When it comes to drug access, should children be considered small adults? Countering coverage denials of FLT3 inhibitors in children with FLT3‐ITD AML

Treatment and curative medical care often require medication. This chapter focuses on the provision of medications in impoverished settings and the challenges that inhibit access to life-saving drugs. It will review the failure of the for-profit market to increase drug access for the poor. The evolving concept of essential drugs will be explored by reviewing the history the WHO Essential Medicines List (EML) and the fight to expand the list to include new, and often patented medicines. The international treaties and policies that impact drug availability will be highlighted as will novel systems for drug development and distribution. Finally, the chapter will highlight the growing movement to decrease costs, increase supply, and advance development of drugs for neglected diseases affecting impoverished people.

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Synergy of FLT3 inhibitors and the small molecule inhibitor of LIM kinase1/2 CEL_Amide in FLT3-ITD mutated Acute Myeloblastic Leukemia (AML) cells

Leukemia Research ◽

10.1016/j.leukres.2020.106490 ◽

2021 ◽

Vol 100 ◽

pp. 106490

Author(s):

Hanane Djamai ◽

Jeannig Berrou ◽

Mélanie Dupont ◽

Anna Kaci ◽

Jan Erik Ehlert ◽

...

Keyword(s):

Small Molecule ◽

Small Molecule Inhibitor ◽

Acute Myeloblastic Leukemia ◽

Molecule Inhibitor ◽

Flt3 Inhibitors

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The FMS like Tyrosine Kinase 3 (FLT3) Is Overexpressed in a Subgroup of Multiple Myeloma Patients with Inferior Prognosis

Cancers ◽

10.3390/cancers12092341 ◽

2020 ◽

Vol 12 (9) ◽

pp. 2341

Author(s):

Normann Steiner ◽

Karin Jöhrer ◽

Selina Plewan ◽

Andrea Brunner-Véber ◽

Georg Göbel ◽

...

Keyword(s):

Multiple Myeloma ◽

Tyrosine Kinase ◽

Real Time ◽

Cell Lines ◽

Real Time Pcr ◽

Tyrosine Kinase Receptor ◽

Bone Marrow Biopsies ◽

Flt3 Inhibitors ◽

Flt3 Expression

Therapy resistance remains a major challenge in the management of multiple myeloma (MM). We evaluated the expression of FLT3 tyrosine kinase receptor (FLT3, CD135) in myeloma cells as a possible clonal driver. FLT3 expression was analyzed in bone marrow biopsies of patients with monoclonal gammopathy of undetermined significance or smoldering myeloma (MGUS, SMM), newly diagnosed MM (NDMM), and relapsed/refractory MM (RRMM) by immunohistochemistry (IHC). FLT3 gene expression was analyzed by RNA sequencing (RNAseq) and real-time PCR (rt-PCR). Anti-myeloma activity of FLT3 inhibitors (midostaurin, gilteritinib) was tested in vitro on MM cell lines and primary MM cells by 3H-tymidine incorporation assays or flow cytometry. Semi-quantitative expression analysis applying a staining score (FLT3 expression IHC-score, FES, range 1–6) revealed that a high FES (>3) was associated with a significantly shorter progression-free survival (PFS) in NDMM and RRMM patients (p = 0.04). RNAseq and real-time PCR confirmed the expression of FLT3 in CD138-purified MM samples. The functional relevance of FLT3 expression was corroborated by demonstrating the in vitro anti-myeloma activity of FLT3 inhibitors on FLT3-positive MM cell lines and primary MM cells. FLT3 inhibitors might offer a new targeted therapy approach in a subgroup of MM patients displaying aberrant FLT3 signaling.

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ATM/G6PD-driven redox metabolism promotes FLT3 inhibitor resistance in acute myeloid leukemia

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1603876113 ◽

2016 ◽

Vol 113 (43) ◽

pp. E6669-E6678 ◽

Cited By ~ 35

Author(s):

Mark A. Gregory ◽

Angelo D’Alessandro ◽

Francesca Alvarez-Calderon ◽

Jihye Kim ◽

Travis Nemkov ◽

...

Keyword(s):

Oxidative Stress ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Mitochondrial Oxidative Stress ◽

Flt3 Inhibitor ◽

A Genome ◽

Flt3 Inhibitors ◽

Acute Myeloid

Activating mutations in FMS-like tyrosine kinase 3 (FLT3) are common in acute myeloid leukemia (AML) and drive leukemic cell growth and survival. Although FLT3 inhibitors have shown considerable promise for the treatment of AML, they ultimately fail to achieve long-term remissions as monotherapy. To identify genetic targets that can sensitize AML cells to killing by FLT3 inhibitors, we performed a genome-wide RNA interference (RNAi)-based screen that identified ATM (ataxia telangiectasia mutated) as being synthetic lethal with FLT3 inhibitor therapy. We found that inactivating ATM or its downstream effector glucose 6-phosphate dehydrogenase (G6PD) sensitizes AML cells to FLT3 inhibitor induced apoptosis. Examination of the cellular metabolome showed that FLT3 inhibition by itself causes profound alterations in central carbon metabolism, resulting in impaired production of the antioxidant factor glutathione, which was further impaired by ATM or G6PD inactivation. Moreover, FLT3 inhibition elicited severe mitochondrial oxidative stress that is causative in apoptosis and is exacerbated by ATM/G6PD inhibition. The use of an agent that intensifies mitochondrial oxidative stress in combination with a FLT3 inhibitor augmented elimination of AML cells in vitro and in vivo, revealing a therapeutic strategy for the improved treatment of FLT3 mutated AML.

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The effects of lestaurtinib (CEP701) and PKC412 on primary AML blasts: the induction of cytotoxicity varies with dependence on FLT3 signaling in both FLT3-mutated and wild-type cases

Blood ◽

10.1182/blood-2006-04-015487 ◽

2006 ◽

Vol 108 (10) ◽

pp. 3494-3503 ◽

Cited By ~ 88

Author(s):

Steven Knapper ◽

Kenneth I. Mills ◽

Amanda F. Gilkes ◽

Steve J. Austin ◽

Val Walsh ◽

...

Keyword(s):

Myeloid Leukemia ◽

Wild Type ◽

Mutation Status ◽

Activating Mutations ◽

Drug Concentrations ◽

Flt3 Inhibitors ◽

Show Evidence ◽

Flt3 Expression ◽

Molecular Therapeutic ◽

Cytotoxic Responses

Abstract The receptor tyrosine kinase FLT3 is a promising molecular therapeutic target in acute myeloid leukemia (AML). Activating mutations of FLT3 are present in approximately one-third of patients, while many nonmutants show evidence of FLT3 activation, which appears to play a significant role in leukemogenesis. We studied the effects of lestaurtinib (CEP701) and PKC412, 2 small molecule inhibitors of FLT3, on 65 diagnostic AML blast samples. Both agents induced concentration-dependent cytotoxicity in most cases, although responses to PKC412 required higher drug concentrations. Cytotoxic responses were highly heterogeneous and were only weakly associated with FLT3 mutation status and FLT3 expression. Importantly, lestaurtinib induced cytotoxicity in a synergistic fashion with cytarabine, particularly in FLT3 mutant samples. Both lestaurtinib and PKC412 caused inhibition of FLT3 phosphorylation in all samples. Translation of FLT3 inhibition into cytotoxicity was influenced by the degree of residual FLT3 phosphorylation remaining and correlated with deactivation of STAT5 and MAP kinase. FLT3 mutant and wild-type cases both varied considerably in their dependence on FLT3 signaling for survival. These findings support the continued clinical assessment of FLT3 inhibitors in combination with cytotoxic chemotherapy: Entry to future clinical trials should include FLT3 wild-type patients and should remain unrestricted by FLT3 expression level.

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