Lucy Swift1, Aarthi Jayanthan1, Yibing Ruan1, Ronald Anderson1, Jessica Boklan2, Tanya Trippett3, Aru Narendran4. 1. POETIC Laboratory for Preclinical and Drug Discovery Studies, University of Calgary and the Division of Pediatric Oncology, Alberta Children's Hospital, 2888 Shaganappi Trail NW, Calgary, Alberta, T3B 6A8, Canada. 2. Center for Cancer and Blood Disorders, Phoenix Children's Hospital, Phoenix, AZ, USA. 3. Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA. 4. POETIC Laboratory for Preclinical and Drug Discovery Studies, University of Calgary and the Division of Pediatric Oncology, Alberta Children's Hospital, 2888 Shaganappi Trail NW, Calgary, Alberta, T3B 6A8, Canada. a.narendran@ucalgary.ca.
Abstract
BACKGROUND: Leukemia accounts for 30% of all childhood cancers and although the survival rate for pediatric leukemia has greatly improved, relapse is a major cause of treatment failure. Therefore, the development and introduction of novel therapeutics to treat relapsed pediatric leukemia is urgently needed. The proteasome inhibitor bortezomib has been shown to be effective against adult hematological malignancies such as multiple myeloma and lymphoma, but is frequently associated with the development of resistance. Carfilzomib is a next-generation proteasome inhibitor that has shown promising results against refractory adult hematological malignancies. OBJECTIVE: Carfilzomib has been extensively studied in adult hematological malignancies, providing the rationale for evaluating proof-of-concept activity of carfilzomib in pediatric leukemia. METHODS: The effects of carfilzomib on pediatric leukemia cell lines and primary pediatric leukemia patient samples were investigated in vitro using the alamar blue cytotoxicity assay, western blotting, and a proteasome activity assay. Synergy with commonly used anticancer drugs was determined by calculation of combination indices. RESULTS: In vitro preclinical data show pharmacologically relevant concentrations of carfilzomib are cytotoxic to pediatric leukemia cell lines and primary pediatric leukemia cells. Target modulation studies validate the effective inhibition of the proteasome and induction of apoptosis. We also identify agents that have effective synergy with carfilzomib in these cells. CONCLUSIONS: Our data provide pre-clinical information that can be incorporated into future early-phase clinical trials for the assessment of carfilzomib as a treatment for children with refractory hematological malignancies.
BACKGROUND:Leukemia accounts for 30% of all childhood cancers and although the survival rate for pediatric leukemia has greatly improved, relapse is a major cause of treatment failure. Therefore, the development and introduction of novel therapeutics to treat relapsed pediatric leukemia is urgently needed. The proteasome inhibitor bortezomib has been shown to be effective against adult hematological malignancies such as multiple myeloma and lymphoma, but is frequently associated with the development of resistance. Carfilzomib is a next-generation proteasome inhibitor that has shown promising results against refractory adult hematological malignancies. OBJECTIVE:Carfilzomib has been extensively studied in adult hematological malignancies, providing the rationale for evaluating proof-of-concept activity of carfilzomib in pediatric leukemia. METHODS: The effects of carfilzomib on pediatric leukemia cell lines and primary pediatric leukemiapatient samples were investigated in vitro using the alamar bluecytotoxicity assay, western blotting, and a proteasome activity assay. Synergy with commonly used anticancer drugs was determined by calculation of combination indices. RESULTS: In vitro preclinical data show pharmacologically relevant concentrations of carfilzomib are cytotoxic to pediatric leukemia cell lines and primary pediatric leukemia cells. Target modulation studies validate the effective inhibition of the proteasome and induction of apoptosis. We also identify agents that have effective synergy with carfilzomib in these cells. CONCLUSIONS: Our data provide pre-clinical information that can be incorporated into future early-phase clinical trials for the assessment of carfilzomib as a treatment for children with refractory hematological malignancies.
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