Skip to main content
Key Specialties
Anesthesiology Cardiology Dermatology Diabetology Endocrinology Gastroenterology General Medicine Geriatrics Hematology Infectious Diseases Internal Medicine Nephrology Neurology Obstetrics and Gynecology Oncology Ophthalmology Pediatrics Psychiatry Radiology Respiratory Medicine Rheumatology Surgery Urology
Congress Coverage
ASH 2024 Annual Meeting 2024 ESMO Congress 2024 ERS Congress 2024 EASD Congress 2024 ESC Congress 2024 EAN Congress 2024 ASCO Annual Meeting 2024 ACC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on adolescent vaping

LIVE: Wednesday 29th January, 18:00-19:30 CET

Growing numbers of young people are using e-cigarettes, despite warnings of respiratory effects and addiction. How can doctors tackle the epidemic, and what health effects should you prepare to manage in your clinics?
ADVANCED SEARCH
Log in
Top
Clinical and Translational Medicine
Published in:

Open Access 01-12-2017 | Review

ETS-targeted therapy: can it substitute for MEK inhibitors?

Authors: Osamu Tetsu, Frank McCormick

Published in: Clinical and Translational Medicine | Issue 1/2017

Login to get access

Abstract

Background

The RAS/MAPK pathway has been intensively studied in cancer. Constitutive activation of ERK1 and ERK2 is frequently found in cancer cells from a variety of tissues. In clinical practice and clinical trials, small molecules targeting receptor tyrosine kinases or components in the MAPK cascade are used for treatment. MEK1 and MEK2 are ideal targets because these enzymes are physiologically important and have narrow substrate specificities and distinctive structural characteristics. Despite success in pre-clinical testing, only two MEK inhibitors, trametinib and cobimetinib, have been approved, both for treatment of BRAF-mutant melanoma. Surprisingly, the efficacy of MEK inhibitors in other tumors has been disappointing. These facts suggest the need for a different approach. We here consider transcription factor ETS1 and ETS2 as alternate therapeutic targets because they are major MAPK downstream effectors.

Main text

The lack of clinical efficacy of MEK inhibitors is attributed mostly to a subsequent loss of negative feedback regulation in the MAPK pathway. To overcome this obstacle, second-generation MEK inhibitors, so-called “feedback busters,” have been developed. However, their efficacy is still unsatisfactory in the majority of cancers. To substitute ETS-targeted therapy, therapeutic strategies to modulate the transcription factor in cancer must be considered. Chemical targeting of ETS1 for proteolysis is a promising strategy; Src and USP9X inhibitors might achieve this by accelerating ETS1 protein turnover. Targeting the ETS1 interface might have great therapeutic value because ETS1 dimerizes itself or with other transcription factors to regulate target genes. In addition, transcriptional cofactors, including CBP/p300 and BRD4, represent intriguing targets for both ETS1 and ETS2.

Conclusions

ETS-targeted therapy appears to be promising. However, it may have a potential problem. It might inhibit autoregulatory negative feedback loops in the MAPK pathway, with consequent resistance to cell death by ERK1 and ERK2 activation. Further research is warranted to explore clinically applicable ways to inhibit ETS1 and ETS2.
Literature
1.
Rodriguez-Viciana P, Tetsu O, Oda K et al (2005) Cancer targets in the Ras pathway. In: Cold Spring Harb Symp Quant Biol, vol 70. pp 461–467
2.
Senawong T, Phuchareon J, Ohara O et al (2008) Germline mutations of MEK in cardio-facio-cutaneous syndrome are sensitive to MEK and RAF inhibition: implications for therapeutic options. Hum Mol Genet 17:419–430PubMedCrossRef
3.
Zhao Y, Adjei AA (2014) The clinical development of MEK inhibitors. Nat Rev Clin Oncol 11:385–400PubMedCrossRef
4.
Caunt CJ, Sale MJ, Smith PD et al (2015) MEK1 and MEK2 inhibitors and cancer therapy: the long and winding road. Nat Rev Cancer 15:577–592PubMedCrossRef
5.
Gavrilov D, Kenzior O, Evans M et al (2001) Expression of urokinase plasminogen activator and receptor in conjunction with the ets family and AP-1 complex transcription factors in high grade prostate cancers. Eur J Cancer 37:1033–1040PubMedCrossRef
6.
Gutman A, Wasylyk B (1990) The collagenase gene promoter contains a TPA and oncogene-responsive unit encompassing the PEA3 and AP-1 binding sites. EMBO J 9:2241–2246PubMedPubMedCentral
7.
D’Orazio D, Besser D, Marksitzer R et al (1997) Cooperation of two PEA3/AP1 sites in uPA gene induction by TPA and FGF-2. Gene 201:179–187PubMedCrossRef
8.
Wei G, Srinivasan R, Cantemir-Stone CZ et al (2009) Ets1 and Ets2 are required for endothelial cell survival during embryonic angiogenesis. Blood 114:1123–1130PubMedPubMedCentralCrossRef
9.
Albanese C, Johnson J, Watanabe G et al (1995) Transforming p21ras mutants and c-Ets-2 activate the cyclin D1 promoter through distinguishable regions. J Biol Chem 270:23589–23597PubMedCrossRef
10.
Tetsu O, McCormick F (1999) Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature 398:422–426PubMedCrossRef
11.
Tetsu O, McCormick F (2003) Proliferation of cancer cells despite CDK2 inhibition. Cancer Cell 3:233–245PubMedCrossRef
12.
Meloche S, Pouyssegur J (2007) The ERK1/2 mitogen-activated protein kinase pathway as a master regulator of the G1- to S-phase transition. Oncogene 26:3227–3239PubMedCrossRef
13.
Hoshino R, Chatani Y, Yamori T et al (1999) Constitutive activation of the 41-/43-kDa mitogen-activated protein kinase signaling pathway in human tumors. Oncogene 18:813–822PubMedCrossRef
14.
Mansour SJ, Matten WT, Hermann AS et al (1994) Transformation of mammalian cells by constitutively active MAP kinase kinase. Science 265:966–970PubMedCrossRef
15.
Cowley S, Paterson H, Kemp P et al (1994) Activation of MAP kinase kinase is necessary and sufficient for PC12 differentiation and for transformation of NIH 3T3 cells. Cell 77:841–852PubMedCrossRef
16.
Klein PJ, Schmidt CM, Wiesenauer CA et al (2006) The effects of a novel MEK inhibitor PD184161 on MEK-ERK signaling and growth in human liver cancer. Neoplasia 8:1–8PubMedPubMedCentralCrossRef
17.
Luciano F, Jacquel A, Colosetti P et al (2003) Phosphorylation of Bim-EL by Erk1/2 on serine 69 promotes its degradation via the proteasome pathway and regulates its proapoptotic function. Oncogene 22:6785–6793PubMedCrossRef
18.
Ley R, Balmanno K, Hadfield K et al (2003) Activation of the ERK1/2 signaling pathway promotes phosphorylation and proteasome-dependent degradation of the BH3-only protein, Bim. J Biol Chem 278:18811–18816PubMedCrossRef
19.
Roskoski R Jr (2012) MEK1/2 dual-specificity protein kinases: structure and regulation. Biochem Biophys Res Commun 417:5–10PubMedCrossRef
20.
Cargnello M, Roux PP (2012) Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases. Microbiol Mol Biol Rev 75:50–83CrossRef
21.
22.
Garuti L, Roberti M, Bottegoni G (2010) Non-ATP competitive protein kinase inhibitors. Curr Med Chem 17:2804–2821PubMedCrossRef
23.
Ohren JF, Chen H, Pavlovsky A et al (2004) Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition. Nat Struct Mol Biol 11:1192–1197PubMedCrossRef
24.
Gilmartin AG, Bleam MR, Groy A et al (2011) GSK1120212 (JTP-74057) is an inhibitor of MEK activity and activation with favorable pharmacokinetic properties for sustained in vivo pathway inhibition. Clin Cancer Res 17:989–1000PubMedCrossRef
25.
Ascierto PA, McArthur GA, Dreno B et al (2016) Cobimetinib combined with vemurafenib in advanced BRAF(V600)-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial. Lancet Oncol 17:1248–1260PubMedCrossRef
26.
Solit DB, Garraway LA, Pratilas CA et al (2006) BRAF mutation predicts sensitivity to MEK inhibition. Nature 439:358–362PubMedCrossRef
27.
Yeh JJ, Routh ED, Rubinas T et al (2009) KRAS/BRAF mutation status and ERK1/2 activation as biomarkers for MEK1/2 inhibitor therapy in colorectal cancer. Mol Cancer Ther 8:834–843PubMedPubMedCentralCrossRef
28.
Long GV, Stroyakovskiy D, Gogas H et al (2014) Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med 371:1877–1888PubMedCrossRef
29.
Menzies AM, Long GV (2014) Dabrafenib and trametinib, alone and in combination for BRAF-mutant metastatic melanoma. Clin Cancer Res 20:2035–2043PubMedCrossRef
30.
Robert C, Karaszewska B, Schachter J et al (2015) Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med 372:30–39PubMedCrossRef
31.
32.
Kidger AM, Keyse SM (2016) The regulation of oncogenic Ras/ERK signalling by dual-specificity mitogen activated protein kinase phosphatases (MKPs). Semin Cell Dev Biol 50:125–132PubMedPubMedCentralCrossRef
33.
34.
Kidger AM, Rushworth LK, Stellzig J et al (2017) Dual-specificity phosphatase 5 controls the localized inhibition, propagation, and transforming potential of ERK signaling. Proc Natl Acad Sci USA 114:E317–E326PubMedPubMedCentralCrossRef
35.
36.
Sun C, Wang L, Huang S et al (2014) Reversible and adaptive resistance to BRAF(V600E) inhibition in melanoma. Nature 508:118–122PubMedCrossRef
37.
38.
39.
El-Khoueiry A, Kurkjian C, Semrad T et al (2013) A first in-human phase I study to evaluate the MEK1/2 inhibitor GDC-0623 in patients with advanced solid tumors. Mol Cancer Ther 11(Supplement):B75CrossRef
40.
Martinez-Garcia M, Banerji U, Albanell J et al (2012) First-in-human, phase I dose-escalation study of the safety, pharmacokinetics, and pharmacodynamics of RO5126766, a first-in-class dual MEK/RAF inhibitor in patients with solid tumors. Clin Cancer Res 18:4806–4819PubMedCrossRef
41.
Wang S, Ghosh RN, Chellappan SP (1998) Raf-1 physically interacts with Rb and regulates its function: a link between mitogenic signaling and cell cycle regulation. Mol Cell Biol 18:7487–7498PubMedPubMedCentralCrossRef
42.
43.
44.
Phuchareon J, McCormick F, Eisele DW et al (2015) EGFR inhibition evokes innate drug resistance in lung cancer cells by preventing Akt activity and thus inactivating Ets-1 function. Proc Natl Acad Sci USA 112:E3855–E3863PubMedPubMedCentralCrossRef
45.
Robles AI, Rodriguez-Puebla ML, Glick AB et al (1998) Reduced skin tumor development in cyclin D1-deficient mice highlights the oncogenic ras pathway in vivo. Genes Dev 12:2469–2474PubMedPubMedCentralCrossRef
46.
Yu Q, Geng Y, Sicinski P (2001) Specific protection against breast cancers by cyclin D1 ablation. Nature 411:1017–1021PubMedCrossRef
47.
48.
Yu Q, Sicinska E, Geng Y et al (2006) Requirement for CDK4 kinase function in breast cancer. Cancer Cell 9:23–32PubMedCrossRef
49.
Landis MW, Pawlyk BS, Li T et al (2006) Cyclin D1-dependent kinase activity in murine development and mammary tumorigenesis. Cancer Cell 9:13–22PubMedCrossRef
50.
Musgrove EA, Caldon CE, Barraclough J et al (2011) Cyclin D as a therapeutic target in cancer. Nat Rev Cancer 11:558–572PubMedCrossRef
51.
Finn RS, Dering J, Conklin D et al (2009) PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res 11:R77PubMedPubMedCentralCrossRef
52.
Keshamouni VG, Mattingly RR, Reddy KB (2002) Mechanism of 17-beta-estradiol-induced Erk1/2 activation in breast cancer cells. A role for HER2 AND PKC-delta. J Biol Chem 277:22558–22565PubMedCrossRef
53.
O’Leary B, Finn RS, Turner NC (2016) Treating cancer with selective CDK4/6 inhibitors. Nat Rev Clin Oncol 13:417–430PubMedCrossRef
54.
Finn RS, Crown JP, Lang I et al (2015) The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol 16:25–35PubMedCrossRef
55.
Santamaria D, Barriere C, Cerqueira A et al (2007) Cdk1 is sufficient to drive the mammalian cell cycle. Nature 448:811–815PubMedCrossRef
56.
Moore JD (2013) In the wrong place at the wrong time: does cyclin mislocalization drive oncogenic transformation? Nat Rev Cancer 13:201–208PubMedCrossRef
57.
Malumbres M, Sotillo R, Santamaria D et al (2004) Mammalian cells cycle without the D-type cyclin-dependent kinases Cdk4 and Cdk6. Cell 118:493–504PubMedCrossRef
58.
Plotnik JP, Budka JA, Ferris MW et al (2014) ETS1 is a genome-wide effector of RAS/ERK signaling in epithelial cells. Nucleic Acids Res 42:11928–11940PubMedPubMedCentralCrossRef
59.
Imler JL, Schatz C, Wasylyk C et al (1988) A Harvey-ras responsive transcription element is also responsive to a tumour-promoter and to serum. Nature 332:275–278PubMedCrossRef
60.
Martin ME, Piette J, Yaniv M et al (1988) Activation of the polyomavirus enhancer by a murine activator protein 1 (AP1) homolog and two contiguous proteins. Proc Natl Acad Sci USA 85:5839–5843PubMedPubMedCentralCrossRef
61.
Xin JH, Cowie A, Lachance P et al (1992) Molecular cloning and characterization of PEA3, a new member of the Ets oncogene family that is differentially expressed in mouse embryonic cells. Genes Dev 6:481–496PubMedCrossRef
62.
Wasylyk B, Wasylyk C, Flores P et al (1990) The c-ets proto-oncogenes encode transcription factors that cooperate with c-Fos and c-Jun for transcriptional activation. Nature 346:191–193PubMedCrossRef
63.
Oka T, Rairkar A, Chen JH (1991) Structural and functional analysis of the regulatory sequences of the ets-1 gene. Oncogene 6:2077–2083PubMed
64.
65.
Hollenhorst PC, McIntosh LP, Graves BJ (2011) Genomic and biochemical insights into the specificity of ETS transcription factors. Annu Rev Biochem 80:437–471PubMedCrossRef
66.
Selvaraj N, Kedage V, Hollenhorst PC (2015) Comparison of MAPK specificity across the ETS transcription factor family identifies a high-affinity ERK interaction required for ERG function in prostate cells. Cell Commun Signal 13:12PubMedPubMedCentralCrossRef
67.
Hollenhorst PC, Jones DA, Graves BJ (2004) Expression profiles frame the promoter specificity dilemma of the ETS family of transcription factors. Nucleic Acids Res 32:5693–5702PubMedPubMedCentralCrossRef
68.
Kabbout M, Dakhlallah D, Sharma S et al (2014) MicroRNA 17-92 cluster mediates ETS1 and ETS2-dependent RAS-oncogenic transformation. PLoS ONE 9:e100693PubMedPubMedCentralCrossRef
69.
Yang BS, Hauser CA, Henkel G et al (1996) Ras-mediated phosphorylation of a conserved threonine residue enhances the transactivation activities of c-Ets1 and c-Ets2. Mol Cell Biol 16:538–547PubMedPubMedCentralCrossRef
70.
Slupsky CM, Gentile LN, Donaldson LW et al (1998) Structure of the Ets-1 pointed domain and mitogen-activated protein kinase phosphorylation site. Proc Natl Acad Sci USA 95:12129–12134PubMedPubMedCentralCrossRef
71.
Nelson ML, Kang HS, Lee GM et al (2010) Ras signaling requires dynamic properties of Ets1 for phosphorylation-enhanced binding to coactivator CBP. Proc Natl Acad Sci USA 107:10026–10031PubMedPubMedCentralCrossRef
72.
73.
Muthusamy N, Barton K, Leiden JM (1995) Defective activation and survival of T cells lacking the Ets-1 transcription factor. Nature 377:639–642PubMedCrossRef
74.
Bories JC, Willerford DM, Grevin D et al (1995) T-cell apoptosis and terminal B-cell differentiation induced by inactivation of the Ets-1 proto-oncogene. Nature 377:635–638PubMedCrossRef
75.
Paumelle R, Tulasne D, Kherrouche Z et al (2002) Hepatocyte growth factor/scatter factor activates the ETS1 transcription factor by a RAS-RAF-MEK-ERK signaling pathway. Oncogene 21:2309–2319PubMedCrossRef
76.
77.
Potu H, Peterson LF, Kandarpa M et al (2017) Usp9x regulates Ets-1 ubiquitination and stability to control NRAS expression and tumorigenicity in melanoma. Nat Commun 8:14449PubMedPubMedCentralCrossRef
78.
Yu JC, Chen JR, Lin CH et al (2009) Tensile strain-induced Ets-2 phosphorylation by CaMKII and the homeostasis of cranial sutures. Plast Reconstr Surg 123(2 Suppl):83S–93SPubMedCrossRef
79.
Lu G, Zhang Q, Huang Y, Song J et al (2014) Phosphorylation of ETS1 by Src family kinases prevents its recognition by the COP1 tumor suppressor. Cancer Cell 26:222–234PubMedPubMedCentralCrossRef
80.
81.
Bartholomeusz GA, Talpaz M, Kapuria V et al (2007) Activation of a novel Bcr/Abl destruction pathway by WP1130 induces apoptosis of chronic myelogenous leukemia cells. Blood 109:3470–3478PubMedPubMedCentralCrossRef
82.
Cooper CD, Newman JA, Gileadi O (2014) Recent advances in the structural molecular biology of Ets transcription factors: interactions, interfaces and inhibition. Biochem Soc Trans 42:130–138PubMedPubMedCentralCrossRef
83.
Taniguchi H, Fujiwara Y, Doki Y et al (2007) Gene therapy using ets-1 transcription factor decoy for peritoneal dissemination of gastric cancer. Int J Cancer 121:1609–1617PubMedCrossRef
84.
85.
Babayeva ND, Wilder PJ, Shiina M et al (2010) Structural basis of Ets1 cooperative binding to palindromic sequences on stromelysin-1 promoter DNA. Cell Cycle 9:3054–3062PubMedPubMedCentralCrossRef
86.
Babayeva ND, Baranovskaya OI, Tahirov TH (2012) Structural basis of Ets1 cooperative binding to widely separated sites on promoter DNA. PLoS ONE 7:e33698PubMedPubMedCentralCrossRef
87.
Garvie CW, Hagman J, Wolberger C (2001) Structural studies of Ets-1/Pax5 complex formation on DNA. Mol Cell 8:1267–1276PubMedCrossRef
88.
Kim WY, Sieweke M, Ogawa E et al (1999) Mutual activation of Ets-1 and AML1 DNA binding by direct interaction of their autoinhibitory domains. EMBO J 18:1609–1620PubMedPubMedCentralCrossRef
89.
Foulds CE, Nelson ML, Blaszczak AG et al (2004) Ras/mitogen-activated protein kinase signaling activates Ets-1 and Ets-2 by CBP/p300 recruitment. Mol Cell Biol 24:10954–10964PubMedPubMedCentralCrossRef
90.
91.
92.
Tetsu O, Phuchareon J, Eisele DW et al (2015) AKT inactivation causes persistent drug tolerance to EGFR inhibitors. Pharmacol Res 102:132–137PubMedCrossRef
93.
Phuchareon J, McCormick F, Eisele DW et al (2015) EGFR inhibition generates drug-tolerant persister cells by blocking AKT activity. Cancer Cell Microenviron 2:e1045
94.
95.
Huang WC, Chen CC (2005) Akt phosphorylation of p300 at Ser-1834 is essential for its histone acetyltransferase and transcriptional activity. Mol Cell Biol 25:6592–6602PubMedPubMedCentralCrossRef
96.
de Launoit Y, Audette M, Pelczar H et al (1998) The transcription of the intercellular adhesion molecule-1 is regulated by Ets transcription factors. Oncogene 16:2065–2073PubMedCrossRef
97.
Yockell-Lelievre J, Spriet C, Cantin P et al (2009) Functional cooperation between Stat-1 and ets-1 to optimize icam-1 gene transcription. Biochem Cell Biol 87:905–918PubMedCrossRef
98.
Yang C, Shapiro LH, Rivera M et al (1998) A role for CREB binding protein and p300 transcriptional coactivators in Ets-1 transactivation functions. Mol Cell Biol 18:2218–2229PubMedPubMedCentralCrossRef
99.
Ogryzko VV, Schiltz RL, Russanova V et al (1996) The transcriptional coactivators p300 and CBP are histone acetyltransferases. Cell 87:953–959PubMedCrossRef
100.
Filippakopoulos P, Knapp S (2014) Targeting bromodomains: epigenetic readers of lysine acetylation. Nat Rev Drug Discov 13:337–356PubMedCrossRef
101.
Hay DA, Fedorov O, Martin S et al (2014) Discovery and optimization of small-molecule ligands for the CBP/p300 bromodomains. J Am Chem Soc 136:9308–9319PubMedPubMedCentralCrossRef
102.
Chekler EL, Pellegrino JA, Lanz TA et al (2015) Transcriptional profiling of a selective CREB binding protein bromodomain inhibitor highlights therapeutic opportunities. Chem Biol 22:1588–1596PubMedCrossRef
103.
Ding N, Hah N, Yu RT et al (2015) BRD4 is a novel therapeutic target for liver fibrosis. Proc Natl Acad Sci USA 112:15713–15718PubMedPubMedCentral
104.
105.
Boi M, Gaudio E, Bonetti P et al (2015) The BET bromodomain inhibitor OTX015 affects pathogenetic pathways in preclinical B-cell tumor models and synergizes with targeted drugs. Clin Cancer Res 21:1628–1638PubMedCrossRef
106.
107.
Massie CE, Adryan B, Barbosa-Morais NL et al (2007) New androgen receptor genomic targets show an interaction with the ETS1 transcription factor. EMBO Rep 8:871–878PubMedPubMedCentralCrossRef
108.
Kalet BT, Anglin SR, Handschy A et al (2013) Transcription factor Ets1 cooperates with estrogen receptor α to stimulate estradiol-dependent growth in breast cancer cells and tumors. PLoS ONE 8:e68815PubMedPubMedCentralCrossRef
109.
Cao P, Feng F, Dong G et al (2015) Estrogen receptor α enhances the transcriptional activity of ETS-1 and promotes the proliferation, migration and invasion of neuroblastoma cell in a ligand dependent manner. BMC Cancer 15:491PubMedPubMedCentralCrossRef
110.
Cabrita MA, Christofori G (2008) Sprouty proteins, masterminds of receptor tyrosine kinase signaling. Angiogenesis 11:53–62PubMedCrossRef
Metadata
Title
ETS-targeted therapy: can it substitute for MEK inhibitors?
Authors
Osamu Tetsu
Frank McCormick
Publication date
01-12-2017
Publisher
Springer Berlin Heidelberg
Published in
Clinical and Translational Medicine / Issue 1/2017
Electronic ISSN: 2001-1326
DOI
https://doi.org/10.1186/s40169-017-0147-4

Other articles of this Issue 1/2017

Single-cell RNA-sequencing of the brain

  • Open Access
  • Review

Optimization of culture conditions for rapid clinical-scale expansion of human umbilical cord blood-derived mesenchymal stem cells

  • Open Access
  • Research

Can glypican-3 be a disease-specific biomarker?

  • Open Access
  • Review

Heterogeneity in retinoblastoma: a tale of molecules and models

  • Open Access
  • Review

Contact allergy to aluminium induced by commonly used pediatric vaccines

  • Open Access
  • Commentary

Cancer nanomedicine: a review of recent success in drug delivery

  • Open Access
  • Review