In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 1925-1925
Abstract:
BACKGROUND: Acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) represent the most common types of cancer among children. Although the survival rates of pediatric ALL and AML have improved substantially over the last decades, the prognosis for some subgroups of pediatric leukemia remain poor. MLL-rearranged infant ALL, MLL-rearranged AML, and NUP98-rearranged AML, for instance, still have 5-year event-free survival rates of only ~40%. Evidently, these high-risk subtypes of childhood leukemia urgently require new treatment strategies in order to improve clinical outcome. AIM: Identification of effective therapeutic drugs for high-risk leukemia subtypes harboring a translocation in the MLL or NUP98 gene, by using a drug repurposing strategy involving high-throughput screening of & gt; 4000 compounds. METHODS: Primary leukemic cells derived from six patients with either MLL-rearranged infant ALL, pediatric MLL-rearranged AML, or pediatric NUP98-rearranged AML at diagnosis, were screened using commercially available drug libraries comprising a total of 4165 compounds. Drug sensitivity was assessed after 4 days treatment with 10 nM, 100 nM and 1000 nM of the library compounds using MTT assays. Potential hits were subsequently validated using cytotoxicity assays with a more extensive range of drug concentrations. RESULTS: The results of our drug screens showed that the most effective drugs, by far, were found for MLL-rearranged infant ALL. For MLL-rearranged AML the number of identified potent drugs was considerably less; notably, all of these compounds identified overlapped with the effective agents also found for MLL-rearranged infant ALL. Remarkably, for NUP98-translocated AML, only a few potential drug hits were identified, suggesting that this type of leukemia might be extremely chemo-resistant. In addition to novel candidate compounds, we also found several agents either recently described to have strong anti-leukemic effects against MLL-rearranged leukemia, such as the BCL2 inhibitors Venetoclax (ABT199) and Navitoclax (ABT263), or the MDM2 inhibitor Idasanutlin (RG7388), as well as finding drugs currently being used in the treatment of MLL-rearranged acute leukemias. Taken together, these observations indicate that high-throughput drug screening on primary patient samples is indeed able to identify effective compounds, validating our experimental approach. Interestingly, while validating newly identified drug hits, we observed a remarkable pattern for compounds effective against MLL-rearranged acute leukemia: the top hits seem to either directly or indirectly associate with p53 activity, albeit from various angles. CONCLUSION: Our data suggests a potential role for p53 in MLL-rearranged acute leukemia, and indicates that targeting p53 may well become an important therapeutic strategy for these types of childhood leukemia. Citation Format: Priscilla Wander, Sandra S. Pinhanços, Bianca Koopmans, M. Emmy M. Dolman, Pauline Schneider, Patricia Garrido Castro, Luke Jones, Susan T.C.J.M. Arentsen-Peters, Mark Kerstjens, Jan Molenaar, Huib N. Caron, Rob Pieters, Michel C. Zwaan, Ronald W. Stam. High-throughput drug library screening identifies potent drugs and novel drug targets for high-risk acute leukemia in children [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1925.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2018-1925
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2018
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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