0% and 33.3%, respectively; 47.4% and 46.7% of patients who were transfusion dependent at baseline achieved independence. Median overall survival (95% confidence interval) was 9.2 (6.2-14.0) months and 15.8 (9.3-21.9) months, respectively, and response was associated with molecular mutation clearance. Glasdegib + azacitidine in patients with newly diagnosed AML or MDS demonstrated an acceptable safety profile and preliminary evidence of clinical benefits.Trial registration: ClinicalTrials.gov NCT02367456.


Sujet(s)
Leucémie aigüe myéloïde , Syndromes myélodysplasiques , Adulte , Azacitidine/effets indésirables , Benzimidazoles/effets indésirables , Association de médicaments/effets indésirables , Humains , Leucémie aigüe myéloïde/traitement médicamenteux , Syndromes myélodysplasiques/traitement médicamenteux , Phénylurées/effets indésirables , Appréciation des risques , Résultat thérapeutique
2.
Am J Pathol ; 183(5): 1446-1460, 2013 Nov.
Article de Anglais | MEDLINE | ID: mdl-24035511

RÉSUMÉ

Human epidermal growth factor receptor 2 (HER2) is an important biomarker for breast and gastric cancer prognosis and patient treatment decisions. HER2 positivity, as defined by IHC or fluorescent in situ hybridization testing, remains an imprecise predictor of patient response to HER2-targeted therapies. Challenges to correct HER2 assessment and patient stratification include intratumoral heterogeneity, lack of quantitative and/or objective assays, and differences between measuring HER2 amplification at the protein versus gene level. We developed a novel immunofluorescence method for quantitation of HER2 protein expression at the single-cell level on FFPE patient samples. Our assay uses automated image analysis to identify and classify tumor versus non-tumor cells, as well as quantitate the HER2 staining for each tumor cell. The HER2 staining level is converted to HER2 protein expression using a standard cell pellet array stained in parallel with the tissue sample. This approach allows assessment of HER2 expression and heterogeneity within a tissue section at the single-cell level. By using this assay, we identified distinct subgroups of HER2 heterogeneity within traditional definitions of HER2 positivity in both breast and gastric cancers. Quantitative assessment of intratumoral HER2 heterogeneity may offer an opportunity to improve the identification of patients likely to respond to HER2-targeted therapies. The broad applicability of the assay was demonstrated by measuring HER2 expression profiles on multiple tumor types, and on normal and diseased heart tissues.


Sujet(s)
Hétérogénéité génétique , Tumeurs/classification , Tumeurs/métabolisme , Récepteur ErbB-2/métabolisme , Analyse sur cellule unique/méthodes , Animaux , Tumeurs du sein/classification , Tumeurs du sein/métabolisme , Tumeurs du sein/anatomopathologie , Lignée cellulaire tumorale , Analyse de regroupements , Femelle , Technique d'immunofluorescence , Humains , Souris , Souris nude , Tumeurs/anatomopathologie , Normes de référence , Reproductibilité des résultats , Tumeurs de l'estomac/classification , Tumeurs de l'estomac/métabolisme , Tumeurs de l'estomac/anatomopathologie , Analyse sur puce à tissus , Tumeurs de la vessie urinaire/classification , Tumeurs de la vessie urinaire/métabolisme , Tumeurs de la vessie urinaire/anatomopathologie
3.
Mol Cancer Ther ; 11(3): 582-93, 2012 Mar.
Article de Anglais | MEDLINE | ID: mdl-22248472

RÉSUMÉ

The prevalence of ErbB2 amplification in breast cancer has resulted in the heavy pursuit of ErbB2 as a therapeutic target. Although both the ErbB2 monoclonal antibody trastuzumab and ErbB1/ErbB2 dual kinase inhibitor lapatinib have met with success in the clinic, many patients fail to benefit. In addition, the majority of patients who initially respond will unfortunately ultimately progress on these therapies. Activation of ErbB3, the preferred dimerization partner of ErbB2, plays a key role in driving ErbB2-amplified tumor growth, but we have found that current ErbB2-directed therapies are poor inhibitors of ligand-induced activation. By simulating ErbB3 inhibition in a computational model of ErbB2/ErbB3 receptor signaling, we predicted that a bispecific antibody that docks onto ErbB2 and subsequently binds to ErbB3 and blocks ligand-induced receptor activation would be highly effective in ErbB2-amplified tumors, with superior activity to a monospecific ErbB3 inhibitor. We have developed a bispecific antibody suitable for both large scale production and systemic therapy by generating a single polypeptide fusion protein of two human scFv antibodies linked to modified human serum albumin. The resulting molecule, MM-111, forms a trimeric complex with ErbB2 and ErbB3, effectively inhibiting ErbB3 signaling and showing antitumor activity in preclinical models that is dependent on ErbB2 overexpression. MM-111 can be rationally combined with trastuzumab or lapatinib for increased antitumor activity and may in the future complement existing ErbB2-directed therapies to treat resistant tumors or deter relapse.


Sujet(s)
Anticorps bispécifiques/pharmacologie , Tumeurs/traitement médicamenteux , Neuréguline-1/pharmacologie , Récepteur ErbB-2/antagonistes et inhibiteurs , Récepteur ErbB-3/antagonistes et inhibiteurs , Animaux , Anticorps bispécifiques/métabolisme , Anticorps bispécifiques/pharmacocinétique , Antinéoplasiques/métabolisme , Antinéoplasiques/pharmacocinétique , Antinéoplasiques/pharmacologie , Technique de Western , Lignée cellulaire tumorale , Prolifération cellulaire/effets des médicaments et des substances chimiques , Cycline D1/métabolisme , Conception de médicament , Femelle , Humains , Concentration inhibitrice 50 , Souris , Souris de lignée NOD , Souris nude , Souris SCID , Complexes multiprotéiques/métabolisme , Tumeurs/métabolisme , Tumeurs/anatomopathologie , Phosphatidylinositol 3-kinases/métabolisme , Liaison aux protéines , Récepteur ErbB-2/métabolisme , Récepteur ErbB-3/métabolisme , Transduction du signal/effets des médicaments et des substances chimiques , Tests d'activité antitumorale sur modèle de xénogreffe
4.
Sci Signal ; 2(77): ra31, 2009 Jun 30.
Article de Anglais | MEDLINE | ID: mdl-19567914

RÉSUMÉ

The signaling network downstream of the ErbB family of receptors has been extensively targeted by cancer therapeutics; however, understanding the relative importance of the different components of the ErbB network is nontrivial. To explore the optimal way to therapeutically inhibit combinatorial, ligand-induced activation of the ErbB-phosphatidylinositol 3-kinase (PI3K) axis, we built a computational model of the ErbB signaling network that describes the most effective ErbB ligands, as well as known and previously unidentified ErbB inhibitors. Sensitivity analysis identified ErbB3 as the key node in response to ligands that can bind either ErbB3 or EGFR (epidermal growth factor receptor). We describe MM-121, a human monoclonal antibody that halts the growth of tumor xenografts in mice and, consistent with model-simulated inhibitor data, potently inhibits ErbB3 phosphorylation in a manner distinct from that of other ErbB-targeted therapies. MM-121, a previously unidentified anticancer therapeutic designed using a systems approach, promises to benefit patients with combinatorial, ligand-induced activation of the ErbB signaling network that are not effectively treated by current therapies targeting overexpressed or mutated oncogenes.


Sujet(s)
Phosphatidylinositol 3-kinases/métabolisme , Récepteur ErbB-3/métabolisme , Animaux , Anticorps monoclonaux/immunologie , Anticorps monoclonaux humanisés , Récepteurs ErbB/métabolisme , Humains , Ligands , Souris , Phosphorylation , Liaison aux protéines , Récepteur ErbB-3/immunologie , Transduction du signal , Transplantation hétérologue
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