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Review
. 2018 May;4(5):385-396.
doi: 10.1016/j.trecan.2018.03.006. Epub 2018 Apr 19.

New Therapies in Head and Neck Cancer

Rodell T Santuray  1 , Daniel E Johnson  2 , Jennifer R Grandis  3
Affiliations
Review

New Therapies in Head and Neck Cancer

Rodell T Santuray et al. Trends Cancer. 2018 May.

Abstract

Head and neck squamous cell carcinoma (HNSCC) is a common malignancy with high rates of mortality and morbidity. Beginning with cetuximab, investigators continue to optimize antibody technology to target cell-surface receptors that promote HNSCC growth. Small molecules and oligonucleotides have also emerged as therapeutic inhibitors of key receptor-mediated signaling pathways. Although many such therapies have been disappointing in clinical trials as single agents, they continue to be studied in combination with standard therapies. Approvals of pembrolizumab and nivolumab opened a new era of immunotherapy that aims to stimulate antitumor immunity in the tumor microenvironment. Immunotherapies are being intensively investigated in new HNSCC clinical trials, with the goal of optimizing the therapeutic potential of this new class of anticancer agent.

Keywords: cancer; head; immunotherapy; neck; squamous cell.

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Figures

Figure 1
Figure 1. Stimulation of the EGFR Pathway Drives Survival and Proliferation of Tumor Cells
The epidermal growth factor receptor (EGFR) transduces extracellular signals by activating phosphoinositide 3-kinase (PI3K), which in turn facilitates the conversion of phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-trisphosphate (PIP3). Presence of PIP3 ultimately results in cell survival and proliferation via several downstream mediators, notably the mechanistic target of rapamycin (mTOR). EGFR can also activate the signal transducer and activator of transcription 3 (STAT3), which is a transcription factor for genes involved in cell survival and proliferation. Monoclonal antibody-based therapeutics include cetuximab, panitumumab, nimotuzumab, zalutumumab, Sym004, ABBV-221, and imgatuzumab, which all target the EGFR extracellular domain. Erlotinib, gefitinib, dacomitinib, and afatinib are small molecule tyrosine kinase inhibitors that are directed toward the EGFR intracellular domain. PI3K is targeted by small molecules that include buparlisib, SF1126, alpelisib, INCB050465, copanlisib, and IPI-549. Sirolimus, everolimus, and temsirolimus are related compounds that inhibit mTOR. In addition to small molecule inhibition, therapeutic oligonucleotide decoys can bind to STAT3, and antisense oligonucleotides like AZD9150 can silence STAT3 mRNA.
Figure 2
Figure 2. Immunotherapy Landscape in Head and Neck Cancer
Binding of programmed cell death protein 1 (PD-1) to its ligand, PD-L, causes T cell suppression. Pembrolizumab and nivolumab are mAbs that bind to PD-1 and antagonize its immunosuppressive effects. Activation of cytotoxic T-lymphocyte-associated protein (CTLA-4) also causes T cell suppression. Moreover, binding of CTLA-4 to B7 causes B7 downregulation, which is also immunosuppressive. Ipilimumab prevents ligand binding to CTLA-4, thereby antagonizing this immunosuppression. Activation of co-stimulatory receptors, such as CD40, glucocorticoid-induced tumor necrosis factor receptor (GITR), and toll-like receptors (TLRs), causes immune system stimulation. Binding of mAb SEA-CD40 to CD40 causes antigen presenting cell (APC) maturation and can also induce antibody-dependent cell-mediated cytotoxicity (ADCC) by binding the FcγRIIIα receptor. The mAb INCAGN01876 binds GITR and ultimately leads to T cell proliferation. The small molecule motolimod, and oligonucleotide SD-101 bind TLRs on APCs, thereby stimulating host defense. Indoleamine 2,3-dioxygenase (IDO) and arginase 1 (Arg1) deplete tryptophan and L-arginine, respectively. Both amino acids are essential for T cell proliferation. Epacadostat inhibits IDO while INCB001158 inhibits Arg1. Inducible nitric oxide synthase (NOS2) produces nitric oxide (NO), which causes T cell suppression. L-NMMA is a NOS2 inhibitor.
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References

    1. Ferlay J, et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. International Journal of Cancer. 2010;127:2893–2917. - PubMed
    1. Fitzmaurice C, et al. Global, Regional, and National Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life-years for 32 Cancer Groups, 1990 to 2015: A Systematic Analysis for the Global Burden of Disease Study. JAMA Oncology. 2017;3:524–548. - PMC - PubMed
    1. Schöder H. Head and Neck Cancer. In: Strauss HW, et al., editors. Nuclear Oncology: Pathophysiology and Clinical Applications. Springer; New York: 2013. pp. 269–295.
    1. Salomon DS, et al. Epidermal growth factor-related peptides and their receptors in human malignancies. Critical Reviews in Oncology and Hematology. 1995;19:183–232. - PubMed
    1. Baselga J, Mendelsohn J. Status of Epidermal Growth Factor Receptor Antagonists in the Biology and Treatment of Cancer. Journal of Clinical Oncology. 2003;21:2787–2799. - PubMed

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