pci-32765 and Pancreatic-Neoplasms

In preclinical studies of pancreatic ductal adenocarcinoma (PDAC), ibrutinib improved the antitumor efficacy of the standard of care chemotherapy. This led to a phase 1b clinical trial to determine the safety, tolerability, and immunologic effects of ibrutinib treatment in patients with advanced PDAC.. Previously untreated patients with PDAC were enrolled in a phase 1b clinical trial (ClinicalTrials.gov) to determine the safety, toxicity, and maximal tolerated dose of ibrutinib when administered with the standard regimen of gemcitabine and nab-paclitaxel. To study the immune response to ibrutinib alone, the trial included an immune response arm where patients were administered with ibrutinib daily for a week followed by ibrutinib combined with gemcitabine and nab-paclitaxel. Endoscopic ultrasonography-guided primary PDAC tumor biopsies and blood were collected before and after ibrutinib monotherapy. Changes in abundance and functional state of immune cells in the blood was evaluated by mass cytometry by time of flight and statistical scaffold analysis, while that in the local tumor microenvironment (TME) were assessed by multiplex immunohistochemistry. Changes in B-cell receptor and T-cell receptor repertoire were assessed by sequencing and analysis of clonality.. In the blood, ibrutinib monotherapy significantly increased the frequencies of activated inducible T cell costimulator. Ibrutinib monotherapy skewed the immune landscape both in the circulation and TME towards activated T cells, monocytes and DCs. These effects were not observed when combining ibrutinib with standard of care chemotherapy. Future studies may focus on other therapeutic combinations that augment the immunomodulatory effects of ibrutinib in solid tumors.. NCT02562898.

Topics: Adenocarcinoma; Antineoplastic Agents; Carcinoma, Pancreatic Ductal; Gemcitabine; Humans; Pancreatic Neoplasms; Programmed Cell Death 1 Receptor; Tumor Microenvironment; Tyrosine Kinase Inhibitors

Ibrutinib is an orally administered inhibitor of Bruton's tyrosine kinase (Btk). Preclinical data suggest that mast cells are recruited within neuroendocrine neoplasms (NENs) where they stimulate angiogenesis and tumor growth. Ibrutinib inhibits mast cell degranulation and has been associated with regression of tumors in a mouse insulinoma model.. A prospective, phase II trial evaluated patients with advanced gastrointestinal (GI)/lung NENs and pancreatic NENs (pNENs) who had evidence of progression within 12 months of study entry on at least one prior therapy. Patients received ibrutinib 560 mg daily until unacceptable toxicity, progression of disease, or withdrawal of consent. The primary endpoint was objective response rate.. Twenty patients were enrolled on protocol from November 2015 to December 2017 (15 advanced GI/lung NENs and 5 pNENs). No patient reached an objective response. Median PFS was 3.0 months. A total of 44 drug-related adverse events (AEs) were captured as probably or definitely associated with ibrutinib. Five patients experienced probably or definitely related grade 3 AEs, and 1 patient experienced a probably related grade 4 AE. Five patients discontinued treatment prior to radiographic assessment.. Ibrutinib does not show significant evidence of activity in well-differentiated gastroenteropancreatic and lung NENs.

Topics: Adenine; Adult; Agammaglobulinaemia Tyrosine Kinase; Aged; Carcinoid Tumor; Female; Gastrointestinal Neoplasms; Humans; Lung Neoplasms; Male; Middle Aged; Neuroendocrine Tumors; Pancreatic Neoplasms; Piperidines; Prospective Studies; Protein Kinase Inhibitors; Treatment Failure

Topics: Adenine; Adenocarcinoma; Albumins; B-Lymphocytes; Deoxycytidine; Gemcitabine; Humans; Paclitaxel; Pancreatic Neoplasms; Piperidines

Radiotherapy is an effective treatment for pancreatic cancer. However, radio-resistance often resulted in poor prognostic. Ibrutinib is an orally small molecule drug in B cell malignancies. Here, we investigated for the first time the effect of ibrutinib on radio-sensitivity of human pancreatic cancer cells in vitro and the potential mechanism involved in it. Human BXPC3 and Capan2 cell lines were treated with ibrutinib, and cell viability was conducted with CCK-8 assay. Cell clone formation was observed after treated with ibrutinib and (or) radiation by clone formation assay. The cell cycle and cell apoptosis were measured by flow cytometry. Protein levels was analyzed by western blot. The results revealed that ibrutinib inhibited the proliferation of pancreatic cancer cells. Ibrutinib enhanced the effect of radiation with a sensitization enhancement ratio (SER) of 1.34, 1.68 in BXPC3 and Capan2 cells respectively. Ibrutinib combined with radiation induced G2/M arrest and cell apoptosis. Further investigations revealed that ibrutinib decreased the phosphorylation of EGFR, then reversed the upregulation of p-AKT and downstream genes by radiation. In conclusion, these results suggested that ibrutinib might be an excellent radiosensitizer in pancreatic cancer.

Topics: Adenine; Apoptosis; Cell Line, Tumor; Cell Proliferation; ErbB Receptors; G2 Phase Cell Cycle Checkpoints; Humans; Pancreatic Neoplasms; Phosphorylation; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Radiation Tolerance; Radiation-Sensitizing Agents; Signal Transduction; TOR Serine-Threonine Kinases

We synthesized a library of aminopyrazole analogs to systematically explore the hydrophobic pocket adjacent to the hinge region and the solvent exposed region of cyclin dependent kinases. Structure-activity relationship studies identified an optimal substitution for the hydrophobic pocket and analog 24 as a potent and selective CDK2/5 inhibitor.

Topics: Amination; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Cell Proliferation; Cyclin-Dependent Kinase 2; Cyclin-Dependent Kinase 5; Humans; Molecular Docking Simulation; Pancreatic Neoplasms; Protein Kinase Inhibitors; Pyrazoles; Structure-Activity Relationship

There is a great unmet medical need in pancreatic carcinoma (PC) for novel drugs with other mechanisms of action than existing. PC cells express the onco-fetal RTK ROR1, absent on most normal post-partem cells. ROR1 is involved in proliferation, survival, EMT and metastasis of tumor cells in various malignancies. A small molecule inhibitor (KAN0439834) (530 Da) targeting the TK domain of ROR1 was developed and the activity in ROR1 expressing human PC cell lines (n = 8) evaluated. The effects were compared to a murine mAb against the external part of ROR1, gemcitabine, erlotinib and ibrutinib. KAN0439834 induced significant apoptosis of the tumor cells. EC50 values for KAN0439834 varied between 250-650 nM depending on the cell line. The corresponding values for erlotinib and ibrutinib were 10-40 folds higher. KAN0439834 was much more effective in inducing tumor cell death than the ROR1 mAb although both inhibited ROR1 phosphorylation and downstream non-canonical Wnt pathway molecules. Combination of KAN0439834 with erlotinib or ibrutinib had significant additive effects on tumor cell death. A first-in-class small molecule ROR1 inhibitor (KAN0439834) showed promising in vitro activity against a number of human PC cell lines. Interesting is the additive effects of erlotinib and ibrutinib which warrants further studies as both these agents are in clinical trials for pancreatic carcinoma.

Topics: Adenine; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Drug Synergism; Erlotinib Hydrochloride; Gene Expression Regulation, Neoplastic; Humans; Low Density Lipoprotein Receptor-Related Protein-6; Organic Chemicals; Pancreas; Pancreatic Neoplasms; Phosphorylation; Piperidines; Protein Kinase Inhibitors; Protein Multimerization; Protein Structure, Quaternary; Pyrazoles; Pyrimidines; Receptor Tyrosine Kinase-like Orphan Receptors

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense stromal fibroinflammatory reaction that is a major obstacle to effective therapy. The desmoplastic stroma comprises many inflammatory cells, in particular mast cells as key components of the PDAC microenvironment, and such infiltration correlates with poor patient outcome. Indeed, it has been hypothesized that stromal ablation is critical to improve clinical response in patients with PDAC. Ibrutinib is a clinically approved Bruton's tyrosine kinase inhibitor that inhibits mast cells and tumor progression in a mouse model of β-cell tumorigenesis. Here, we show that ibrutinib is highly effective at limiting the growth of PDAC in both transgenic mouse and patient-derived xenograft models of the disease. In these various experimental settings, ibrutinib effectively diminished fibrosis, extended survival, and improved the response to clinical standard-of-care therapy. Our results offer a preclinical rationale to immediately evaluate the clinical efficacy of ibrutinib in patients with PDAC.

Topics: Adenine; Adenocarcinoma; Animals; Antineoplastic Agents; Female; Fibrosis; Male; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, SCID; Pancreatic Neoplasms; Piperidines; Pyrazoles; Pyrimidines; Tumor Cells, Cultured; Tumor Microenvironment; Xenograft Model Antitumor Assays

Myc, a pleiotropic transcription factor that is deregulated and/or overexpressed in most human cancers, instructs multiple extracellular programs that are required to sustain the complex microenvironment needed for tumor maintenance, including remodeling of tumor stroma, angiogenesis, and inflammation. We previously showed in a model of pancreatic β-cell tumorigenesis that acute Myc activation in vivo triggers rapid recruitment of mast cells to the tumor site and that this is absolutely required for angiogenesis and macroscopic tumor expansion. Moreover, systemic inhibition of mast cell degranulation with sodium cromoglycate induced death of tumor and endothelial cells in established tumors. Hence, mast cells are required both to establish and to maintain the tumors. Whereas this intimates that selective inhibition of mast cell function could be therapeutically efficacious, cromoglycate is not a practical drug for systemic delivery in humans, and no other systemic inhibitor of mast cell degranulation has hitherto been available. PCI-32765 is a novel inhibitor of Bruton tyrosine kinase (Btk) that blocks mast cell degranulation and is currently in clinical trial as a therapy for B-cell non-Hodgkin lymphoma. Here, we show that systemic treatment of insulinoma-bearing mice with PCI-32765 efficiently inhibits Btk, blocks mast cell degranulation, and triggers collapse of tumor vasculature and tumor regression. These data reinforce the notion that mast cell function is required for maintenance of certain tumor types and indicate that the Btk inhibitor PCI-32765 may be useful in treating such diseases.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Animals; Cell Degranulation; Cell Proliferation; Cell Transformation, Neoplastic; Disease Models, Animal; Down-Regulation; Genes, myc; Insulinoma; Mast Cells; Mice; Mice, Transgenic; Models, Theoretical; Pancreatic Neoplasms; Piperidines; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Tumor Cells, Cultured