Initial testing of lenalidomide by the pediatric preclinical testing program
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.
- [Show abstract] [Hide abstract]
ABSTRACT: The failure of EGFR inhibitors in colorectal tumors with KRAS mutations requires the development of alternative treatment strategies for this patient subgroup. Among the hallmarks of cancer the disturbed immunosurveillance and cancer immune evasion have become emerging targets for cancer therapy. Due to their pleiotropic functions immunomodulatory drugs (IMiDs) are interesting agents for combination therapies in solid tumors. However, their possible contribution and a way of monitoring their biological effects have yet to be revealed. In a heavily pretreated patient with advanced colorectal cancer carrying mutations in APC and KRAS genes, we show an early metabolic response and enhanced NK cell activity to monotherapy with lenalidomide. After subsequent lenalidomide/cetuximab combination treatment, the patient had progressive disease. At the same time a reduced performance status, complicated by febrile neutropenia, occurred, as well as a slight increase in metabolic activity and NK cell activity droped back to baseline. Thus, laboratory measurements and metabolic response assessment correlated with clinical conditions. This case report describes the feasibility and potential of a functional assessment of patient derived immune competent cells in combination with functional imaging for the detection of a biological response.Cancer biology & therapy 12/2013; 15(3). · 3.29 Impact Factor
- [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 01/2013; 3:132.
- [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).