pazopanib and Leukemia--Myeloid--Acute

We evaluated pazopanib (800 mg orally QD) in patients not eligible for intensive treatment with relapsed/refractory AML or at initial diagnosis. Patients receiving pazopanib for > 14 days were analyzed for safety, tolerability, and efficacy. Co-primary endpoints were cumulative response rate and reduction of bone marrow microvessel density. Twenty patients (median age 76 years, range 52-86) were treated. Fifteen had relapsed/refractory and five had newly diagnosed AML. Median ECOG performance status was 1 (range 1-3). Four patients had adverse, 15 intermediate, and 1 patient favorable cytogenetic/molecular risk (ELN 2010 criteria). The safety profile of pazopanib was as reported. The most common adverse events of any grade were gastrointestinal. Two patients achieved PR (blast reduction > 50%), 14 stable disease (SD), and 4 progressive disease. Median PFS was 65 days (95% CI 29-105). After the end of the study, 1 CRi and 1 CRp occurred on demethylating agents, and 1 CR upon alloSCT. In these patients, SD and improved general condition on pazopanib allowed therapy escalation. Median OS for the overall study population was 191 days (95% CI 87-435) and 1-year survival was 35%. There was no significant change in microvessel density. Clinical trial information: NCT01361334.

Topics: Aged; Aged, 80 and over; Angiogenesis Inhibitors; Antineoplastic Agents; Bone Marrow; Female; Gastrointestinal Diseases; Humans; Indazoles; Kaplan-Meier Estimate; Leukemia, Myeloid, Acute; Male; Microvessels; Middle Aged; Progression-Free Survival; Protein Kinase Inhibitors; Pyrimidines; Recurrence; Salvage Therapy; Sulfonamides; Treatment Outcome; Tumor Microenvironment

Topics: Activin Receptors, Type II; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; beta-Thalassemia; Graft vs Host Disease; Hematologic Diseases; Humans; Immunoglobulin Fc Fragments; Indazoles; Interleukin-1 Receptor-Associated Kinases; Internet; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Myeloid, Acute; Lymphoma, B-Cell; Multiple Myeloma; Protein Kinase Inhibitors; Pyrimidines; Recombinant Fusion Proteins; Sulfonamides; Telangiectasia, Hereditary Hemorrhagic

Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cytokines; Drug Discovery; fms-Like Tyrosine Kinase 3; Humans; Leukemia, Myeloid, Acute; Lung Neoplasms; Mice; Molecular Targeted Therapy; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Proteomics; Xenograft Model Antitumor Assays

Topics: Aminopyridines; Antineoplastic Agents; Benzothiazoles; Biomarkers; Bone Marrow; Cell Line, Tumor; Clinical Trials as Topic; Dasatinib; fms-Like Tyrosine Kinase 3; Gene Expression; Hair; Hematopoietic Stem Cells; Humans; Indazoles; Leukemia, Myeloid, Acute; Niacinamide; Phenylurea Compounds; Pigmentation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-kit; Pyrimidines; Pyrroles; Sorafenib; Sulfonamides; Thiazoles

In acute myeloid leukemia (AML), refractory disease is a major challenge and the leukemia microenvironment may harbor refractory disease. Human AML cell lines KG-1 and HL-60 expressed receptors also found on endothelial cells (ECs) such as VEGFRs, PDGFRs, and cKit. When human AML cells were co-cultured with human umbilical vein endothelial cells (HUVECs) and primary bone marrow endothelial cell (BMECs), the AML cells were more resistant to cytarabine chemotherapy, even in transwell co-culture suggesting angiocrine regulation. Primary BMECs secreted significantly increased levels of VEGF-A and PDGF-AB after exposure to cytarabine. Pazopanib, a receptor tyrosine kinase inhibitor (RTKI) of VEGFRs, PDGFRs, and cKit, removed EC protection of AML cells and enhanced AML cell sensitivity to cytarabine. Xenograft modeling showed significant regression of AML cells and abrogation of BM hypervascularity in RTKI treated cohorts. Together, these results show direct cytotoxicity of RTKIs on AML cells and reversal of EC protection. Combining RTKIs with chemotherapy may serve as promising therapeutic strategy for patients with AML.

Topics: Animals; Antimetabolites, Antineoplastic; Bone Marrow Cells; Cell Line, Tumor; Cell Proliferation; Coculture Techniques; Cytarabine; Drug Resistance, Neoplasm; Endothelial Cells; Gene Expression Regulation, Leukemic; Human Umbilical Vein Endothelial Cells; Humans; Indazoles; Leukemia, Myeloid, Acute; Mice; Mice, SCID; Neoplasm Transplantation; Neovascularization, Pathologic; Platelet-Derived Growth Factor; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-kit; Pyrimidines; Receptors, Platelet-Derived Growth Factor; Receptors, Vascular Endothelial Growth Factor; Signal Transduction; Sulfonamides; Tumor Burden; Vascular Endothelial Growth Factor A