Current and Future Molecular Targets for Acute Myeloid Leukemia Therapy
Acute myeloid leukemia (AML) disease prognosis is poor and there is a high risk of chemo-resistant relapse for both young and old patients. Thus, there is a demand for alternative and target-specific drugs to improve the 5-year survival rate. Current treatment mainstays include chemotherapy, or mutation-specific targeting molecules including FLT3 inhibitors, IDH inhibitors, and monoclonal antibodies. Efforts to devise new, targeted therapy have included recent advances in methods for high-throughput genomic screening and the availability of computer-assisted techniques for the design of novel agents predicted to specifically inhibit mutant molecules involved in leukemogenesis. Crosstalk between the leukemia cells and the bone marrow microenvironment through cell surface molecules, such as the integrins αvβ3 and αvβ5, might influence drug response and AML progression. This review article focuses on current AML treatment options, new AML targeted therapies, the role of integrins in AML progression, and a potential therapeutic agent—integrin αvβ3 antagonist.
KeywordsB-cell lymphoma gene 2 FMS-like tyrosine kinase 3 Isocitrate dehydrogenase Nano-diamino-tetrac l-Thyroxine tetraiodothyroacetic acid
Acute myeloid leukemia
B-cell lymphoma gene 2
Chick egg chorioallantoic membrane
C-kit is a type of receptor tyrosine kinase, also called CD117
Proto-oncogene that codes for the MCSF (CSF1) receptor
Epidermal growth factor
Focal adhesion kinase
Basic fibroblast growth factor
FMS-like tyrosine kinase 3
Mitogen-activated protein kinase
Mouse double minute chromosome 2
Nuclear factor kappa-light-chain-enhancer of activated B cells
Polyethylene glycol (PEG) covalently bonded with two bi-tri-azole tetraiodothyroacetic acid molecules
Programmed cell death protein 1
Programmed death-ligand 1
Platelet-derived growth factor
Signal transducer and activator of transcription
Transforming growth factor β
There is no funding to report.
Compliance with Ethical Standards
Conflict of Interest
Shaheedul A. Sami declares that he has no conflict of interest.
Noureldien H. E. Darwish declares that he has no conflict of interest.
Amanda N. M. Barile declares that she has no conflict of interest.
Shaker A. Mousa was issued a patent that is owned by NanoPharmaceuticals LLC, and he owns stock in NanoPharmaceuticals LLC, which is developing anticancer drugs.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
References and Recommended Reading
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 1.Greenberg PL, Gordeuk V, Issaragrisil S, Siritanaratkul N, Fucharoen S, Ribeiro RC. Major hematologic diseases in the developing world—new aspects of diagnosis and management of thalassemia, malarial anemia, and acute leukemia. Hematology Am Soc Hematol Educ Program. 2001:479–98.CrossRefGoogle Scholar
- 3.American Cancer Society. Key statistics for acute myeloid leukemia (AML). 2019. https://www.cancer.org/cancer/acute-myeloid-leukemia/about/key-statistics.html. Accessed 1 May 2019.
- 25.American Cancer Society. Chemotherapy for acute myeloid leukemia (AML). 2019. https://www.cancer.org/cancer/acute-myeloid-leukemia/treating/chemotherapy.html. Accessed 1 May 2019.
- 26.American Cancer Society. Risk factors for acute myeloid leukemia (AML). 2019. https://www.cancer.org/cancer/acute-myeloid-leukemia/causes-risks-prevention/risk-factors.html. Accessed 1 May 2019.
- 29.Elsevier Inc. Clinical pharmacology: Cytarabine. 2019. https://www.clinicalkey.com/pharmacology/monograph/161?n=Cytarabine, ARA-C. Accessed 1 May 2019.
- 30.Elsevier Inc. Clinical pharmacology: Idarubicin. 2019. https://www.clinicalkey.com/pharmacology/monograph/305?n=Idarubicin. Accessed 1 May 2019.
- 32.American Cancer Society. Cancer facts & Figs. 2017. 2017. https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2017/cancer-facts-and-figures-2017.pdf. Accessed 1 May 2019.
- 34.• Lee LY, Hernandez D, Rajkhowa T, Smith SC, Raman JR, Nguyen B, et al. Preclinical studies of gilteritinib, a next-generation FLT3 inhibitor. Blood. 2017;129:257–60 The inhibitory activity of gilteritinib against different forms of FLT3 mutations in leukemia cells was studied with immunoblotting. Gilteritinib showed significant inhibitor activity against different FLT3 mutations including the resistant mutations.PubMedPubMedCentralCrossRefGoogle Scholar
- 36.Mendel DB, Laird AD, Xin X, Louie SG, Christensen JG, Li G, et al. In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res. 2003;9:327–37.PubMedGoogle Scholar
- 40.Kampa-Schittenhelm KM, Heinrich MC, Akmut F, Dohner H, Dohner K, Schittenhelm MM. Quizartinib (AC220) is a potent second generation class III tyrosine kinase inhibitor that displays a distinct inhibition profile against mutant-FLT3, -PDGFRA and -KIT isoforms. Mol Cancer. 2013;12:19.PubMedPubMedCentralCrossRefGoogle Scholar
- 41.Kampa-Schittenhelm KM, Frey J, Haeusser LA, Illing B, Pavlovsky AA, Blumenstock G, et al. Crenolanib is a type I tyrosine kinase inhibitor that inhibits mutant KIT D816 isoforms prevalent in systemic mastocytosis and core binding factor leukemia. Oncotarget. 2017;8:82897–909.PubMedPubMedCentralCrossRefGoogle Scholar
- 50.U.S. Food and Drug Administration. Novel drug approvals for 2018. 2018. https://www.fda.gov/drugs/developmentapprovalprocess/druginnovation/ucm592464.htm. Accessed 1 May 2019.
- 58.Willems E, Dedobbeleer M, Digregorio M, Lombard A, Lumapat PN, Rogister B. The functional diversity of Aurora kinases: a comprehensive review. Cell Div. 2018;13:7.Google Scholar
- 59.Kim S-J, Jang JE, Cheong J-W, Eom J-I, Jeung H-K, Kim Y, et al. Aurora A kinase expression is increased in leukemia stem cells, and a selective Aurora A kinase inhibitor enhances Ara-C-induced apoptosis in acute myeloid leukemia stem cells. Korean J Hematol. 2012;47:178–85.PubMedPubMedCentralCrossRefGoogle Scholar
- 62.Melichar B, Adenis A, Lockhart AC, Bennouna J, Dees EC, Kayaleh O, et al. Safety and activity of alisertib, an investigational aurora kinase A inhibitor, in patients with breast cancer, small-cell lung cancer, non-small-cell lung cancer, head and neck squamous-cell carcinoma, and gastro-oesophageal adenocarcinoma: a five-arm phase 2 study. Lancet Oncol. 2015;16:395–405.PubMedCrossRefGoogle Scholar
- 65.Kantarjian HM, Martinelli G, Jabbour EJ, Quintas-Cardama A, Ando K, Bay JO, et al. Stage I of a phase 2 study assessing the efficacy, safety, and tolerability of barasertib (AZD1152) versus low-dose cytosine arabinoside in elderly patients with acute myeloid leukemia. Cancer. 2013;119:2611–9.PubMedPubMedCentralCrossRefGoogle Scholar
- 67.U.S. Food and Drug Administration. FDA approves venetoclax in combination for AML in adults. 2018. https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm626499.htm. Accessed 1 May 2019.
- 68.Elsevier Inc. Clinical pharmacology: Venetoclax. 2019. https://www.clinicalkey.com/pharmacology/monograph/4844?n=Venetoclax. Accessed 1 May 2019.
- 69.AbbVie Inc. Highlights of prescribing information (venclexta). 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/208573s000lbl.pdf. Accessed 1 May 2019.
- 81.Elsevier Inc. Clinical pharmacology: Gemtuzumab ozogamicin. 2019. https://www.clinicalkey.com/pharmacology/monograph/2471?n=Gemtuzumab Ozogamicin. Accessed 1 May 2019.
- 82.•• Chin YT, Wei PL, Ho Y, Nana AW, Changou CA, Chen YR, et al. Thyroxine inhibits resveratrol-caused apoptosis by PD-L1 in ovarian cancer cells. Endocr Relat Cancer. 2018;25:533–45 Authors demonstrated the potential impact of thyroid hormones on cancer apoptosis. T4 inhibited COX-2-dependent apoptosis in ovarian cancer cells by retaining inducible COX-2 with PD-L1 in the cytoplasm. These findings provide new insights into the effect of T4 antagonizing factors on cancer properties.PubMedCrossRefGoogle Scholar
- 88.Bailey EB, Tantravahi SK, Poole A, Agarwal AM, Straubhar AM, Batten JA, et al. Correlation of degree of hypothyroidism with survival outcomes in patients with metastatic renal cell carcinoma receiving vascular endothelial growth factor receptor tyrosine kinase inhibitors. Clin Genitourin Cancer. 2014;ed2015:e131–7.Google Scholar
- 95.Yi H, Zeng D, Shen Z, Liao J, Wang X, Liu Y, et al. Integrin alphavbeta3 enhances β-catenin signaling in acute myeloid leukemia harboring Fms-like tyrosine kinase-3 internal tandem duplication mutations: implications for microenvironment influence on sorafenib sensitivity. Oncotarget. 2016;7:40387–97.PubMedPubMedCentralGoogle Scholar
- 99.Zhang P, Chen L, Song Y, Li X, Sun Y, Xiao Y, et al. Tetraiodothyroacetic acid and transthyretin silencing inhibit pro-metastatic effect of L-thyroxin in anoikis-resistant prostate cancer cells through regulation of MAPK/ERK pathway. Exp Cell Res. 2016;347:350–9.PubMedCrossRefPubMedCentralGoogle Scholar
- 101.•• Sudha T, Bharali DJ, Yalcin M, Darwish NH, Debreli Coskun M, Keating KA, et al. Targeted delivery of paclitaxel and doxorubicin to cancer xenografts via the nanoparticle of nano-diamino-tetrac. Int J Nanomedicine. 2017;12:1305–15 Authors discuss the potential impact of therapies that target integrin αvβ3. They demonstrated the feasibility of chemotherapy delivery using a nanoparticle system that achieved higher intratumoral concentrations and improved antitumor efficacy of chemotherapies than via the conventional administration route of these agents.PubMedCrossRefGoogle Scholar
- 110.Mousa SA, Rajabi M, inventors. Non-cleaveable polymer conjugated with αvβ3 integrin thyroid antagonists. USA patent 10, 201,616. 2019.Google Scholar