New drugs creating new challenges in acute myeloid leukemia

Tiong, Ing Soo; Wei, Andrew H.

doi:10.1002/gcc.22750

Cited by 40 publications

(38 citation statements)

References 131 publications

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“…One method to combat this is to use two or more drugs in combination. Combination therapy is rapidly becoming the standard of care in a variety of cancers because it has several advantages, including limiting the development of resistance and potential drug synergies that may allow reduced drug concentrations to be used (53,54). Repurposing existing drugs in new combinations could provide new possibilities with reduced cost and time for development, while potentially minimizing side effects by lowering drug dosages (6).…”

Section: Discussionmentioning

confidence: 99%

Utilizing Synergistic Potential of Mitochondria-Targeting Drugs for Leukemia Therapy

et al. 2020

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Acute myeloid leukemia (AML) is an aggressive group of cancers with high mortality rates and significant relapse risks. Current treatments are insufficient, and new therapies are needed. Recent discoveries suggest that AML may be particularly sensitive to chemotherapeutics that target mitochondria. To further investigate this sensitivity, six compounds that target mitochondria [IACS-010759, rotenone, cytarabine, etoposide, ABT-199 (venetoclax), and carbonyl cyanide m-chlorophenylhydrazone] were each paired with six compounds with other activities, including tyrosine kinase inhibitors (midostaurin and dasatinib), glycolytic inhibitors (2-deoxy-D-glucose, 3-bromopyruvate, and lonidamine), and the microtubule destabilizer vinorelbine. The 36 resulting drug combinations were tested for synergistic cytotoxicity against MOLM-13 and OCI-AML2 AML cell lines. Four combinations (IACS-010759 with vinorelbine, rotenone with 2-deoxy-D-glucose, carbonyl cyanide m-chlorophenylhydrazone with dasatinib, and venetoclax with lonidamine) showed synergistic cytotoxicity in both AML cell lines and were selective for tumor cells, as survival of healthy PBMCs was dramatically higher. Among these drug pairs, IACS-010759/vinorelbine decreased ATP level and impaired mitochondrial respiration and coupling efficiency most profoundly. Some of these four treatments were also effective in K-562, KU812 (chronic myelogenous leukemia) and CCRF-CEM, MOLT-4 (acute lymphoblastic leukemia) cells, suggesting that these treatments may have value in treating other forms of leukemia. Finally, two of the four combinations retained high synergy and strong selectivity in primary AML cells from patient samples, supporting the potential of these treatments for patients.

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Section: Discussionmentioning

confidence: 99%

Utilizing Synergistic Potential of Mitochondria-Targeting Drugs for Leukemia Therapy

et al. 2020

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“…Several tyrosine kinase inhibitors (TKIs) are in development as targeted therapy for FLT3 mutant AML [38]. Sorafenib (first generation of TKIs) has been shown to improve EFS, but not OS in younger adults with AML; Midostaurin (first generation of TKIs) improves OS with a HR of 0.78 [39]. Crenolanib(second generation of TKIs) in combination with chemotherapy resulted in CR/CRi rates of 96% among FLT3 mutant subjects, Gilteritinib (second generation of TKIs) also produced CR/CRi rates of 89% [39].…”

Section: Prognosis and Current Treatments Of Mutant Flt3 In Patientsmentioning

confidence: 99%

“…Sorafenib (first generation of TKIs) has been shown to improve EFS, but not OS in younger adults with AML; Midostaurin (first generation of TKIs) improves OS with a HR of 0.78 [39]. Crenolanib(second generation of TKIs) in combination with chemotherapy resulted in CR/CRi rates of 96% among FLT3 mutant subjects, Gilteritinib (second generation of TKIs) also produced CR/CRi rates of 89% [39]. Though adding FLT3 inhibitors to standard frontline chemotherapy in FLT3 mutant AML patients results in a survival benefit [37], unfortunately, FLT3-ITD TKIs only have a relatively modest and transient effect, indicating that TKIs do not completely eradicate LSCs.…”

Section: Prognosis and Current Treatments Of Mutant Flt3 In Patientsmentioning

confidence: 99%

Targeting on glycosylation of mutant FLT3 in acute myeloid leukemia

Chen

2019

Hematology

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Objective: To summarize the abnormal location of FLT3 caused by different glycosylation status which further leads to the distinguishing signaling pathways and discuss targeting on FLT3 glycosylation by drugs reported in recent literatures. Methods: We review FLT3 glycosylation in endoplasmic reticulum. The abnormal signal of mutant FLT3 with different glycosylation status is discussed. We also address potential FLT3 glycosylation-targeting strategies for the treatment. Results: Inhibition of FLT3 mutant cells by drugs reported in recent literatures involves the influence of glycosylation of FLT3: 2-deoxy-D-glucose, Tunicamycin and Fluvastatin are reported to inhibit N-glycosylation of FLT3; Pim-1 inhibitors are proved to block the inhibition of Pim-1 on FLT3 Oglycosylation; HSP90 inhibitors and Tyrosine Kinase Inhibitors are shown to increase fully glycosylated form of FLT3. Discussion: The FMS-like tyrosine kinase 3 (FLT3) gene expressed only in CD34+ progenitor cells in bone marrow is located on chromosome 13q12 encoding FLT3 protein. FLT3 is initially synthesized as a 110 KD protein, which glycosylated in the endoplasmic reticulum to a 130 KD immature protein rich in mannose, and further processed into a mature 160 KD protein in the Golgi apparatus, which could be transferred to the cell surface. Therapy targeting on FLT3 glycosylation is a promising direction for AML treatment. Conclusions: The abnormal location of FLT3 caused by different glycosylation status leads to the distinguishing signaling pathways. Targeting on FLT3 glycosylation may provide a new perspective for therapeutic strategies.

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“…The standard therapy for AML has predominantly been 7 + 3 induction cytotoxic chemotherapy with cytarabine and daunuroubicin [3]. However, in the past 2 years, eight drugs were approved by the Federal Drug Administration (FDA) [reviewed in [4]]: Midostaurin [5], CPX-351 [6], gemtuzumab ozogamicin [7], enasidenib [8], ivosidenib [9], gilteritnib [10], venetoclax [11,12], and glasdegib [13]. Despite the clinical progress of targeted therapies driven by advances in highthroughput sequencing, AML remains difficult to treat and ultimately to cure.…”

Section: Introductionmentioning

confidence: 99%

Preclinical efficacy for a novel tyrosine kinase inhibitor, ArQule 531 against acute myeloid leukemia

et al. 2020

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Background: Acute myeloid leukemia (AML) is the most common type of adult leukemia. Several studies have demonstrated that oncogenesis in AML is enhanced by kinase signaling pathways such as Src family kinases (SFK) including Src and Lyn, spleen tyrosine kinase (SYK), and bruton's tyrosine kinase (BTK). Recently, the multi-kinase inhibitor ArQule 531 (ARQ 531) has demonstrated potent inhibition of SFK and BTK that translated to improved preclinical in vivo activity as compared with the irreversible BTK inhibitor ibrutinib in chronic lymphocytic leukemia (CLL) models. Given the superior activity of ARQ 531 in CLL, and recognition that this molecule has a broad kinase inhibition profile, we pursued its application in pre-clinical models of AML. Methods: The potency of ARQ 531 was examined in vitro using FLT3 wild type and mutated (ITD) AML cell lines and primary samples. The modulation of pro-survival kinases following ARQ 531 treatment was determined using AML cell lines. The effect of SYK expression on ARQ 531 potency was evaluated using a SYK overexpressing cell line (Ba/F3 murine cells) constitutively expressing FLT3-ITD. Finally, the in vivo activity of ARQ 531 was evaluated using MOLM-13 disseminated xenograft model. Results: Our data demonstrate that ARQ 531 treatment has anti-proliferative activity in vitro and impairs colony formation in AML cell lines and primary AML cells independent of the presence of a FLT3 ITD mutation. We demonstrate decreased phosphorylation of oncogenic kinases targeted by ARQ 531, including SFK (Tyr416), BTK, and fms-related tyrosine kinase 3 (FLT3), ultimately leading to changes in downstream targets including SYK, STAT5a, and ERK1/2. Based upon in vitro drug synergy data, we examined ARQ 531 in the MOLM-13 AML xenograft model alone and in combination with venetoclax. Despite ARQ 531 having a less favorable pharmacokinetics profile in rodents, we demonstrate modest single agent in vivo activity and synergy with venetoclax. Conclusions: Our data support consideration of the application of ARQ 531 in combination trials for AML targeting higher drug concentrations in vivo.

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New drugs creating new challenges in acute myeloid leukemia

Cited by 40 publications

References 131 publications

Utilizing Synergistic Potential of Mitochondria-Targeting Drugs for Leukemia Therapy

Utilizing Synergistic Potential of Mitochondria-Targeting Drugs for Leukemia Therapy

Targeting on glycosylation of mutant FLT3 in acute myeloid leukemia

Preclinical efficacy for a novel tyrosine kinase inhibitor, ArQule 531 against acute myeloid leukemia

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