Relapsed or primary refractory AML: moving past MEC and FLAG-ida

Koenig, Kristin; Mims, Alice S.

doi:10.1097/moh.0000000000000561

Cited by 28 publications

(20 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In clonogenic assays, EDK compounds were able to eliminate not only bulk AML blasts, but also the leukemic stem cell subpopulation [ 14 ]. More importantly, we provided a solid in vivo proof of concept of the efficacy of the EDK family in two different AML models corresponding to two AML subtypes, including the most aggressive and chemoresistant MonoMac1, suggesting that EDK compounds might be an effective line of treatment for relapse/refractory AML patients, who constitute the main unmet need in this disease [ 43 ].…”

Section: Discussionmentioning

confidence: 99%

A Novel Family of Lysosomotropic Tetracyclic Compounds for Treating Leukemia

Carbó

Cornet-Masana

Cuesta-Casanovas

et al. 2023

Cancers

View full text Add to dashboard Cite

Acute myeloid leukemia (AML) is a heterogeneous hematological cancer characterized by poor prognosis and frequent relapses. Aside from specific mutation-related changes, in AML, the overall function of lysosomes and mitochondria is drastically altered to fulfill the elevated biomass and bioenergetic demands. On the basis of previous results, in silico drug discovery screening was used to identify a new family of lysosome-/mitochondria-targeting compounds. These novel tetracyclic hits, with a cationic amphiphilic structure, specifically eradicate leukemic cells by inducing both mitochondrial damage and apoptosis, and simultaneous lysosomal membrane leakiness. Lysosomal leakiness does not only elicit canonical lysosome-dependent cell death, but also activates the terminal differentiation of AML cells through the Ca2+–TFEB–MYC signaling axis. In addition to being an effective monotherapy, its combination with the chemotherapeutic arsenic trioxide (ATO) used in other types of leukemia is highly synergistic in AML cells, widening the therapeutic window of the treatment. Moreover, the compounds are effective in a wide panel of cancer cell lines and possess adequate pharmacological properties rendering them promising drug candidates for the treatment of AML and other neoplasias.

show abstract

Section: Discussionmentioning

confidence: 99%

A Novel Family of Lysosomotropic Tetracyclic Compounds for Treating Leukemia

Carbó

Cornet-Masana

Cuesta-Casanovas

et al. 2023

Cancers

View full text Add to dashboard Cite

show abstract

“…With standard therapy, between 60% and 75% of children achieve an overall survival of 5 years, largely due to fewer genetic mutations and their greater ability to tolerate both high-intensity chemotherapy and HCT [ 1 , 20 , 21 ]. In contrast, only 24% of adult patients who are selected for intensive therapy and 10%–15% of older patients not eligible for intensive therapy survive to five years, [ 1 , 6 , 22 , 23 ] and almost 80% of patients diagnosed at an age ≥65 years die within one year [ 19 ]. AML in the elderly population is a special therapeutic challenge due to the poor functional status of this age group, which results in an increase in therapy-related toxicity [ 24 ].…”

Section: Chemoresistance As Relapse and Refractory Diseasementioning

confidence: 99%

“…R/R may exist prior to exposure to chemotherapeutic agents (intrinsic or primary resistance), or it can develop or increase during drug treatment (acquired or secondary resistance), leading to chemoresistance and relapse [ 29 ]. Sixty percent of patients in the favorable risk category and 85% in the adverse risk category develop R/R, and only 10–20% survive to five years [ 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ].…”

Section: Chemoresistance As Relapse and Refractory Diseasementioning

confidence: 99%

Inhibitors of Chemoresistance Pathways in Combination with Ara-C to Overcome Multidrug Resistance in AML. A Mini Review

Fajardo-Orduña

Ledesma‐Martínez

Aguíñiga-Sánchez

et al. 2021

IJMS

View full text Add to dashboard Cite

Acute myeloid leukemia (AML), the most common type of leukemia in older adults, is a heterogeneous disease that originates from the clonal expansion of undifferentiated hematopoietic progenitor cells. These cells present a remarkable variety of genes and proteins with altered expression and function. Despite significant advances in understanding the molecular panorama of AML and the development of therapies that target mutations, survival has not improved significantly, and the therapy standard is still based on highly toxic chemotherapy, which includes cytarabine (Ara-C) and allogeneic hematopoietic cell transplantation. Approximately 60% of AML patients respond favorably to these treatments and go into complete remission; however, most eventually relapse, develop refractory disease or chemoresistance, and do not survive for more than five years. Therefore, drug resistance that initially occurs in leukemic cells (primary resistance) or that develops during or after treatment (acquired resistance) has become the main obstacle to AML treatment. In this work, the main molecules responsible for generating chemoresistance to Ara-C in AML are discussed, as well as some of the newer strategies to overcome it, such as the inclusion of molecules that can induce synergistic cytotoxicity with Ara-C (MNKI-8e, emodin, metformin and niclosamide), subtoxic concentrations of chemotherapy (PD0332991), and potently antineoplastic treatments that do not damage nonmalignant cells (heteronemin or hydroxyurea + azidothymidine).

show abstract

“…The strategies for treating AML have remained relatively unchanged over the past three decades. While the “7+3” combined chemotherapy regimen reportedly leads to complete remission in 60-80% in patients younger than 60-years-old and 40%-60% in patients older than 60 years of age ( 10 ), in addition to the durable complete remission in the limited group of patients eligible for allogeneic hematopoietic stem cell transplantation (HSCT), both HSCT and chemotherapy treatments have long been associated with high relapse rates ( 11 ). Emerging tumor immunotherapy approaches that rely on T cell activation (including CAR-T, TCR-T, or cancer vaccines, etc.)…”

Section: Introductionmentioning

confidence: 99%

Identification and validation of a novel CD8+ T cell-associated prognostic model based on ferroptosis in acute myeloid leukemia

et al. 2023

View full text Add to dashboard Cite

Acute myeloid leukemia (AML) is a highly aggressive cancer with great heterogeneity and variability in prognosis. Though European Leukemia Net (ELN) 2017 risk classification has been widely used, nearly half of patients were stratified to “intermediate” risk and requires more accurate classification via excavating biological features. As new evidence showed that CD8+ T cell can kill cancer cells through ferroptosis pathway. We firstly use CIBERSORT algorithm to divide AMLs into CD8+ high and CD8+ low T cell groups, then 2789 differentially expressed genes (DEGs) between groups were identified, of which 46 ferroptosis-related genes associated with CD8+ T cell were sorted out. GO, KEGG analysis and PPI network were conducted based on these 46 DEGs. By jointly using LASSO algorithm and Cox univariate regression, we generated a 6-gene prognostic signature comprising VEGFA, KLHL24, ATG3, EIF2AK4, IDH1 and HSPB1. Low-risk group shows a longer overall survival. We then validated the prognostic value of this 6-gene signature using two independent external datasets and patient sample collection dataset. We also proved that incorporation of the 6-gene signature obviously enhanced the accuracy of ELN risk classification. Finally, gene mutation analysis, drug sensitive prediction, GSEA and GSVA analysis were conducted between high-risk and low-risk AML patients. Collectively, our findings suggested that the prognostic signature based on CD8+ T cell-related ferroptosis genes can optimize the risk stratification and prognostic prediction of AML patients.

show abstract

Relapsed or primary refractory AML: moving past MEC and FLAG-ida

Cited by 28 publications

References 56 publications

A Novel Family of Lysosomotropic Tetracyclic Compounds for Treating Leukemia

A Novel Family of Lysosomotropic Tetracyclic Compounds for Treating Leukemia

Inhibitors of Chemoresistance Pathways in Combination with Ara-C to Overcome Multidrug Resistance in AML. A Mini Review

Identification and validation of a novel CD8+ T cell-associated prognostic model based on ferroptosis in acute myeloid leukemia

Contact Info

Product

Resources

About