Oncology Intelligence


Flt3 FLT-3(1)

CD135 or fetal liver kinase-2 (Flk2) is encoded by the FLT3 gene. FLT3 is a class III receptor tyrosine kinase (RTK) class and the receptor for the cytokine Flt3 ligand with an intrinsic TYK domain. Class III subfamily of RTKs include structurally similar members such as c-FMS, c-KIT, and PDGFR.(2,3) It is expressed on the surface of many hematopoietic progenitor cells committed myeloid and lymphoid progenitors with variable expression in the more mature monocytic lineage. FLT3 expression has been described in lymphohematopoietic organs such as the liver, spleen, thymus, and placenta.(1)
AML and the impact of aberrant FLT3 signaling AML represents a malignant proliferation of hematopoietic progenitor cells of the myeloid lineage within the bone marrow. The most common mutation in AML occurs in the FLT3 gene.(2)
FLT3 mutant AML presents both a unique challenge and an important opportunity for the application of targeted therapies. Early FLT3 inhibitors (including sunitinib, midostaurin, and lestaurtinib) demonstrated significant promise in preclinical models of FLT3 mutant AML. However, the relative lack of selectivity or potency of these agents against FLT3 has limited their utility in the treatment of AML, and to date, these agents have only resulted in transient and partial clinical responses.(4) Second-generation FLT3 inhibitors, epitomized by the novel agent quizartinib. Early results with quizartinib have been promising.(2) Newer compounds, such as AC220, have demonstrated excellent selectivity and potency against the FLT3 target.(4) Tandutinib (MLN518, previously referred to as CT53518), KW-2449, and AC220 are selective for the FLT3 TYK, but may also inhibitor c-KIT and PDGFR, both of which share significant structural homology to FLT3.(5-7) In vitro studies found that tandutinib was very selective for type III receptor TYKs, it was not particularly potent. A phase I trial of KW-2449 demonstrated modest single agent, clinical responses consisted of transient decreases in blast count, which correlated with in vivo FLT3 inhibition. The experience with this agent underscores the impression that sustained FLT3 inhibition will be necessary if meaningful clinical responses are to be achieved. AC220 is the most recent kinase inhibitor of FLT3, very selective against FLT3 and has a very long plasma half-life.(4, 7)



1. Appelbaum SMaFR. Structural and Functional Alterations of FLT3 in Acute Myeloid Leukemia Clin Cancer Res. 2009;15:4263-9.

2. Wander SA, Levis MJ, Fathi AT. The evolving role of FLT3 inhibitors in acute myeloid leukemia: quizartinib and beyond. Therapeutic advances in hematology. 2014;5(3):65-77.

3. Geer P, Hunter T, Lindberg RA. Receptor protein-tyrosine kinases and their signal transduction pathways. Annual review of cell biology. 1994;10(1):251-337.

4. Fathi A, Levis M. FLT3 inhibitors: a story of the old and the new. Current opinion in hematology. 2011;18(2):71.

5. Kelly LM, Yu J-C, Boulton CL, Apatira M, Li J, Sullivan CM, et al. CT53518, a novel selective FLT3 antagonist for the treatment of acute myelogenous leukemia (AML). Cancer cell. 2002;1(5):421-32.

6. Shiotsu Y, Kiyoi H, Ishikawa Y, Tanizaki R, Shimizu M, Umehara H, et al. KW-2449, a novel multikinase inhibitor, suppresses the growth of leukemia cells with FLT3 mutations or T315I-mutated BCR/ABL translocation. Blood. 2009;114(8):1607-17.

7. Zarrinkar PP, Gunawardane RN, Cramer MD, Gardner MF, Brigham D, Belli B, et al. AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML). Blood. 2009;114(14):2984-92.

Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: FLT, AML
This pilot study is designed to evaluate the safety and tolerability of oral crenolanib besylate given sequentially during standard induction and consolidation chemotherapy in patients with newly diagnosed AML with FLT3 activating mutations.
Tuesday, September 13, 2016 8:19 PM|Shu-Dong Zhang, Ka Lai Leung, Cian M. McCrudden, Hang Fai Kwok|Journal of Cancer (RSS 2.0)|Labels: FLT, VEGF, brain cancer

Tumor cells require angiogenesis to deliver nutrients and oxygen to support their fast growth and metabolism. The vascular endothelial growth factor (VEGF) pathway plays an important role in promoting angiogenesis, including tumor-induced angiogenesis. Recent clinical trials have demonstrated the benefit of targeting VEGF in the treatment of glioblastoma. However, the prognostic significance of the expression of VEGFA and its receptors VEGFR1 (FLT1) and VEGFR2 (KDR) are still largely elusive. In the present study, we aimed to investigate the prognostic significance of these three factors, alone or in combination, in glioma patients. Gene mRNA expression was extracted from three independent brain tumor cohorts totaling 242 patients and the association between gene expression and survival was tested. We found that when VEGFA, FLT1 and KDR expressions were considered alone, only VEGFA demonstrated a significant association with patient survival. Patients with high expression of both VEGFA and either receptor had significantly worse survival than patients expressing both factors at a low level. Importantly, we found that those patients whose tumors overexpressed all three genes had a significantly shorter survival compared to those patients with a low level expression of these genes. Our results suggest that a high level expression of VEGFA and its receptors, both FLT1 and KDR, may be required for brain tumor progression, and that these three factors should be considered together as a prognostic indicator for brain tumor patients.

Friday, August 26, 2016 1:20 PM|Elsevier|JournalTOCs API - Biochemical and Biophysical Research Communications (50 articles)|Labels: FLT, melanoma

Blockade of FLT4 suppresses metastasis of melanoma cells by impaired lymphatic vessels

Biochemical and Biophysical Research Communications, Vol. , No. (2016) pp. -
Publication date: 16 September 2016 Source:Biochemical and Biophysical Research Communications, Volume 478, Issue 2 Author(s): Ji Yoon Lee, Seok-Ho Hong, Minsang Shin, Hye-Ryeon Heo, In Ho Jang The metastatic spread of tumor cells via lymphatic vessels affects the relapse of tumor patients. New lymphatic vessel formation, including lymphangiogenesis, is promoted in the tumor environment. The lymphangiogenic factor VEGF-C can mediate lymphatic vessel formation and induce tumor metastasis by binding with FLT4. In melanoma, metastasis via lymphatics such as lymph nodes is one of the main predictors of poor outcome. Thus, we investigated whether blockade of FLT4 can reduce metastasis via the suppression of lymphatic capillaries. Proliferative lymphatic capillaries in melanoma were estimated by immunohistochemistry using FLT4 antibody after the injection of the FLT4 antagonist MAZ51. The numbers of tumor modules in metastasised lungs were calculated by gross examination and lymphatic related factors were examined by qRT-PCR. MAZ51 injection resulted in the suppression of tumor size and module number and the inhibition of proliferative lymphatic vessels in the intratumoral region in the lung and proliferating melanoma cells in the lung compared to those of untreated groups. Additionally, high FLT4 and TNF-alpha were detected in melanoma-induced tissue, while lymphatic markers such as VEGF-C, FLT4 and Prox-1 were significantly decreased in MAZ51 treated groups, implying that anti-lymphangiogenesis by MAZ51 may provide a potential strategy to prevent tumor metastasis in melanoma and high number of lymphatic capillaries could be used diagnosis for severe metastasis.

Thursday, August 18, 2016 11:48 AM|Dany, M., Gencer, S., Nganga, R., Thomas, R. J., Oleinik, N., Baron, K. D., Szulc, Z. M., Ruvolo, P., Kornblau, S., Andreeff, M., Ogretmen, B.|BLOOD First Edition Papers|Labels: FLT, AML

Signaling pathways regulated by mutant FLT3-ITD, which mediate resistance to AML cell death are poorly understood. Here, we reveal that pro-cell death lipid ceramide generation is suppressed by FLT3-ITD signaling. Molecular or pharmacologic inhibition of FLT3-ITD reactivated ceramide synthesis, selectively inducing mitophagy and AML cell death. Mechanistically, FLT3-ITD targeting induced ceramide accumulation on the outer mitochondrial membrane, which then directly bound autophagy-inducing light chain 3 (LC3), involving its I35 and F52 residues, to recruit autophagosomes for the execution of lethal mitophagy. shRNA-mediated knockdown of LC3 prevented AML cell death in response to FLT3-ITD inhibition by crenolanib, which was restored by WT-LC3, but not mutants of LC3 with altered ceramide binding (I35A-LC3 or F52A-LC3). Mitochondrial ceramide accumulation and lethal mitophagy induction in response to FLT3-ITD targeting was mediated by dynamin related protein 1 (Drp1) activation via inhibition of PKA-regulated S637 phosphorylation, resulting in mitochondrial fission. Inhibition of Drp1 prevented ceramide-dependent lethal mitophagy, and reconstitution of WT-Drp1 or phospho-null S637A-Drp1 but not its inactive phospho-mimic mutant (S637D-Drp1) mutant, restored mitochondrial fission and mitophagy in response to crenolanib in FLT3-ITD+ AML cells expressing stable shRNA against endogenous Drp1. Moreover, activating FLT3-ITD signaling in crenolanib-resistant AML cells suppressed ceramide-dependent mitophagy and prevented cell death. FLT3-ITD+ AML drug resistance is attenuated by LCL-461, a mitochondria-targeted ceramide analogue drug, in vivo, which also induced lethal mitophagy in human AML blasts with clinically relevant FLT3 mutations. Thus, these data reveal a novel mechanism, which regulates AML cell death by ceramide-dependent mitophagy in response to FLT3-ITD targeting.

Sunday, July 31, 2016 10:05 PM|Jiang, X., Bugno, J., Hu, C., Yang, Y., Herold, T., Qi, J., Chen, P., Gurbuxani, S., Arnovitz, S., Strong, J., Ferchen, K., Ulrich, B., Weng, H., Wang, Y., Huang, H., Li, S., Neilly, M. B., Larson, R. A., Le Beau, M. M., Bohlander, S. K., Jin, J., Li, Z., Bradner, J. E., Hong, S., Chen, J.|Cancer Research recent issues|Labels: FLT, AML
Acute myeloid leukemia (AML) is a common and fatal form of hematopoietic malignancy. Overexpression and/or mutations of FLT3 have been shown to occur in the majority of cases of AML. Our analysis of a large-scale AML patient cohort (N = 562) indicates that FLT3 is particularly highly expressed in some subtypes of AML, such as AML with t(11q23)/MLL-rearrangements or FLT3-ITD. Such AML subtypes are known to be associated with unfavorable prognosis. To treat FLT3-overexpressing AML, we developed a novel targeted nanoparticle system: FLT3 ligand (FLT3L)-conjugated G7 poly(amidoamine) (PAMAM) nanosized dendriplex encapsulating miR-150, a pivotal tumor suppressor and negative regulator of FLT3. We show that the FLT3L-guided miR-150 nanoparticles selectively and efficiently target FLT3-overexpressing AML cells and significantly inhibit viability/growth and promote apoptosis of the AML cells. Our proof-of-concept animal model studies demonstrate that the FLT3L-guided miR-150 nanoparticles tend to concentrate in bone marrow, and significantly inhibit progression of FLT3-overexpressing AML in vivo, while exhibiting no obvious side effects on normal hematopoiesis. Collectively, we have developed a novel targeted therapeutic strategy, using FLT3L-guided miR-150–based nanoparticles, to treat FLT3-overexpressing AML with high efficacy and minimal side effects. Cancer Res; 76(15); 4470–80. ©2016 AACR.
Friday, July 8, 2016 5:00 AM|News-Medical.Net Myeloid Leukemia News Feed|Comments|Labels: FLT, AML
Researchers from the Cancer Science Institute of Singapore (CSI Singapore) at the National University of Singapore have identified a set of genes, including DNMT3A, that could potentially be used to predict clinical outcomes of patients who suffer from a type of Acute Myeloid Leukemia (AML) associated with an FLT3 internal tandem duplication (FLT3-ITD) mutation.
CONCLUSIONSThe current data indicate that FLT3 mutation status did not adversely impact overall survival after HCT, and about 50% of patients with this mutation who underwent HCT were long‐term survivors. Cancer 2016. © 2016 American Cancer Society. (Source: Cancer)
Monday, June 6, 2016 4:58 AM|SERIZAWA, M., KUSUHARA, M., OHNAMI, S., NAGASHIMA, T., SHIMODA, Y., OHSHIMA, K., MOCHIZUKI, T., URAKAMI, K., YAMAGUCHI, K.|Anticancer Research recent issues|Labels: FLT

Background/Aim: The identification of additional therapeutic targets by clinical molecular profiling is necessary to expand the range of molecular-targeted cancer therapeutics. This study aimed to identify novel functional tumor-specific single nucleotide variants (SNVs) in the kinase domain of receptor tyrosine kinases (RTKs), from whole-exome sequencing (WES) data. Materials and Methods: SNVs were selected from WES data of multiple cancer types using both cancer-related databases and the index reflecting molecular evolution. Immunoblotting and luciferase assay were performed to assess the function of selected SNVs. Results: Among the seven selected SNVs, two, namely neurotrophic receptor tyrosine kinase 1 (NTRK1) V710A and fms related tyrosine kinase 3 (FLT3) K868N, detected in kinase subdomain IX, were investigated. These SNVs inhibited the autophosphorylation of the respective RTKs, thereby reducing the activity of extracellular signal-regulated kinases. Conclusion: RTK subdomain IX is a promising target for the molecular design of kinase inhibitors.