New strategies to treat AML: novel insights into AML survival pathways and combination therapies

Nair, Ramya; Salinas-Illarena, Alejandro; Baldauf, Hanna‐Mari

doi:10.1038/s41375-020-01069-1

Cited by 67 publications

(43 citation statements)

References 98 publications

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“…Blast accumulation in the absence of proper haematopoiesis leads to impairment of the immune system and eventually to death. Although, compared to other types of cancers, AML is characterised by a low number of mutations, it is a highly heterogenous hematologic disease classified into many different subtypes, reflected in different clinical manifestations: understanding the relevance of this heterogeneity is critical to develop novel and more personalized clinical therapies ( 1 ). Today, the first line of treatment is still chemotherapy, with a 5-year survival rate of less than 30%: it is now clear that treating all patients with the same starting protocol (i.e.…”

Section: Acute Myeloid Leukemiamentioning

confidence: 99%

“…“one size fits all” strategy) benefits only a specific group of patients. Personalized therapies are aimed at using novel insights into patient specific genetic signatures of AML to define strategies to treat the AML ( 1 , 2 ). Compared to the last 50 years, when administration of cytarabine and anthracyclines was the only standard therapy, the last 6 years has seen the introduction of many novel successful clinical trials, aimed to stratify and treat patients in subgroups tailored on patient specific genomic backgrounds ( 3 ).…”

Section: Acute Myeloid Leukemiamentioning

confidence: 99%

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“Modulating Phosphoinositide Profiles as a Roadmap for Treatment in Acute Myeloid Leukemia”

et al. 2021

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Polyphosphoinositides (PPIns) and their modulating enzymes are involved in regulating many important cellular functions including proliferation, differentiation or gene expression, and their deregulation is involved in human diseases such as metabolic syndromes, neurodegenerative disorders and cancer, including Acute Myeloid Leukemia (AML). Given that PPIns regulating enzymes are highly druggable targets, several studies have recently highlighted the potential of targeting them in AML. For instance many inhibitors targeting the PI3K pathway are in various stages of clinical development and more recently other novel enzymes such as PIP4K2A have been implicated as AML targets. PPIns have distinct subcellular organelle profiles, in part driven by the specific localisation of enzymes that metabolise them. In particular, in the nucleus, PPIns are regulated in response to various extracellular and intracellular pathways and interact with specific nuclear proteins to control epigenetic cell state. While AML does not normally manifest with as many mutations as other cancers, it does appear in large part to be a disease of dysregulation of epigenetic signalling and many novel therapeutics are aimed at reprogramming AML cells toward a differentiated cell state or to one that is responsive to alternative successful but limited AML therapies such as ATRA. Here, we propose that by combining bioinformatic analysis with inhibition of PPIns pathways, especially within the nucleus, we might discover new combination therapies aimed at reprogramming transcriptional output to attenuate uncontrolled AML cell growth. Furthermore, we outline how different part of a PPIns signalling unit might be targeted to control selective outputs that might engender more specific and therefore less toxic inhibitory outcomes.

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Section: Acute Myeloid Leukemiamentioning

confidence: 99%

Section: Acute Myeloid Leukemiamentioning

confidence: 99%

“Modulating Phosphoinositide Profiles as a Roadmap for Treatment in Acute Myeloid Leukemia”

et al. 2021

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“…The major cause of mortality of AML patients after allogeneic transplantation is graft-versus-host disease [4] . The conventional chemotherapeutic approach for AML patients is based on a treatment combining an anthracycline with cytarabine [35][36][37] . However, a majority of patients with AML are refractory to primary therapies or relapse later [35][36][37] .…”

Section: Introductionmentioning

confidence: 99%

“…The conventional chemotherapeutic approach for AML patients is based on a treatment combining an anthracycline with cytarabine [35][36][37] . However, a majority of patients with AML are refractory to primary therapies or relapse later [35][36][37] . Both resistance and relapse are due to the heterogeneity of the disease, where high variability both among and within individual patients exist [35][36][37] .…”

Section: Introductionmentioning

confidence: 99%

The antiangiogenic phloroglucinol hyperforin inhibits the secretion of proMMP-2, proMMP-9 and VEGF-A during apoptosis of primary acute myeloid leukemia cells

Merhi¹,

Tang²,

Legrand³

et al. 2021

JCMT

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Aim: Angiogenesis is observed in acute myeloid leukemia (AML). AML cells abnormally proliferate and are resistant to death. Positive regulators of angiogenesis, VEGF-A and matrix metalloproteinases (MMPs) 2 and 9 are markers of disease status in AML. The natural phloroglucinol hyperforin (HF) displays antitumoral properties of potential pharmacological interest. Herein, we investigated the effects of HF on MMP-2/9 and VEGF-A expression and survival of primary AML cells.Methods: Blood and bone marrow samples were collected in 45 patients with distinct subtypes defined by French American British classification, i.e., M0, M1, M2, M3, M4, and M5. Levels of MMPs and VEGF-A in leukemic blood cells and culture supernatants were determined by RT-PCR, ELISA, and gelatin zymography (MMPs). The balance between cell death and survival was assessed by flow cytometry with analysis of phosphatidylserine externalization and caspase-3 activation. Results:The administration of HF promoted a caspase-associated apoptosis in primary AML blasts (from blood and bone marrow), but not normal blood cells and monocytes. In addition, HF inhibited the levels of secreted proMMP-2, proMMP-9, and VEGF-A without altering transcripts. The induction of apoptosis by HF significantly paralleled the inhibition of MMP-2/9 and VEGF-A release by HF. No differences were seen in response to the deleterious effects of HF between AML cells of distinct subtypes. Conclusion:Our results suggest that HF, through its proapoptotic and potential antiangiogenic properties (by inhibiting MMP-2/9 and VEGF-A) on primary AML cells, might be a useful experimental agent, in combination with existing drugs, for new therapeutic approaches in the treatment of this incurable disease.

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“…The development of all trans retinoic acid (ATRA) in the treatment of APL (reviewed in [ 3 ]) and tyrosine kinase inhibitors (TKI) as targeted therapy in chronic myelocytic leukemia (CML) (reviewed in [ 4 ]), provide a paradigm for targeted therapy in AML. Indeed, revelations of novel insights into pathways that lead to the survival and proliferation of AML cells is opening new therapeutic possibilities [ 5 , 6 ]. One such possible pathway includes reprogramming metabolism.…”

mentioning

confidence: 99%

Reactive oxygen species in leukemias: maintaining cancer cell proliferation via redox signaling and changing metabolic homeostasis

Robinson¹,

Darley²,

Tonks³

2021

Oncotarget

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New strategies to treat AML: novel insights into AML survival pathways and combination therapies

Cited by 67 publications

References 98 publications

“Modulating Phosphoinositide Profiles as a Roadmap for Treatment in Acute Myeloid Leukemia”

“Modulating Phosphoinositide Profiles as a Roadmap for Treatment in Acute Myeloid Leukemia”

The antiangiogenic phloroglucinol hyperforin inhibits the secretion of proMMP-2, proMMP-9 and VEGF-A during apoptosis of primary acute myeloid leukemia cells

Reactive oxygen species in leukemias: maintaining cancer cell proliferation via redox signaling and changing metabolic homeostasis

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