Dactinomycin induces complete remission associated with nucleolar stress response in relapsed/refractory NPM1-mutated AML

AbstractAcute myeloid leukemia (AML) with mutated NPM1 accounts for one-third of newly diagnosed AML. Despite recent advances, treatment of relapsed/refractory NPM1-mutated AML remains challenging, with the majority of patients eventually dying due to disease progression. Moreover, the prognosis is particularly poor in elderly and unfit patients, mainly because they cannot receive intensive treatment. Therefore, alternative treatment strategies are needed. Dactinomycin is a low-cost chemotherapeutic agent, which has been anecdotally reported to induce remission in NPM1-mutated patients, although its mechanism of action remains unclear. Here, we describe the results of a single-center phase 2 pilot study investigating the safety and efficacy of single-agent dactinomycin in relapsed/refractory NPM1-mutated adult AML patients, demonstrating that this drug can induce complete responses and is relatively well tolerated. We also provide evidence that the activity of dactinomycin associates with nucleolar stress both in vitro and in vivo in patients. Finally, we show that low-dose dactinomycin generates more efficient stress response in cells expressing NPM1 mutant compared to wild-type cells, suggesting that NPM1-mutated AML may be more sensitive to nucleolar stress. In conclusion, we establish that dactinomycin is a potential therapeutic alternative in relapsed/refractory NPM1-mutated AML that deserves further investigation in larger clinical studies.

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BET bromodomain inhibitor birabresib in mantle cell lymphoma: in vivo activity and identification of novel combinations to overcome adaptive resistance

ESMO Open ◽

10.1136/esmoopen-2018-000387 ◽

2018 ◽

Vol 3 (6) ◽

pp. e000387 ◽

Cited By ~ 10

Author(s):

Chiara Tarantelli ◽

Elena Bernasconi ◽

Eugenio Gaudio ◽

Luciano Cascione ◽

Valentina Restelli ◽

...

Keyword(s):

Mantle Cell Lymphoma ◽

Cell Lines ◽

Cell Lymphoma ◽

Antitumour Activity ◽

Single Agent ◽

Treatment Strategies ◽

Bet Inhibitor ◽

Mantle Cell

BackgroundThe outcome of patients affected by mantle cell lymphoma (MCL) has improved in recent years, but there is still a need for novel treatment strategies for these patients. Human cancers, including MCL, present recurrent alterations in genes that encode transcription machinery proteins and of proteins involved in regulating chromatin structure, providing the rationale to pharmacologically target epigenetic proteins. The Bromodomain and Extra Terminal domain (BET) family proteins act as transcriptional regulators of key signalling pathways including those sustaining cell viability. Birabresib (MK-8628/OTX015) has shown antitumour activity in different preclinical models and has been the first BET inhibitor to successfully undergo early clinical trials.Materials and methodsThe activity of birabresib as a single agent and in combination, as well as its mechanism of action was studied in MCL cell lines.ResultsBirabresib showed in vitro and in vivo activities, which appeared mediated via downregulation of MYC targets, cell cycle and NFKB pathway genes and were independent of direct downregulation of CCND1. Additionally, the combination of birabresib with other targeted agents (especially pomalidomide, or inhibitors of BTK, mTOR and ATR) was beneficial in MCL cell lines.ConclusionOur data provide the rationale to evaluate birabresib in patients affected by MCL.

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Lipid A’s Structure Mediates Neisseria gonorrhoeae Fitness during Experimental Infection of Mice and Men

mBio ◽

10.1128/mbio.00892-13 ◽

2013 ◽

Vol 4 (6) ◽

Cited By ~ 44

Author(s):

Marcia M. Hobbs ◽

James E. Anderson ◽

Jacqueline T. Balthazar ◽

Justin L. Kandler ◽

Russell W. Carlson ◽

...

Keyword(s):

Neisseria Gonorrhoeae ◽

Genital Tract ◽

Lipid A ◽

Female Genital Tract ◽

Treatment Strategies ◽

Wild Type ◽

Genital Tract Infection ◽

Content Type

ABSTRACT Phosphoethanolamine (PEA) on Neisseria gonorrhoeae lipid A influences gonococcal inflammatory signaling and susceptibility to innate host defenses in in vitro models. Here, we evaluated the role of PEA-decorated gonococcal lipid A in competitive infections in female mice and in male volunteers. We inoculated mice and men with mixtures of wild-type N. gonorrhoeae and an isogenic mutant that lacks the PEA transferase, LptA. LptA production conferred a marked survival advantage for wild-type gonococci in the murine female genital tract and in the human male urethra. Our studies translate results from test tube to animal model and into the human host and demonstrate the utility of the mouse model for studies of virulence factors of the human-specific pathogen N. gonorrhoeae that interact with non-host-restricted elements of innate immunity. These results validate the use of gonococcal LptA as a potential target for development of novel immunoprophylactic strategies or antimicrobial treatments. IMPORTANCE Gonorrhea is one of the most common bacterial sexually transmitted infections, and increasing antibiotic resistance threatens the use of currently available antimicrobial therapies. In this work, encompassing in vitro studies and in vivo studies of animal and human models of experimental genital tract infection, we document the importance of lipid A’s structure, mediated by a single bacterial enzyme, LptA, in enhancing the fitness of Neisseria gonorrhoeae. The results of these studies suggest that novel agents targeting LptA may offer urgently needed prevention or treatment strategies for gonorrhea.

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ABCG2 C.421C>A Is Associated with Higher Trough Imatinib Plasma Levels in Patients with Chronic Myeloid Leukemia.

Blood ◽

10.1182/blood.v114.22.110.110 ◽

2009 ◽

Vol 114 (22) ◽

pp. 110-110

Author(s):

Naoto Takahashi ◽

Masatomo Miura ◽

Stuart A Scott ◽

Kenichi Sawada

Keyword(s):

Chronic Myeloid Leukemia ◽

Plasma Levels ◽

Myeloid Leukemia ◽

Drug Transport ◽

Conflicts Of Interest ◽

Nucleotide Polymorphisms ◽

Wild Type ◽

Large Patient

Abstract Abstract 110 [Background] Despite the excellent efficacy of imatinib for the treatment of chronic myeloid leukemia (CML), trough imatinib plasma levels can vary widely among patients. This may be due, in part, to inter-individual variation in imatinib metabolism and drug transport efficacy. To investigate the role of genetic variation in the pharmacokinetics of imatinib, we analyzed common single nucleotide polymorphisms within important imatinib pathway genes including ABCG2 (BCRP), ABCB1 (MDR1), ABCC2 (MRP2), CYP3A5, and SLC22A1 (OCT1) in 67 CML patients treated with imatinib. In addition, trough imatinib plasma levels were determined using high-performance liquid chromatography-tandem mass spectrometry. [Results] Distinct imatinib pharmacokinetics were identified in association with ABCG2 c.421C>A (p.Q141K; rs2231142) genotype. Specifically, the presence of the variant c.421A allele was significantly (p=0.024) associated with higher imatinib concentrations [median Cmin/Dose 2.70 (range: 1.50-8.30) ng/ml/mg; n=25] compared to patients with the wild-type ABCG2 (c.421C/C) genotype [median Cmin/Dose 2.27 (range: 0.37-5.30) ng/ml/mg; n=42]. ABCG2 is an efflux transporter for many xenobiotics, including imatinib, and is expressed at high levels in the human liver. Previous studies indicate that c.421A causes a 40% reduction in imatinib transport in vitro when compared to the wild-type genotype. Our data suggest that CML patients with ABCG2 c.421A allele may have deficient ABCG2 activity in vivo, resulting in reduced hepatic excretion of imatinib. Of note, although less common among Africans and individuals of European decent, the ABCG2 c.421C>A allele occurs at a high frequency in the Japanese (0.311) and Han Chinese (0.289) populations. [Conclusion] The association of ABCG2 c.421C>A with imatinib pharmacokinetics may explain why some Japanese CML patients administered less than 400 mg/day of imatinib have clinically sufficient trough imatinib plasma levels. Prospective studies are warranted to confirm the association between ABCG2 genotype and imatinib pharmacokinetics in large patient populations. Disclosures: No relevant conflicts of interest to declare.

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The Pim Kinase Inhibitor AZD1208 Enhances Apoptosis Induction By Clinically Active FLT3 Inhibitors in FLT3-ITD Acute Myeloid Leukemia Cells in Vitro and in Vivo through Synergistic Downregulation of Mcl-1 and of Bcl-xL

Blood ◽

10.1182/blood.v124.21.3601.3601 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3601-3601 ◽

Cited By ~ 1

Author(s):

Karthika Natarajan ◽

Trevor J Mathias ◽

Kshama A Doshi ◽

Adriana E Tron ◽

Manfred Kraus ◽

...

Keyword(s):

Cell Lines ◽

Myeloid Leukemia ◽

Kinase Inhibitor ◽

Wild Type ◽

Protein Levels ◽

Flt3 Inhibitors ◽

Synergistic Induction ◽

Induction Of Apoptosis

Abstract Internal tandem duplication (ITD) mutations of the receptor tyrosine kinase fms-like tyrosine kinase 3 (FLT3) are present in acute myeloid leukemia (AML) cells in 30% of cases and are associated with high relapse rate and short disease-free survival. FLT3 inhibitors have clinical activity, but their activity is limited and transient. New therapeutic approaches combining FLT3 inhibitors and inhibitors of downstream or parallel signaling pathways may increase depth and duration of responses. The Pim-1 serine/threonine kinase is transcriptionally upregulated by FLT3-ITD. We previously demonstrated that Pim-1 phosphorylates and stabilizes FLT3 and thereby promotes its signaling in a positive feedback loop. Pim kinase inhibitors are in clinical trials. Here we studied the effect of combinations of the Pim kinase inhibitor AZD1208 and clinically active FLT3 inhibitors on AML with FLT3-ITD in vitro and in vivo. Ba/F3-ITD cells, with FLT3-ITD, were grown in medium with the Pim kinase inhibitor AZD1208 at 1 μM and/or the FLT3 inhibitors quizartinib (Q), sorafenib (S) or crenolanib (C) at their IC50values of 1, 2.5 and 20 nM, respectively, and viable cells were measured at serial time points. While Q, S, C or AZD1208 treatments reduced cell numbers, compared to DMSO control, combined AZD1208 and Q, S or C treatments abrogated proliferation. Because FLT3-ITD cells remain responsive to FLT3 ligand (FLT3L) despite constitutive FLT3 activation and increased FLT3L levels following chemotherapy have been hypothesized to contribute to relapse, we repeated the proliferation experiments in the presence of 0, 1, 3 and 10 ng/ml FLT3L. FLT3L produced a concentration-dependent increase in proliferation and, while Q, S, C or AZD1208 treatments individually reduced cell numbers, combined AZD1208 and Q, S or C abrogated proliferation at all FLT3L concentrations tested, suggesting that these combinations overcome growth stimulation by FLT3L. To understand the anti-proliferative effect of combined Pim-1 and FLT3 inhibitors, we first studied cell cycle effects of AZD1208 and Q, S or C in Ba/F3-ITD cells and of AZD1208 and Q in the additional FLT3-ITD cell lines 32D-ITD, MV4-11 and MOLM14. We found a progressive increase in sub-G1 phase cells at 24, 48 and 72 hours, consistent with induction of apoptosis. Synergistic induction of apoptosis was confirmed by Annexin V/propidium iodide labeling of Ba/F3-ITD and 32D-ITD cells treated for 48 hours with AZD1208 combined with Q (p<0.0001), S (p<0.0001) or C (p<0.001), and of MV4-11 (p<0.0001) and MOLM14 (p<0.05) cells treated with AZD1208 combined with Q, in relation to each drug alone. Apoptosis was additionally confirmed by loss of mitochondrial membrane potential. Synergistic induction of apoptosis was not seen in Ba/F3-WT or 32D-WT cells, with wild-type FLT3, indicating a FLT3-ITD-specific effect. Synergistic (p<0.01) induction of apoptosis was seen in three FLT3-ITD AML patient samples treated in vitro with AZD1208 combined with Q. In an in vivo model, synergistic decrease in tumor volume was seen with combined AZD1208 and Q therapy in mice with subcutaneously implanted MV4-11 cells, with FLT3-ITD, but not with KG1a cells, with wild-type FLT3. Mechanistically, combined AZD1208 and Q treatment in vitro did not increase reactive oxygen species, compared to each drug alone, but increased both cleaved caspase 3 and cleaved poly (ADP-ribose) polymerase (PARP) levels, and caspase 3 cleavage was reduced by co-incubation with the pan-caspase inhibitor Z-VAD. Moreover, combined AZD1208 and Q treatment caused a synergistic decrease in expression of the anti-apoptotic Mcl-1 and of Bcl-xL proteins, but did not significantly alter Bim-1, p-Bad, Bad, Bax, Bak or Bcl-2, pro- and anti-apoptotic protein levels. Bcl-xL mRNA expression decreased along with protein levels, but Mcl-1 mRNA levels remain unchanged, indicating post-transcriptional down-regulation of Mcl-1 by the combination treatment. In summary, synergistic cytotoxicity of AZD1208 and clinically active FLT3 inhibitors was demonstrated in FLT3-ITD cell lines and patient samples in vitro and in cell lines in vivo, via caspase-mediated apoptosis, associated with a synergistic decrease in Mcl-1 and Bcl-xL expression. Our data suggest clinical promise for combination therapy with Pim kinase and FLT3 inhibitors in patients with AML with FLT3-ITD. Disclosures No relevant conflicts of interest to declare.

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The Novel Fluoropyrimidine FdUMP[10] Is Highly Active Against Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v116.21.3302.3302 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3302-3302

Author(s):

Timothy Pardee ◽

Evan Gomes ◽

Jamie Jennings-Gee ◽

David L. Caudell ◽

William Gmeiner

Keyword(s):

Acute Myeloid Leukemia ◽

Cell Lines ◽

Myeloid Leukemia ◽

Single Agent ◽

The Novel ◽

Highly Active ◽

Ic50 Values ◽

Acute Myeloid

Abstract Abstract 3302 Acute Myeloid Leukemia (AML) is an aggressive myeloid malignancy that leads to marrow failure and death. This disease affects approximately 12,000 people per year in the United States, causing 9,000 deaths. Despite decades of research, therapy remains essentially unchanged and outcomes are poor. In patients over the age of 60 less then 10% of patients survive 5 years from diagnosis. There is a desperate need for the identification of new active agents with favorable toxicity profiles. The novel polymeric fluoropyrimidine (FP) FdUMP[10] is an oligodeoxynucleotide pro-drug of the thymidylate synthase (TS)-inhibitory FP metabolite 5-fluoro-2'-deoxyuridine-5`-O-monophosphate (FdUMP). The observation that this compound was highly active against several leukemia lines in the NCI 60 cell line screen prompted us to evaluate its activity in several preclinical models of AML. In vitro, FdUMP[10] exhibited remarkable activity against 3 human acute leukemia cell lines, HL60, Jurkat and THP-1, with IC50 values of 3.378 nM (95% CI 2.984 to 3.825), 5.438 nM (4.609 to 6.417) and 4.093 nM (3.413 to 4.907) respectively. We next tested its efficacy against a more genetically defined murine model of AML driven by expression of MLL-ENL. FdUMP[10] exhibited even greater activity against all murine lines tested. The IC50 values of FdUMP[10] against two MLL-ENL driven murine AML cell lines were 214 pM (95%CI 178.9 to 255.9) and 292.3 pM (251.8 to 339.4). The IC50 values observed for FdUMP[10] for all the murine lines tested were lower than both Ara-C (30-40 nM) and doxorubicin (2-4 nM). We then determined the cytotoxic mechanism for FdUMP[10] in vitro. Upon treatment with FdUMP[10] both the human and murine cell lines undergo extensive apoptosis as indicated by Annexin V and propidium iodide staining. Treated cells developed γH2AX foci, rapid and complete TS inhibition and display trapped Topoisomerase I (Topo I) cleavage complexes. FdUMP[10]-mediated induction of apoptosis was p53 independent as murine AML cells that had p53 knocked down by RNAi demonstrated resistance to both Ara-C and doxorubicin, but not to FdUMP[10]. We next tested the efficacy of FdUMP[10] in vivo. The MLL-ENL driven murine AML model results in blasts that can be transplanted into sublethally irradiated, immunocompetent, syngeneic recipients. The recipients develop a fatal and therapy-resistant AML. Lines were generated that expressed a luciferase reporter. Animals were imaged 6–7 days after injection of the leukemias to ensure engraftment and then began treatment with either the combination of Ara-C plus doxorubicin, single-agent FdUMP[10], or observation. Studies were performed using 2 doses of FdUMP[10] at 150 or 300 mg/kg injected on days 1 and 3 and compared to animals treated with 100 mg/kg Ara-C and 3mg/kg doxorubicin injected on days 1 through 5. Both treatments resulted in a statistically significant survival advantage over observation. A preliminary toxicology study compared FdUMP[10], 150 mg/kg daily, to 5-fluorouracil (5 FU), 150 mg/kg daily, or the combination of Ara-C at 100 mg/kg plus doxorubicin at 3 mg/kg daily. All groups were treated for 3, 4 or 5 days. On day 6 animals were sacrificed and organs harvested, sectioned, and stained. Slides were then reviewed by a veterinary pathologist. Tissues most affected were the small intestine, colon, and the bone marrow. The 5FU-treated animals had severe villous blunting and fusion with crypt necrosis in both large and small intestine. In contrast, FdUMP[10]-treated animals had only mild crypt epithelial apoptosis with mitoses. The 5 FU and Ara-C plus doxorubicin groups had a severe pan-cytopenia in the marrow compared to FdUMP[10] treated animals that showed only minimal to mild apoptosis. These data support the assertion that FdUMP[10] has lower toxicity then either Ara-C plus doxorubicin or identically dosed 5 FU. In summary FdUMP[10] exhibited remarkable activity against AML cells in vitro and in vivo. Additionally, FdUMP[10] had decreased toxicity compared to treatment with either single agent 5 FU or combination treatment with Ara-C plus doxorubicin. Disclosures: Gmeiner: Salzburg Therapeutics: Equity Ownership.

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PGI synthase overexpression protects against bleomycin-induced mortality and is associated with increased Nqo 1 expression

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00224.2010 ◽

2011 ◽

Vol 301 (4) ◽

pp. L615-L622 ◽

Cited By ~ 14

Author(s):

Weisong Zhou ◽

Dustin R. Dowell ◽

Mark W. Geraci ◽

Timothy S. Blackwell ◽

Robert D. Collins ◽

...

Keyword(s):

Airway Epithelium ◽

Death Rate ◽

Treatment Strategies ◽

Oxygen Species ◽

In Vitro Experiments ◽

Wild Type ◽

Potential Therapeutic Target ◽

First Time

The mortality rate for acute lung injury (ALI) is reported to be between 35–40%, and there are very few treatment strategies that improve the death rate from this condition. Previous studies have suggested that signaling through the prostaglandin (PG) I2 receptor may protect against bleomycin-induced ALI in mice. We found that mice that overexpress PGI synthase (PGIS) in the airway epithelium were significantly protected against bleomycin-induced mortality and had reduced parenchymal consolidation, apoptosis of lung tissue, and generation of F2-isoprostanes compared with littermate wild-type controls. In addition, we show for the first time in both in vivo and in vitro experiments that PGI2 induced the expression of NADP (H): quinoneoxidoreductase 1 (Nqo 1), an enzyme that prevents the generation of reactive oxygen species. PGI2 induction of Nqo 1 provides a possible novel mechanism by which this prostanoid protects against bleomycin-induced mortality and identifies a potential therapeutic target for human ALI.

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In Vivo and In Vitro Sensitivity of Fasciola hepatica to Triclabendazole Combined with Artesunate, Artemether, or OZ78

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00828-10 ◽

2010 ◽

Vol 54 (11) ◽

pp. 4596-4604 ◽

Cited By ~ 25

Author(s):

Urs Duthaler ◽

Thomas A. Smith ◽

Jennifer Keiser

Keyword(s):

Negative Binomial ◽

Fasciola Hepatica ◽

Single Agent ◽

Treatment Strategies ◽

Drug Combinations ◽

Antagonistic Effects ◽

Experimental Drugs ◽

New Treatment

ABSTRACT Triclabendazole resistance is continually documented from livestock, and hence new treatment strategies for Fasciola hepatica infections are needed. We investigated the effect of triclabendazole combined with artesunate, artemether, or OZ78 compared to that of monotherapy against adult and juvenile F. hepatica in rats. In vitro experiments with triclabendazole and its sulfoxide and sulfone metabolites, each in combination with the peroxides, complemented our study. F. hepatica-infected rats were subjected to single drugs or drug combinations 3 to 4 weeks (juvenile flukes) and >8 weeks (adult flukes) postinfection. Negative binomial regressions of worm and egg counts were used to analyze dose-response relationships and whether the effects of drug combinations were synergistic or antagonistic. The in vitro assays were evaluated by means of viability scales based on fluke motility. Fifty percent effective dose values of 113.0, 77.7, 22.9, and 2.7 mg/kg of body weight were calculated for monotherapy with artesunate, artemether, OZ78, and triclabendazole, respectively, against adult F. hepatica. Likelihood ratio tests revealed synergistic interactions (P < 0.05) of combinations of triclabendazole (2.5 mg/kg) plus artesunate or artemether on adult worm burden. Antagonistic effects on the adult burden and egg output were observed when a lower triclabendazole dose (1.25 mg/kg) was combined with the artemisinins. No significant interactions (P = 0.07) were observed for OZ78 and triclabendazole combinations and between the triclabendazole effect and the effects of the other partner drugs on juvenile worms. Our in vitro studies of adult worms agreed with the in vivo results, while the in vitro analysis of juvenile worms revealed greater interactions than observed in vivo. In conclusion, single-agent triclabendazole demonstrated a more potent in vivo and in vitro fasciocidal activity than the experimental drugs artesunate, artemether, and OZ78. When combined, synergistic but also antagonistic effects depending on the doses administered were observed, which should be elucidated in more detail in future studies.

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Identification of Wee1 as Target in Combination with Avapritinib for the Treatment of Gastrointestinal Stromal Tumor

10.1101/2020.06.07.138693 ◽

2020 ◽

Author(s):

Shuai Ye ◽

Dinara Sharipova ◽

Marya Kozinova ◽

Lilli Klug ◽

Jimson D’Souza ◽

...

Keyword(s):

Tyrosine Kinase ◽

Gastrointestinal Stromal Tumor ◽

Single Agent ◽

Treatment Strategies ◽

Clinical Problem ◽

Stromal Tumor ◽

Loss Of Function ◽

Rtk Inhibitors

AbstractManagement of gastrointestinal stromal tumor (GIST) has been revolutionized by the identification of activating mutations in KIT and PDGFRA, and the clinical application of receptor tyrosine kinase (RTK) inhibitors in the advanced disease setting. Stratification of GIST into molecularly defined subsets provides insight into clinical behavior and response to approved targeted therapies. Although these RTK inhibitors are effective in the majority of GIST, resistance to these agents remains a significant clinical problem. Development of effective treatment strategies for refractory GIST subtypes requires identification of novel targets to provide additional therapeutic options. Global kinome profiling has the potential to identify critical signaling networks and reveal protein kinases that are essential in GIST. Using Multiplexed Inhibitor Beads and Mass Spectrometry, we explored the majority of the kinome in GIST specimens from the three most common molecular subtypes to identify novel kinase targets. Kinome profiling revealed distinct signatures in GIST subtypes and identified kinases that are universally activated in all GIST, as well as kinases that are unique to each subtype. Kinome profiling in combination with loss-of-function assays identified a significant role for the G2-M tyrosine kinase, Wee1, in GIST cell survival. In vitro and in vivo studies revealed significant efficacy of MK-1775 (Wee1 inhibitor) in combination with avapritinib in KIT and PDGFRA-mutant GIST cell lines, and notable efficacy of MK-1775 as a single agent in the PDGFRA-mutant line. These studies provide strong preclinical justification for the use of MK-1775 in GIST.

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Therapeutic inhibition of GAS6-AS1/YBX1/MYC axis suppresses cell propagation and disease progression of acute myeloid leukemia

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-021-02145-9 ◽

2021 ◽

Vol 40 (1) ◽

Author(s):

Hao Zhou ◽

Wei Liu ◽

Yongming Zhou ◽

Zhenya Hong ◽

Jian Ni ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Disease Progression ◽

Myeloid Leukemia ◽

Target Genes ◽

Leukemia Cell ◽

Treatment Strategies ◽

Network Analyses ◽

Acute Myeloid

Abstract Background Acute myeloid leukemia (AML) is the most common type of leukemia in adults. Its therapy has not significantly improved during the past four decades despite intense research efforts. New molecularly targeted therapies are in great need. The proto-oncogene c-Myc (MYC) is an attractive target due to its transactivation role in multiple signaling cascades. Deregulation of the MYC is considered one of a series of oncogenic events required for tumorigenesis. However, limited knowledge is available on which mechanism underlie MYC dysregulation and how long non-coding RNAs (lncRNAs) are involved in MYC dysregulation in AML. Methods AML microarray chips and public datasets were screened to identify novel lncRNA GAS6-AS1 was dysregulated in AML. Gain or loss of functional leukemia cell models were produced, and in vitro and in vivo experiments were applied to demonstrate its leukemogenic phenotypes. Interactive network analyses were performed to define intrinsic mechanism. Results We identified GAS6-AS1 was overexpressed in AML, and its aberrant function lead to more aggressive leukemia phenotypes and poorer survival outcomes. We revealed that GAS6-AS1 directly binds Y-box binding protein 1 (YBX1) to facilitate its interaction with MYC, leading to MYC transactivation and upregulation of IL1R1, RAB27B and other MYC target genes associated with leukemia progression. Further, lentiviral-based GAS6-AS1 silencing inhibited leukemia progression in vivo. Conclusions Our findings revealed a previously unappreciated role of GAS6-AS1 as an oncogenic lncRNA in AML progression and prognostic prediction. Importantly, we demonstrated that therapeutic targeting of the GAS6-AS1/YBX1/MYC axis inhibits AML cellular propagation and disease progression. Our insight in lncRNA associated MYC-driven leukemogenesis may contribute to develop new anti-leukemia treatment strategies.

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Pre-Clinical Activity of Amino-Alcohol Dimeric Naphthoquinones as Potential Therapeutics for Acute Myeloid Leukemia

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520621666210602131558 ◽

2021 ◽

Vol 21 ◽

Author(s):

Dana Ferraris ◽

Rena Lapidus ◽

Phuc Truong ◽

Dominique Bollino ◽

Brandon Carter-Cooper ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Amino Alcohol ◽

Myeloid Leukemia ◽

Single Agent ◽

Xenograft Model ◽

Clinical Activity ◽

Lead Compound ◽

Acute Myeloid

Background: The clinical outcomes of patients with acute myeloid leukemia (AML) remain unsatisfactory, therefore the development of more efficacious and better-tolerated therapy for AML is critical. We have previously reported the anti-leukemic activity of synthetic halohydroxyl dimeric naphthoquinones (BiQ) and aziridinyl BiQ. Objective: This study aimed to improve the potency and bioavailability of BiQ compounds and investigate the anti-leukemic activity of the lead compound in vitro and in a human AML xenograft mouse model. Methods: We designed, synthesized, and performed structure-activity relationship of several rationally designed BiQ analogues that possess amino alcohol functional groups on the naphthoquinone core rings. The compounds were screened for anti-leukemic activity and the mechanism as well as in vivo tolerability and efficacy of our lead compound was investigated. Results: We report that a dimeric naphthoquinone (designated BaltBiQ) demonstrated potent nanomolar anti-leukemic activity in AML cell lines. BaltBiQ treatment resulted in the generation of reactive oxygen species, induction of DNA damage, and inhibition of indoleamine dioxygenase 1. Although BaltBiQ was tolerated well in vivo, it did not significantly improve survival as a single agent, but in combination with the specific Bcl-2 inhibitor, Venetoclax, tumor growth was significantly inhibited compared to untreated mice. Conclusion: We synthesized a novel amino alcohol dimeric naphthoquinone, investigated its main mechanisms of action, reported its in vitro anti-AML cytotoxic activity, and showed its in vivo promising activity combined with a clinically available Bcl-2 inhibitor in a patient-derived xenograft model of AML.

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