Preclinical Evaluation of Carfilzomib for Infant KMT2A-Rearranged Acute Lymphoblastic Leukemia.
Background: Infants with KMT2A-rearranged B-cell precursor acute lymphoblastic leukemia (ALL) have poor outcomes. There is an urgent need to identify novel agents to improve survival. Proteasome inhibition has emerged as a promising therapeutic strategy for several hematological malignancies. The ai...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Journal Article |
| Language: | English |
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2021
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| Online Access: | http://purl.org/au-research/grants/nhmrc/1142627 http://hdl.handle.net/20.500.11937/83420 |
| _version_ | 1848764584486240256 |
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| author | Cheung, Laurence de Kraa, Rebecca Oommen, Joyce Chua, Grace-Alyssa Singh, Sajla Hughes, Anastasia M Ferrari, Emanuela Ford, Jette Chiu, Sung K Stam, Ronald W Kees, Ursula R Malinge, Sébastien Kotecha, Rishi |
| author_facet | Cheung, Laurence de Kraa, Rebecca Oommen, Joyce Chua, Grace-Alyssa Singh, Sajla Hughes, Anastasia M Ferrari, Emanuela Ford, Jette Chiu, Sung K Stam, Ronald W Kees, Ursula R Malinge, Sébastien Kotecha, Rishi |
| author_sort | Cheung, Laurence |
| building | Curtin Institutional Repository |
| collection | Online Access |
| description | Background: Infants with KMT2A-rearranged B-cell precursor acute lymphoblastic leukemia (ALL) have poor outcomes. There is an urgent need to identify novel agents to improve survival. Proteasome inhibition has emerged as a promising therapeutic strategy for several hematological malignancies. The aim of this study was to determine the preclinical efficacy of the selective proteasome inhibitor carfilzomib, for infants with KMT2A-rearranged ALL.
Methods: Eight infant ALL cell lines were extensively characterized for immunophenotypic and cytogenetic features. In vitro cytotoxicity to carfilzomib was assessed using a modified Alamar Blue assay with cells in logarithmic growth. The Bliss Independence model was applied to determine synergy between carfilzomib and the nine conventional chemotherapeutic agents used to treat infants with ALL. Established xenograft models were used to identify the maximal tolerated dose of carfilzomib and determine in vivo efficacy.
Results: Carfilzomib demonstrated low IC50 concentrations within the nanomolar range (6.0-15.8 nm) across the panel of cell lines. Combination drug testing indicated in vitro synergy between carfilzomib and several conventional chemotherapeutic agents including vincristine, daunorubicin, dexamethasone, L-asparaginase, and 4-hydroperoxycyclophosphamide. In vivo assessment did not lead to a survival advantage for either carfilzomib monotherapy, when used to treat both low or high disease burden, or for carfilzomib in combination with multi-agent induction chemotherapy comprising of vincristine, dexamethasone, and L-asparaginase.
Conclusions: Our study highlights that in vitro efficacy does not necessarily translate to benefit in vivo and emphasizes the importance of in vivo validation prior to suggesting an agent for clinical use. Whilst proteasome inhibitors have an important role to play in several hematological malignancies, our findings guard against prioritization of carfilzomib for treatment of KMT2A-rearranged infant ALL in the clinical setting. |
| first_indexed | 2025-11-14T11:21:41Z |
| format | Journal Article |
| id | curtin-20.500.11937-83420 |
| institution | Curtin University Malaysia |
| institution_category | Local University |
| language | eng |
| last_indexed | 2025-11-14T11:21:41Z |
| publishDate | 2021 |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | curtin-20.500.11937-834202021-05-17T01:53:36Z Preclinical Evaluation of Carfilzomib for Infant KMT2A-Rearranged Acute Lymphoblastic Leukemia. Cheung, Laurence de Kraa, Rebecca Oommen, Joyce Chua, Grace-Alyssa Singh, Sajla Hughes, Anastasia M Ferrari, Emanuela Ford, Jette Chiu, Sung K Stam, Ronald W Kees, Ursula R Malinge, Sébastien Kotecha, Rishi KMT2A MLL PER cell lines acute lymphoblastic leukemia carfilzomib infant Background: Infants with KMT2A-rearranged B-cell precursor acute lymphoblastic leukemia (ALL) have poor outcomes. There is an urgent need to identify novel agents to improve survival. Proteasome inhibition has emerged as a promising therapeutic strategy for several hematological malignancies. The aim of this study was to determine the preclinical efficacy of the selective proteasome inhibitor carfilzomib, for infants with KMT2A-rearranged ALL. Methods: Eight infant ALL cell lines were extensively characterized for immunophenotypic and cytogenetic features. In vitro cytotoxicity to carfilzomib was assessed using a modified Alamar Blue assay with cells in logarithmic growth. The Bliss Independence model was applied to determine synergy between carfilzomib and the nine conventional chemotherapeutic agents used to treat infants with ALL. Established xenograft models were used to identify the maximal tolerated dose of carfilzomib and determine in vivo efficacy. Results: Carfilzomib demonstrated low IC50 concentrations within the nanomolar range (6.0-15.8 nm) across the panel of cell lines. Combination drug testing indicated in vitro synergy between carfilzomib and several conventional chemotherapeutic agents including vincristine, daunorubicin, dexamethasone, L-asparaginase, and 4-hydroperoxycyclophosphamide. In vivo assessment did not lead to a survival advantage for either carfilzomib monotherapy, when used to treat both low or high disease burden, or for carfilzomib in combination with multi-agent induction chemotherapy comprising of vincristine, dexamethasone, and L-asparaginase. Conclusions: Our study highlights that in vitro efficacy does not necessarily translate to benefit in vivo and emphasizes the importance of in vivo validation prior to suggesting an agent for clinical use. Whilst proteasome inhibitors have an important role to play in several hematological malignancies, our findings guard against prioritization of carfilzomib for treatment of KMT2A-rearranged infant ALL in the clinical setting. 2021 Journal Article http://hdl.handle.net/20.500.11937/83420 10.3389/fonc.2021.631594 eng http://purl.org/au-research/grants/nhmrc/1142627 http://creativecommons.org/licenses/by/4.0/ fulltext |
| spellingShingle | KMT2A MLL PER cell lines acute lymphoblastic leukemia carfilzomib infant Cheung, Laurence de Kraa, Rebecca Oommen, Joyce Chua, Grace-Alyssa Singh, Sajla Hughes, Anastasia M Ferrari, Emanuela Ford, Jette Chiu, Sung K Stam, Ronald W Kees, Ursula R Malinge, Sébastien Kotecha, Rishi Preclinical Evaluation of Carfilzomib for Infant KMT2A-Rearranged Acute Lymphoblastic Leukemia. |
| title | Preclinical Evaluation of Carfilzomib for Infant KMT2A-Rearranged Acute Lymphoblastic Leukemia. |
| title_full | Preclinical Evaluation of Carfilzomib for Infant KMT2A-Rearranged Acute Lymphoblastic Leukemia. |
| title_fullStr | Preclinical Evaluation of Carfilzomib for Infant KMT2A-Rearranged Acute Lymphoblastic Leukemia. |
| title_full_unstemmed | Preclinical Evaluation of Carfilzomib for Infant KMT2A-Rearranged Acute Lymphoblastic Leukemia. |
| title_short | Preclinical Evaluation of Carfilzomib for Infant KMT2A-Rearranged Acute Lymphoblastic Leukemia. |
| title_sort | preclinical evaluation of carfilzomib for infant kmt2a-rearranged acute lymphoblastic leukemia. |
| topic | KMT2A MLL PER cell lines acute lymphoblastic leukemia carfilzomib infant |
| url | http://purl.org/au-research/grants/nhmrc/1142627 http://hdl.handle.net/20.500.11937/83420 |