pci-32765 and Osteolysis

Primitive lymphomas of the bone are exceptional tumors, representing 4% of all non-Hodgkin lymphomas. The location at the skull remains the rarest. We report the case of a 56 year old patient with lytic lesions in the skull of a small cell lymphoma B, treated with primary chemotherapy and intensity-modulated radiotherapy in arctherapy with a dose of 30Gy in 15 fractions. With a follow-up time of 18 months after the end of treatment, the patient has no sign of disease evolution.

Topics: Adenine; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Craniotomy; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Magnetic Resonance Imaging; Meningeal Neoplasms; Meningioma; Middle Aged; Neoplasms, Second Primary; Osteolysis; Parietal Bone; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Radiotherapy, Intensity-Modulated; Remission Induction; Skull Neoplasms

Topics: Adenine; Aged; Antineoplastic Agents; Calcification, Physiologic; Combined Modality Therapy; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Magnetic Resonance Imaging; Osteolysis; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Tomography, X-Ray Computed; Treatment Outcome

Bruton tyrosine kinase (Btk) has a well-defined role in B-cell development, whereas its expression in osteoclasts (OCs) further suggests a role in osteoclastogenesis. Here we investigated effects of PCI-32765, an oral and selective Btk inhibitor, on osteoclastogenesis as well as on multiple myeloma (MM) growth within the BM microenvironment. PCI-32765 blocked RANKL/M-CSF-induced phosphorylation of Btk and downstream PLC-γ2 in OCs, resulting in diminished TRAP5b (ED50 = 17 nM) and bone resorption activity. PCI-32765 also inhibited secretion of multiple cytokines and chemokines from OC and BM stromal cell cultures from both normal donors (ED50 = 0.5 nM) and MM patients. It decreased SDF-1-induced migration of MM cells, and down-regulated MIP1-α/CCL3 in MM cells. It also blocked MM cell growth and survival triggered by IL-6 or coculture with BM stromal cells or OCs in vitro. Importantly, PCI-32765 treatment significantly inhibits in vivo MM cell growth (P < .03) and MM cell-induced osteolysis of implanted human bone chips in SCID mice. Moreover, PCI-32765 prevents in vitro colony formation by stem-like cells from MM patients. Together, these results delineate functional sequelae of Btk activation mediating osteolysis and growth of MM cells, supporting evaluation of PCI-32765 as a novel therapeutic in MM.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Animals; Bone Marrow; Cell Line, Tumor; Cell Proliferation; Cell Survival; Chemokines; Coculture Techniques; Cytokines; Down-Regulation; Gene Expression; Humans; Immunoblotting; Mice; Mice, SCID; Multiple Myeloma; Osteoclasts; Osteolysis; Piperidines; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Reverse Transcriptase Polymerase Chain Reaction; Stromal Cells; Tumor Microenvironment; Xenograft Model Antitumor Assays