Novel Approaches to Target Mutant FLT3 Leukaemia

Müller, Jörg P.; Schmidt-Arras, Dirk

doi:10.3390/cancers12102806

Cited by 17 publications

(18 citation statements)

References 142 publications

(177 reference statements)

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“…Analogously, cSCC, which arises from KCs upon lineage commitment for the fully cornified epidermis [ 166 ], is a more amenable target for PD-1 blockade than mucosal SCC or BCC [ 186 , 187 , 188 , 189 ]. By extension, the differentiation treatment of acute promyelocytic leukemia with tretinoin (all- trans -retinoic acid) [ 237 ] or acute myeloid leukemia with inhibitors of FMS-like tyrosine kinase 3 [ 238 ] reprograms gene expression. However, this sometimes provokes the differentiation syndrome.…”

Section: Discussionmentioning

confidence: 99%

Cutaneous Squamous Cell Carcinoma in the Age of Immunotherapy

Ishitsuka

Hanaoka

Tanemura

et al. 2021

Cancers

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Cutaneous squamous cell carcinoma (cSCC) is the second most prevalent skin cancer globally. Because most cSCC cases are manageable by local excision/radiotherapy and hardly become life-threatening, they are often excluded from cancer registries in most countries. Compared with cutaneous melanoma that originates from the melanin-producing, neural crest-derived epidermal resident, keratinocyte (KC)-derived cancers are influenced by the immune system with regards to their pathogenetic behaviour. Congenital or acquired immunosurveillance impairments compromise tumoricidal activity and raises cSCC incidence rates. Intriguingly, expanded applications of programmed death-1 (PD-1) blockade therapies have revealed cSCC to be one of the most amenable targets, particularly when compared with the mucosal counterparts arisen in the esophagus or the cervix. The clinical observation reminds us that cutaneous tissue has a peculiarly high immunogenicity that can evoke tumoricidal recall responses topically. Here we attempt to redefine cSCC biology and review current knowledge about cSCC from multiple viewpoints that involve epidemiology, clinicopathology, molecular genetics, molecular immunology, and developmental biology. This synthesis not only underscores the primal importance of the immune system, rather than just a mere accumulation of ultraviolet-induced mutations but also reinforces the following hypothesis: PD-1 blockade effectively restores the immunity specially allowed to exist within the fully cornified squamous epithelium, that is, the epidermis.

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Section: Discussionmentioning

confidence: 99%

Cutaneous Squamous Cell Carcinoma in the Age of Immunotherapy

Ishitsuka

Hanaoka

Tanemura

et al. 2021

Cancers

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“…ITD-FLT3 mutations in human AML stem cells are present in 20–30% of AML patients and have been implicated in the poor prognosis and refractory phenotype of this disease [ 77 , 78 , 79 , 80 , 81 , 82 ]. Onish et al reported that ITD-FLT3 mutations enhance the leukemic cell migration toward the chemokine Cxcl12 by inhibiting the downregulation of ROCK1 and dephosphorylation of MYPT1 [ 76 , 83 ]. This can result in the hematopoietic stem cells being retained in the bone marrow and protected from AML therapy [ 76 , 84 , 85 ].…”

Section: Discussionmentioning

confidence: 99%

DJ4 Targets the Rho-Associated Protein Kinase Pathway and Attenuates Disease Progression in Preclinical Murine Models of Acute Myeloid Leukemia

Golla

Ehudin

Annageldiyev

et al. 2021

Cancers

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The poor prognosis of acute myeloid leukemia (AML) and the highly heterogenous nature of the disease motivates targeted gene therapeutic investigations. Rho-associated protein kinases (ROCKs) are crucial for various actin cytoskeletal changes, which have established malignant consequences in various cancers, yet are still not being successfully utilized clinically towards cancer treatment. This work establishes the therapeutic activity of ROCK inhibitor (5Z)-2–5-(1H-pyrrolo[2,3-b]pyridine-3-ylmethylene)-1,3-thiazol-4(5H)-one (DJ4) in both in vitro and in vivo preclinical models of AML to highlight the potential of this class of inhibitors. Herein, DJ4 induced cytotoxic and proapoptotic effects in a dose-dependent manner in human AML cell lines (IC50: 0.05–1.68 μM) and primary patient cells (IC50: 0.264–13.43 μM); however, normal hematopoietic cells were largely spared. ROCK inhibition by DJ4 disrupts the phosphorylation of downstream targets, myosin light chain (MLC2) and myosin-binding subunit of MLC phosphatase (MYPT), yielding a potent yet selective treatment response at micromolar concentrations, from 0.02 to 1 μM. Murine models injected with luciferase-expressing leukemia cell lines subcutaneously or intravenously and treated with DJ4 exhibited an increase in overall survival and reduction in disease progression relative to the vehicle-treated control mice. Overall, DJ4 is a promising candidate to utilize in future investigations to advance the current AML therapy.

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“…The documentation of recurring driver mutations in genes encoding tyrosine kinase leading to the development of molecular targeted treatment strategies designed to increase the outcome of acute myeloid leukemia patients. 63 The FLT3 is the most frequently mutated gene in AML, with internal tandem duplications within a juxta-membrane domain (FLT3-ITD) or missense mutation in the tyrosine kinase domain which accounts for 30%-35% of AML patients at diagnosis. 64 It has appeared as a potential therapeutic target and therefore encourages the synthesis of FLT3 tyrosine kinase inhibitors.…”

Section: Fms-like Tyrosine Kinase 3 As a Therapeutic Target In Leukemiamentioning

confidence: 99%

A recent development of new therapeutic agents and novel drug targets for cancer treatment

et al. 2021

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Despite recent advances in cancer diagnosis, prevention, detection, as well as management, the disease is expected to be the top cause of death globally. The chemotherapy approach for cancer has become more advanced in its design, yet no medication can cure enough against all types of cancer and its stage. Thus, this review aimed to summarize a recent development of new therapeutic agents and novel drug targets for the treatment of cancer. Several obstacles stand in the way of effective cancer treatment and drug development, including inaccessibility of tumor site by appropriate drug concentration, debilitating untoward effects caused by non-selective tissue distribution of chemotherapeutic agents, and occurrence of drug resistance, which leads to cross-resistance to a variety of drugs. Resistance to treatment with anticancer drugs results from multiple factors and the most common reason for acquiring drug resistance is marking and expelling drugs that prevent cancer cells to be targeted by chemotherapeutic agents. Moreover, insensitivity to drug-induced apoptosis, alteration, and mutation of drug target and interference/change of DNA replication are other main causes of treatment failure.

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Novel Approaches to Target Mutant FLT3 Leukaemia

Cited by 17 publications

References 142 publications

Cutaneous Squamous Cell Carcinoma in the Age of Immunotherapy

Cutaneous Squamous Cell Carcinoma in the Age of Immunotherapy

DJ4 Targets the Rho-Associated Protein Kinase Pathway and Attenuates Disease Progression in Preclinical Murine Models of Acute Myeloid Leukemia

A recent development of new therapeutic agents and novel drug targets for cancer treatment

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