Initial Testing of Lenalidomide by the Pediatric Preclinical Testing Program

Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine and Abramson Family Cancer Research Institute, Philadelphia, Pennsylvania
Pediatric Blood & Cancer (Impact Factor: 2.39). 10/2011; 57(4):606 - 611. DOI: 10.1002/pbc.22877


Lenalidomide, a novel immunomodulatory agent, is reported to modulate stem cell differentiation, and have direct antiproliferative activity as well as inhibit inflammation and hyperalgesia. On the basis of this varied pharmacological profile, lenalidomide is under investigation as a treatment for a range of oncologic indications.ProceduresLenalidomide was evaluated against the PPTP in vitro panel using 96-hr exposure at concentrations ranging from 1 nM to 10 µM. It was tested against the PPTP in vivo panels at a dose of 30 mg/kg administered orally (PO) once daily for a planned for 6 weeks.ResultsIn vitro activity was not observed at concentrations up to 10 µM. Lenalidomide was well tolerated, and induced significant differences in EFS distribution compared to control in 7 of 37 (18.9%) of the evaluable solid tumor xenografts and in 0 of 8 (0%) of the evaluable ALL xenografts. The best response in the solid tumor panel was PD2 [progressive disease with growth delay (EFS T/C > 1.5)], observed in 4 of 37 (10.8%) solid tumor xenografts. A single ALL xenograft showed a PD2 response.Conclusions
Direct antiproliferative effects of lenalidomide were not observed in vitro. In vivo lenalidomide demonstrated low activity against tumors in immune-deficient mice. Our results suggest that lenalidomide's utility in the pediatric clinical setting may depend upon its ability to induce antitumor activity through effects on host immune and stromal cells rather than through direct effects on tumor cells. Pediatr Blood Cancer 2011; 57: 606–611. © 2011 Wiley-Liss, Inc.

7 Reads
  • [Show abstract] [Hide abstract]
    ABSTRACT: Basic science research holds the promise of rounds of discovery that will help to overcome treatment barriers for primary bone tumors. The management of primary bone sarcomas has achieved a consistently high level around the world. The growth and development of international specialty organizations such as the European Musculoskeletal Oncology Society, Musculoskeletal Tumor Society, Asia-Pacific Tumor Society, International Society of Limb Salvage, and Connective Tissue Oncology Society, as well as of domestic orthopaedic and collaborative study groups, have made great strides in educating the medical and surgical communities about the best practices in the modern care of primary bone tumors. However, these marked improvements have brought us to a plateau over the past two decades. Unacceptably high rates of tumor resistance to chemotherapy and of local and distant relapse remain. Only incremental progress has been achieved in managing the three most common bone cancers: osteogenic sarcoma (OGS), Ewing’s sarcoma, and chondrosarcoma. The management of benign tumors is generally successful, but not universally so. For example, certain benign tumors, such as giant cell tumor and aneurysmal bone cyst, have persistently high local recurrence rates. Basic science research holds the key to solve the refractory clinical problems. Important strides have been made in understanding the etiology and factors contributing to the progression of these primary tumors. This article summarizes many of the exciting ideas and results in primary bone tumor research, focusing on the most common skeletal cancer: OGS.
    LO SCALPELLO-OTODI Educational 10/2011; 25(3). DOI:10.1007/s11639-011-0119-1
  • [Show abstract] [Hide abstract]
    ABSTRACT: Thalidomide has indications for the treatment of several immune-related, neoplastic, and inflammatory diseases, in both adults and children. Despite numerous therapeutic indications for the application of thalidomide, the influence of that drug upon skeletal system has not been recognized. The aim of the present study was to investigate the effects of thalidomide on the osseous tissue in young rats. The experiments were carried out on 5-week-old male Wistar rats. The animals were administered thalidomide in the doses of 15, 30 or 60 mg/kg p.o. over the period of 1, 3 or 6 weeks. The body mass gain, bone mass in the tibia, femur and L-4 vertebra, histomorphometric parameters of the femur (width of trabeculae, width of epiphyseal cartilage, the transverse cross-sectional area of the bone marrow cavity and the cortical bone) and the tibia (width of osteoid, diaphysis transverse growth, the transverse cross-sectional area of the bone marrow cavity and the cortical bone) were studied. The investigations carried out provide, for the first time, information concerning the influence of thalidomide upon bone remodeling processes in young rats. The effects of thalidomide on the skeletal system of young rats depended on the dose and upon application time. After administration of doses 15, 30 and 60 mg/kg p.o. for 1 and 3 weeks, no influence of thalidomide was noted upon the examined macrometric parameters and histomorphometric parameters of femur, tibia and L-4 vertebra in young rats. Significant disturbances of bone remodeling in young rats have been observed after 6 weeks of thalidomide application, while the progression of those changes increased with the increase of the dose administered. After administering the dose of 15 mg/kg p.o. for the period of 6 weeks, no significant changes were found, as regards the macrometric and histomorphometric parameters of bones. Thalidomide, applied 6 weeks in the dose of 30 mg/kg p.o., and in particular in the dose of 60 mg/kg p.o., turned out to disturb bone remodeling processes. In animals administered thalidomide in the dose of 60 mg/kg p.o., reduction mass of tibia, femur, and L-4 vertebra has been observed. In compact bone, thalidomide reduced the diaphysis transverse growth of tibia, reduced the width of osteoid, as well as reduced the transverse cross-sectional area of cortical bone, increased the transverse cross-sectional area of marrow cavity, and increased the transverse cross-sectional area of the marrow cavity/transverse cross-sectional area of the diaphysis ratio of tibia and femur. In cancellous bone, thalidomide reduced the width of bone trabeculae, and increased the width of epiphyseal cartilage. On the basis of the results obtained, one can conclude that thalidomide applied for 6 weeks in the dose of 60 mg/kg p.o. inhibited the bone formation processes and increased the bone resorption in young rats.
    Acta poloniae pharmaceutica 03/2013; 70(2):323-31. · 0.74 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Osteosarcoma, the most common malignant bone tumor of childhood, is a high-grade primary bone sarcoma that occurs mostly in adolescence. Standard treatment consists of surgery in combination with multi-agent chemotherapy regimens. The development and approval of imatinib for Philadelphia chromosome-positive acute lymphoblastic leukemia in children and the fully human monoclonal antibody, anti-GD2, as part of an immune therapy for high-risk neuroblastoma patients have established the precedent for use of targeted inhibitors along with standard chemotherapy backbones. However, few targeted agents tested have achieved traditional clinical endpoints for osteosarcoma. Many biological agents demonstrating anti-tumor responses in preclinical and early-phase clinical testing have failed to reach response thresholds to justify randomized trials with large numbers of patients. The development of targeted therapies for pediatric cancer remains a significant challenge. To aid in the prioritization of new agents for clinical testing, the Pediatric Preclinical Testing Program (PPTP) has developed reliable and robust preclinical pediatric cancer models to rapidly screen agents for activity in multiple childhood cancers and establish pharmacological parameters and effective drug concentrations for clinical trials. In this article, we examine a range of standard and novel agents that have been evaluated by the PPTP, and we discuss the preclinical and clinical development of these for the treatment of osteosarcoma. We further demonstrate that committed resources for hypothesis-driven drug discovery and development are needed to yield clinical successes in the search for new therapies for this pediatric disease.
    Frontiers in Oncology 05/2013; 3:132. DOI:10.3389/fonc.2013.00132
Show more