scholarly journals Targeting acute myeloid leukemia dependency on VCP-mediated DNA repair through a selective second-generation small-molecule inhibitor

2021 ◽  
Vol 13 (587) ◽  
pp. eabg1168
Author(s):  
Blandine Roux ◽  
Camille Vaganay ◽  
Jesse D. Vargas ◽  
Gabriela Alexe ◽  
Chaima Benaksas ◽  
...  
Keyword(s):  
Dna Repair ◽  
Acute Myeloid Leukemia ◽  
Cancer Cells ◽  
Myeloid Leukemia ◽  
Second Generation ◽  
Single Agent ◽  
Dominant Negative ◽  
Aaa Atpase ◽  
Chemical Inhibition ◽  
Acute Myeloid

The development and survival of cancer cells require adaptive mechanisms to stress. Such adaptations can confer intrinsic vulnerabilities, enabling the selective targeting of cancer cells. Through a pooled in vivo short hairpin RNA (shRNA) screen, we identified the adenosine triphosphatase associated with diverse cellular activities (AAA-ATPase) valosin-containing protein (VCP) as a top stress-related vulnerability in acute myeloid leukemia (AML). We established that AML was the most responsive disease to chemical inhibition of VCP across a panel of 16 cancer types. The sensitivity to VCP inhibition of human AML cell lines, primary patient samples, and syngeneic and xenograft mouse models of AML was validated using VCP-directed shRNAs, overexpression of a dominant-negative VCP mutant, and chemical inhibition. By combining mass spectrometry–based analysis of the VCP interactome and phospho-signaling studies, we determined that VCP is important for ataxia telangiectasia mutated (ATM) kinase activation and subsequent DNA repair through homologous recombination in AML. A second-generation VCP inhibitor, CB-5339, was then developed and characterized. Efficacy and safety of CB-5339 were validated in multiple AML models, including syngeneic and patient-derived xenograft murine models. We further demonstrated that combining DNA-damaging agents, such as anthracyclines, with CB-5339 treatment synergizes to impair leukemic growth in an MLL-AF9–driven AML murine model. These studies support the clinical testing of CB-5339 as a single agent or in combination with standard-of-care DNA-damaging chemotherapy for the treatment of AML.

scholarly journals Co-inhibition of HDAC and MLL-menin interaction targets MLL-rearranged acute myeloid leukemia cells via disruption of DNA damage checkpoint and DNA repair

2019 ◽  
Vol 11 (1) ◽  
Author(s):  
Jing Ye ◽  
Jie Zha ◽  
Yuanfei Shi ◽  
Yin Li ◽  
Delin Yuan ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Clinical Investigation ◽  
Combined Treatment ◽  
Single Agent ◽  
Ros Generation ◽  
Dna Damage Checkpoint ◽  
Acute Myeloid

Abstract While the aberrant translocation of the mixed-lineage leukemia (MLL) gene drives pathogenesis of acute myeloid leukemia (AML), it represents an independent predictor for poor prognosis of adult AML patients. Thus, small molecule inhibitors targeting menin-MLL fusion protein interaction have been emerging for the treatment of MLL-rearranged AML. As both inhibitors of histone deacetylase (HDAC) and menin-MLL interaction target the transcription-regulatory machinery involving epigenetic regulation of chromatin remodeling that governs the expression of genes involved in tumorigenesis, we hypothesized that these two classes of agents might interact to kill MLL-rearranged (MLL-r) AML cells. Here, we report that the combination treatment with subtoxic doses of the HDAC inhibitor chidamide and the menin-MLL interaction inhibitor MI-3 displayed a highly synergistic anti-tumor activity against human MLL-r AML cells in vitro and in vivo, but not those without this genetic aberration. Mechanistically, co-exposure to chidamide and MI-3 led to robust apoptosis in MLL-r AML cells, in association with loss of mitochondrial membrane potential and a sharp increase in ROS generation. Combined treatment also disrupted DNA damage checkpoint at the level of CHK1 and CHK2 kinases, rather than their upstream kinases (ATR and ATM), as well as DNA repair likely via homologous recombination (HR), but not non-homologous end joining (NHEJ). Genome-wide RNAseq revealed gene expression alterations involving several potential signaling pathways (e.g., cell cycle, DNA repair, MAPK, NF-κB) that might account for or contribute to the mechanisms of action underlying anti-leukemia activity of chidamide and MI-3 as a single agent and particularly in combination in MLL-r AML. Collectively, these findings provide a preclinical basis for further clinical investigation of this novel targeted strategy combining HDAC and Menin-MLL interaction inhibitors to improve therapeutic outcomes in a subset of patients with poor-prognostic MLL-r leukemia.

scholarly journals FLT3 mutated acute myeloid leukemia: 2021 treatment algorithm

2021 ◽  
Vol 11 (5) ◽  
Author(s):  
Naval Daver ◽  
Sangeetha Venugopal ◽  
Farhad Ravandi
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Single Agent ◽  
Prognostic Significance ◽  
Treatment Algorithm ◽  
Molecular Testing ◽  
Prognostic Impact ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Acute Myeloid

AbstractApproximately 30% of patients with newly diagnosed acute myeloid leukemia (AML) harbor mutations in the fms-like tyrosine kinase 3 (FLT3) gene. While the adverse prognostic impact of FLT3-ITDmut in AML has been clearly proven, the prognostic significance of FLT3-TKDmut remains speculative. Current guidelines recommend rapid molecular testing for FLT3mut at diagnosis and earlier incorporation of targeted agents to achieve deeper remissions and early consideration for allogeneic stem cell transplant (ASCT). Mounting evidence suggests that FLT3mut can emerge at any timepoint in the disease spectrum emphasizing the need for repetitive mutational testing not only at diagnosis but also at each relapse. The approval of multi-kinase FLT3 inhibitor (FLT3i) midostaurin with induction therapy for newly diagnosed FLT3mut AML, and a more specific, potent FLT3i, gilteritinib as monotherapy for relapsed/refractory (R/R) FLT3mut AML have improved outcomes in patients with FLT3mut AML. Nevertheless, the short duration of remission with single-agent FLT3i’s in R/R FLT3mut AML in the absence of ASCT, limited options in patients refractory to gilteritinib therapy, and diverse primary and secondary mechanisms of resistance to different FLT3i’s remain ongoing challenges that compel the development and rapid implementation of multi-agent combinatorial or sequential therapies for FLT3mut AML.

scholarly journals Single-agent and combination biologics in acute myeloid leukemia

Hematology ◽  
2019 ◽  
Vol 2019 (1) ◽  
pp. 548-556 ◽  
Author(s):  
Guillaume Richard-Carpentier ◽  
Courtney D. DiNardo
Keyword(s):  
Acute Myeloid Leukemia ◽  
Older Patients ◽  
Myeloid Leukemia ◽  
Single Agent ◽  
Gemtuzumab Ozogamicin ◽  
Targeted Agents ◽  
Newly Diagnosed ◽  
Rational Drug ◽  
Genomic Characterization ◽  
Acute Myeloid

Abstract Acute myeloid leukemia (AML) is a heterogeneous malignancy characterized by recurrent genetic, epigenetic, and metabolic abnormalities. As a result of our increasing knowledge of the underlying biology of AML leading to rational drug development, several new targeted agents have been recently added to our therapeutic arsenal. The BCL2 inhibitor venetoclax in combination with low-dose cytarabine (LDAC) or hypomethylating agents (HMAs) is safe and effective in older patients with newly diagnosed AML ineligible for intensive chemotherapy. Glasdegib, a hedgehog pathway inhibitor, may be used in combination with LDAC for the same indication and improves survival compared with LDAC alone. In newly diagnosed, fit, older patients with therapy-related AML or AML with myelodysplasia-related changes, the liposome-encapsulated combination of daunorubicin and cytarabine (CPX-351) has shown superiority over the 7 + 3 regimen. The presence of an IDH1 or IDH2 mutation can be effectively targeted by ivosidenib or enasidenib, respectively. Gemtuzumab ozogamicin improves event-free survival in CD33+ patients with favorable or intermediate-risk cytogenetics. With new targeted agents available, comprehensive genomic characterization of AML at diagnosis and relapse is increasingly necessary to select optimal treatment. Herein, we review the new single-agent and combination biologics (omitting FLT3 inhibitors, which are discussed separately) and provide recommendations on how to best use and manage patients on these regimens in clinical practice.

scholarly journals Genetic Variants of ATM & Non-Homologous End Joining Pathway Genes in Acute Myeloid Leukemia: A South India Case-Control Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5076-5076
Author(s):  
Sugunakar Vuree ◽  
Anuradha Cingeetham ◽  
Dunna Nageswara Rao ◽  
Manjula Gorre ◽  
Sudha Sinha ◽  
...  
Keyword(s):  
Dna Repair ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Case Control Study ◽  
Case Control ◽  
South Indian Population ◽  
End Joining ◽  
Non Homologous End Joining ◽  
Control Study ◽  
Acute Myeloid

Purpose of the study: Deregulated DNA repair is one of the hallmarks of cancers including Acute Myeloid Leukemia (AML), as it results in genomic instability. ATM gene functions as a sensor, activates cascade of events leading to stimulation of multiple DNA damage- responsive signaling pathways. Principal DNA repair mechanism activated in the hematopoietic stem cells is the Non Homologous End Joining (NHEJ) pathway. However, this pathway was shown to be error prone. Functional SNPs in the genes involved in DNA repair might influence the gene expression leading to altered DNA repair which might confer the risk to AML. Materials & Methods: This hospital-based case-control study included 225 AML patients and 326 cancer-free controls from South Indian population. Six polymorphisms of XRCC5, XRCC6, XRCC7 and ATM were genotyped using polymerase chain reaction (PCR)-Restriction Fragment Length Polymorphism (PCR- RFLP) method. Statistical analyses were performed by using SPSS (version20v) and SNPSTAT online tool. Protein-Protein Interaction (PPI) analysis was also done to see the relationship between these genes. Results: We found that there was an elevated risk of AML associated with the XRCC5 VNTR 0R repeat and A allele of 2408G>A polymorphism (p-0.04 and p<0.0001 respectively), the frequencies of G allele (p-<0.0001) of XRCC6 -1310C>G and T allele (p-0.003) of ATM -5144A>T polymorphisms were also significantly increased in AML cases. Further, analyses of the variant genotypes with epidemiological and clinical variables revealed a significant association of the risk genotypes with development and progression of AML. Conclusion: The XRCC5 0R repeat, 2408G>A, XRCC6 -1310 C>G and ATM- 5144A>T polymorphisms, but not XRCC6 -61C>G and XRCC7 6721G>T polymorphisms, play an important role in the pathogenesis of AML. Figure Disclosures No relevant conflicts of interest to declare.

Quizartinib in the treatment of FLT3-internal-tandem duplication-positive acute myeloid leukemia

2019 ◽  
Vol 15 (34) ◽  
pp. 3885-3894 ◽  
Author(s):  
Shilpa Paul ◽  
Adam J DiPippo ◽  
Farhad Ravandi ◽  
Tapan M Kadia
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Tandem Duplication ◽  
Kinase Inhibitors ◽  
Single Agent ◽  
Tyrosine Kinase Domain ◽  
Missense Mutations ◽  
Internal Tandem Duplication ◽  
Acute Myeloid

FLT3 mutations, characterized by an internal-tandem duplication or missense mutations in the tyrosine kinase domain, are observed in a third of patients with newly diagnosed acute myeloid leukemia. FLT3-ITD mutations are associated with high relapse rates and short overall survival with conventional chemotherapy. Several tyrosine kinase inhibitors targeting FLT3 have been developed in an effort to improve survival and therapeutic options. This review focuses on quizartinib, a second-generation FLT3 inhibitor that has demonstrated efficacy and safety as a single agent and in combination with chemotherapy. We discuss its clinical development as well as its place in the treatment of FLT3-mutated acute myeloid leukemia among the other FLT3 inhibtors currently available and its mechanisms of resistance.

scholarly journals STAT3β is a tumor suppressor in acute myeloid leukemia

2019 ◽  
Vol 3 (13) ◽  
pp. 1989-2002 ◽  
Author(s):  
Petra Aigner ◽  
Tatsuaki Mizutani ◽  
Jaqueline Horvath ◽  
Thomas Eder ◽  
Stefan Heber ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Messenger Rna ◽  
Myeloid Leukemia ◽  
Dominant Negative ◽  
Expression Ratio ◽  
Mrna Ratio ◽  
Dominant Negative Form ◽  
Alternatively Spliced ◽  
Regulatory Functions ◽  
Acute Myeloid

Abstract Signal transducer and activator of transcription 3 (STAT3) exists in 2 alternatively spliced isoforms, STAT3α and STAT3β. Although truncated STAT3β was originally postulated to act as a dominant-negative form of STAT3α, it has been shown to have various STAT3α-independent regulatory functions. Recently, STAT3β gained attention as a powerful antitumorigenic molecule in cancer. Deregulated STAT3 signaling is often found in acute myeloid leukemia (AML); however, the role of STAT3β in AML remains elusive. Therefore, we analyzed the STAT3β/α messenger RNA (mRNA) expression ratio in AML patients, where we observed that a higher STAT3β/α mRNA ratio correlated with a favorable prognosis and increased overall survival. To gain better understanding of the function of STAT3β in AML, we engineered a transgenic mouse allowing for balanced Stat3β expression. Transgenic Stat3β expression resulted in decelerated disease progression and extended survival in PTEN- and MLL-AF9–dependent AML mouse models. Our findings further suggest that the antitumorigenic function of STAT3β depends on the tumor-intrinsic regulation of a small set of significantly up- and downregulated genes, identified via RNA sequencing. In conclusion, we demonstrate that STAT3β plays an essential tumor-suppressive role in AML.

scholarly journals The AAA+ATPase RUVBL2 is essential for the oncogenic function of c-MYB in acute myeloid leukemia

Leukemia ◽  
2019 ◽  
Vol 33 (12) ◽  
pp. 2817-2829 ◽  
Author(s):  
Elena Armenteros-Monterroso ◽  
Lu Zhao ◽  
Luca Gasparoli ◽  
Tony Brooks ◽  
Kerra Pearce ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Aaa Atpase ◽  
Oncogenic Function ◽  
Acute Myeloid

Phase I Study of Decitabine Alone or in Combination With Valproic Acid in Acute Myeloid Leukemia

2007 ◽  
Vol 25 (25) ◽  
pp. 3884-3891 ◽  
Author(s):  
William Blum ◽  
Rebecca B. Klisovic ◽  
Bjoern Hackanson ◽  
Zhongfa Liu ◽  
Shujun Liu ◽  
...  
Keyword(s):  
Valproic Acid ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Dna Methyltransferase ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Dna Hypomethylation ◽  
Drug Induced ◽  
Histone Hyperacetylation ◽  
Acute Myeloid

Purpose To determine an optimal biologic dose (OBD) of decitabine as a single agent and then the maximum-tolerated dose (MTD) of valproic acid (VA) combined with decitabine in acute myeloid leukemia (AML). Patients and Methods Twenty-five patients (median age, 70 years) were enrolled; 12 were untreated and 13 had relapsed AML. To determine an OBD (based on a gene re-expression end point), 14 patients received decitabine alone for 10 days. To determine the MTD, 11 patients received decitabine (at OBD, days 1 through 10) plus dose-escalating VA (days 5 through 21). Results The OBD of decitabine was 20 mg/m2/d intravenously, with limited nonhematologic toxicity. In patients treated with decitabine plus VA, dose-limiting encephalopathy occurred in two of two patients at VA 25 mg/kg/d and one of six patients at VA 20 mg/kg/d. Drug-induced re-expression of estrogen receptor (ER) was associated with clinical response (P ≤ .05). ER promoter demethylation, global DNA hypomethylation, depletion of DNA methyltransferase enzyme, and histone hyperacetylation were also observed. In an intent-to-treat analysis, the response rate was 44% (11 of 25). Of 21 assessable patients, 11 (52%) responded: four with morphologic and cytogenetic complete remission (CR; each had complex karyotype), four with incomplete CR, and three with partial remission. In untreated AML, four of nine assessable patients achieved CR. Clinical responses appeared similar for decitabine alone or with VA. Conclusion Low-dose decitabine was safe and showed encouraging clinical and biologic activity in AML, but the addition of VA led to encephalopathy at relatively low doses. On the basis of these results, additional studies of decitabine (20 mg/m2/d for 10 days) alone or with an alternative deacetylating agent are warranted.

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