An mTORC1/2 dual inhibitor, AZD2014, acts as a lysosomal function activator and enhances gemtuzumab ozogamicin-induced apoptosis in primary human leukemia cells

Mizutani, Yu; Inase, Aki; Maimaitili, Yimamu; Miyata, Yoshiharu; Kitao, Akihito; Matsumoto, Hidenari; Kawaguchi, Koji; Higashime, Ako; Goto, Hideaki; Kurata, Keiji; Yakushijin, Kimikazu; Minami, Hironobu; Matsuoka, Hiroshi

doi:10.1007/s12185-019-02701-2

Cited by 17 publications

(24 citation statements)

References 42 publications

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“…The combination of GO with the poly (ADP-ribose) polymerase inhibitors olaparib and talazoparib showed an intense antileukemic effect in preclinical models and could be included in novel combinations suitable for clinical trials in the near future [ 94 , 95 , 96 ].…”

Section: Harnessing Immunitymentioning

confidence: 99%

New Perspectives in Treating Acute Myeloid Leukemia: Driving towards a Patient-Tailored Strategy

Andreozzi

Massaro

Wittnebel

et al. 2022

IJMS

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For decades, intensive chemotherapy (IC) has been considered the best therapeutic option for treating acute myeloid leukemia (AML), with no curative option available for patients who are not eligible for IC or who have had failed IC. Over the last few years, several new drugs have enriched the therapeutic arsenal of AML treatment for both fit and unfit patients, raising new opportunities but also new challenges. These include the already approved venetoclax, the IDH1/2 inhibitors enasidenib and ivosidenib, gemtuzumab ozogamicin, the liposomal daunorubicin/cytarabine formulation CPX-351, and oral azacitidine. Venetoclax, an anti BCL2-inhibitor, in combination with hypomethylating agents (HMAs), has markedly improved the management of unfit and elderly patients from the perspective of improved quality of life and better survival. Venetoclax is currently under investigation in combination with other old and new drugs in early phase trials. Recently developed drugs with different mechanisms of action and new technologies that have already been investigated in other settings (BiTE and CAR-T cells) are currently being explored in AML, and ongoing trials should determine promising agents, more synergic combinations, and better treatment strategies. Access to new drugs and inclusion in clinical trials should be strongly encouraged to provide scientific evidence and to define the future standard of treatment in AML.

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Section: Harnessing Immunitymentioning

confidence: 99%

New Perspectives in Treating Acute Myeloid Leukemia: Driving towards a Patient-Tailored Strategy

Andreozzi

Massaro

Wittnebel

et al. 2022

IJMS

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“…Upon surface CD33 recognition, this antibody-drug conjugate is internalized and translocated to lysosomes. The acidic-labile linker is hydrolyzed in the acidic environment of the lysosome, releasing the cytotoxic drug that is exported to the nucleus, where the pharmacological effect occurs [105] . Thus, the effectiveness of gemtuzumab ozogamicin greatly depends on lysosome functionality.…”

Section: Lysosomal Destabilizersmentioning

confidence: 99%

Lysosome-mediated chemoresistance in acute myeloid leukemia

Cuesta-Casanovas¹,

Delgado-Martínez²,

Cornet-Masana³

et al. 2022

CDR

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Despite the outstanding advances in understanding the biology underlying the pathophysiology of acute myeloid leukemia (AML) and the promising preclinical data published lastly, AML treatment still relies on a classic chemotherapy regimen largely unchanged for the past five decades. Recently, new drugs have been approved for AML, but the real clinical benefit is still under evaluation. Nevertheless, primary refractory and relapse AML continue to represent the main clinical challenge, as the majority of AML patients will succumb to the disease despite achieving a complete remission during the induction phase. As such, treatments for chemoresistant AML represent an unmet need in this disease. Although great efforts have been made to decipher the biological basis for leukemogenesis, the mechanism by which AML cells become resistant to chemotherapy is largely unknown. The identification of the signaling pathways involved in resistance may lead to new combinatory therapies or new therapeutic approaches suitable for this subset of patients. Several mechanisms of chemoresistance have been identified, including drug transporters, key secondary messengers, and metabolic regulators. However, no therapeutic approach targeting chemoresistance has succeeded in clinical trials, especially due to broad secondary effects in healthy cells. Recent research has highlighted the importance of lysosomes in this phenomenon. Lysosomes’ key role in resistance to chemotherapy includes the potential to sequester drugs, central metabolic signaling role, and gene expression regulation. These results provide further evidence to support the development of new therapeutic approaches that target lysosomes in AML.

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“…Phase I/II studies with rapalogs as single agents in AML have been disappointing, whereas combination studies with chemotherapy have demonstrated some promise [95]. Interestingly, the mTORC1/2 dual inhibitor AZD2014 was found to reduce the pH of lysosomes in AML cells and this enhanced the cytotoxicity of the antibody-drug conjugate Gemtuzumab ozogamicin (GO) [96]. The use of an antibody conjugate such as GO in AML is particularly appealing as most AMLs express CD33.…”

Section: Interference With Ph or Other Aspects Of Luminal Homeostasismentioning

confidence: 99%

Lysosomes in acute myeloid leukemia: potential therapeutic targets?

et al. 2021

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Lysosomes, since their discovery, have been primarily known for degrading cellular macromolecules. However, in recent studies, they have begun to emerge as crucial regulators of cell homeostasis. They are at the crossroads of catabolic and anabolic pathways and are intricately involved in cellular trafficking, nutrient signaling, energy metabolism, and immune regulation. Their involvement in such essential cellular functions has renewed clinical interest in targeting the lysosome as a novel way to treat disease, particularly cancer. Acute myeloid leukemia (AML) is an aggressive blood cancer with a low survival probability, particularly in older patients. The genomic landscape of AML has been extensively characterized but few targeted therapies (with the exception of differentiation therapy) can achieve a long-term cure. Therefore, there is an unmet need for less intensive and more tolerable therapeutic interventions. In this review, we will give an overview on the myriad of functions performed by lysosomes and their importance in malignant disease. Furthermore, we will discuss their relevance in hematopoietic cells and different ways to potentially target them in AML.

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An mTORC1/2 dual inhibitor, AZD2014, acts as a lysosomal function activator and enhances gemtuzumab ozogamicin-induced apoptosis in primary human leukemia cells

Cited by 17 publications

References 42 publications

New Perspectives in Treating Acute Myeloid Leukemia: Driving towards a Patient-Tailored Strategy

New Perspectives in Treating Acute Myeloid Leukemia: Driving towards a Patient-Tailored Strategy

Lysosome-mediated chemoresistance in acute myeloid leukemia

Lysosomes in acute myeloid leukemia: potential therapeutic targets?

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