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Targeted therapy in head neck tumours

Lorenzo Lo Muzio1, 2*
  • 1 University of Foggia, Italy
  • 2 Department of Clinical and Experimental Medicine, University of Foggia, Italy

Head and neck tumours (HNSCC) is a collective term for tumours of several different locations within head and neck area, locations showing widely varying histology. Notwithstanding the progress in diagnosis and treatment of other malignant tumors, HNSCCs are characterized by dreadfully insufficient therapeutic approaches and meager rates of response to treatment with a limited 5-year survival rate, not exceeding 55%, mainly for locally aggressive tumor phenotypes and the presence of lymph node involvement. Conventional cytotoxic chemotherapy presents a wide range of side effects and is not efficacious in the treatment of these tumours. For these reasons, researchers focused on the study of new therapeutic aids. In the last 20 years there has been an explosion of knowledge in the field of tumor biology. For the first time, researchers have at their disposal a series of increasingly sophisticated techniques for studying genes, their protein products, and the various aspects of the cell cycle. Thanks to the identification of molecules that interact with a specific defect, the approach to antineoplastic pharmacology has radically changed, moving from a disease-based pharmacology to a guided cross-therapy on the molecular defect. The future of cancer therapy seems to be the “targeted therapy”. Unlike the classic chemotherapy approach, which acts on nonspecific mechanisms linked to the characteristics of all rapidly proliferating cells, including normal ones, “targeted therapy” acts on the mechanisms linked to the expression of oncogenes and tumor suppressor genes, based on the specific tumor promotion action, which results in the transformation of the cell from normal to pathological.(1, 2) The development of a molecular type drug capable of blocking these enzymes or of humanized monoclonal antibodies, which act on the chains of signals interfering with the receptors present on the cell surface has radically changed the prognosis of several types of cancers(3). Several classes of anticancer drugs are actually experimented in clinical trials, such as monoclonal antibodies, tyrosine kinase inhibitors, mTOR inhibitors, immune check point inhibitors. Monoclonal antibodies Members of the HER family are established therapeutic targets for the development of novel anticancer agents, and several approaches are being used to block these receptors. EGFR is a member of the receptor tyrosine kinases ErbB family and is a cell surface molecule whose activation leads to an intracellular signalling cascade affecting invasion, apoptosis and angiogenesis. The structure of the EGFR family receptor members is composed by an extra-cellular ligand binding domain. The binding to the domain receptors induces dimerization and autophosphorylation of intracellular tyrosine kinase domain which leads to the activation of downstream signalling pathways of ras, raf, mitogen activated protein kinase (MAPK), phosphatidylinositol-3-kinase (PI3K) Akt and the signal transduction and activator of transcription (STAT) pathways(4). Targeting EGFR for cancer therapy has been the focus of several researches. In the late 1980’s there was the first systematic attempts to develop anticancer agents by targeting the EGFR and researches led to the development of anti-EGFR monoclonal antibodies and small molecules EGFR tyrosine kinase inhibitors(5). The blockade may be directed either to extracellular binding sites or to intracellular sites of EGFR. At present, predicting which of these 2 strategies will be more effective is difficult. A molecule that has dual action would be ideal. The strong points of humanized EGFR MAbs (extracellular blockade) are as follows:1) Prolonged half-life, 2) Some cytolytic actions by immune mediated pathways, 3) induction of receptor down-regulation, 3) No gastrointestinal toxicity. The strong points of low-molecular-weight EGFR tyrosine kinase inhibitors (intracellular blockade) are as follows: 1) Long-term therapy with oral administration, 2) inhibition of EGFR-homologous kinases such as HER-2, 3) direct inhibition of HER-2, 4) Less potential for anaphylaxis or allergic reactions, 5) inhibition of mutant EGFRvIII kinase found in some tumors. The extracellular strategy for blockade of the HER/epidermal growth factor receptor (EGFR) family uses antibodies to block the extracellular ligand-binding region of the receptor. Several phase II clinical trials of cetuximab in combination with chemotherapy, radiotherapy, or both have been completed for a range of indications, including non–small cell lung carcinoma (NSCLC), HNSCC, and colorectal cancer(6-8). The US Food and Drug Administration (FDA) has approved this drug for clinical use. A systematic review and meta-analysis of randomized controlled trials showed that addition of cetuximab to standard therapy may improve outcomes for recurrent or metastatic (R/M) HNSCC patients, while causing a moderate increase in severe adverse event); in stage III/IV patients, anti-EGFR mAb plus RT can improve Overall Survivall compared with RT alone; replacement of chemotherapy with EGFR mAb or adding EGFR mAb to combined chemotherapy and RT did not improve outcomes(9). Panitumumab is a recent fully human anti-EGFR monoclonal antibody commonly used for the treatment of metastatic colorectal cancer. A recently published phase III, open-label randomized control trial (SPECTRUM) assessed the efficacy and safety of panitumumab combined with cisplatin and fluorouracil as first-line treatment for the patients with recurrent or metastatic HNSCC(10). A total of 657 patients were included in this study, of which 330 received only chemotherapy (cisplatin + 5-FU) and 327 received the same chemotherapy regimen along with the panitumumab(10). There was no significant improvement of median overall survival in the panitumumab plus chemotherapy group compared with chemotherapy alone group (11.1 mo vs 9 mo, P =.1403), and median progression-free survival was better in the panitumumab plus chemotherapy group (5.8 months vs 4.6 months, P =.0036)(10). On further subgroup analysis, it was observed that patients HPV- (assessed by p16 immunohistochemistry) had a statistically better median overall survival in the panitumumab group compared with the chemotherapy alone group (11.7 mo vs 8.6 mo, P =.0115)(10). The median overall survival was numerically but not statistically better in the chemotherapy alone group (12.6 mo vs 11 mo in the panitumumab group, P =.998) in patients whose tumor were p16 positive. The authors concluded that p16 status could be a predictive factor to select patients for panitumumab with chemotherapy(10). However, Panitumumab monotherapy in pretreated HNSCC patients was well tolerated but moderately active(11). In a recent study, the addition of nimotuzumab to standard treatment showed promising response rate as well as survival outcomes in recurrent and/or metastatic HNSCC patients without producing additional toxicity(12). Tyrosine Kinase Inhibitors Tyrosine kinase inhibitors is an unique class of orally administered small molecule therapeutics employed into the standard of care treatment in a wide variety of cancer types including non small cell lung cancer(4). The Eastern Cooperative Oncology Group conducted a randomized controlled trial Phase III to test the role of gefitinib plus docetaxel versus docetaxel plus placebo in the treatment of recurrent or metastatic HNSCC(13). This study was closed early and interim analysis showed the addition of gefitinib failed to improve outcome (overall or progression-free survival) in this group of patients(13). Another tyrosine kinase inhibitor, afatinib, given for 2 weeks to newly diagnosed HNSCC patients induces a high rate of FDG-PET partial metabolic response and partial response according to RECISTv1.1 and afatinib can be safely administered before surgery(14). mTOR Inhibitors The PI3K/Akt/mTOR pathway belongs to the family of signal transduction inhibitors and has a pivotal role in cancer cell functions such as growth, proliferation, survival and mortality. mTOR was identified in 1994 by several groups of investigators as the kinase targeted by rapamycin linked to the cellular protein FKBP12 (15). Rapamycin and its analogues are the first generation of mTOR inhibitors. The target of rapamycin (mTor in mammalian cells) is a 289 kDa serine/threonine protein kinase belonging to a bigger family of phosphatidyl-inositol 3- kinase (PI3K)-related kinase (PIKK). The mechanism of action of Rapamycin and its analogues is based on the inhibition of the activity of mTORC1 through the binding to FKBP-12 and the formation of a ternary complex with mTOR (16). Everolimus was not active as monotherapy in unselected patients with recurrent/metastatic HNSCC(17). The combination of temsirolimus with low-dose weekly carboplatin and paclitaxel appears to have meaningful clinical efficacy in the treatment of R/M HNSCC(18). This regimen has a relatively high response rate compared to other treatments evaluated in R/M HNSCC, and potential associations with genetic alterations in the PI3K/mTOR pathway should be further explored(18). Immune checkpoint inhibitors. Another therapeutic possibility is the control of immune activity. Tumor cells can escape immune surveillance through the programmed cell death protein 1 (PD-1) axis suppressing T cells. Some molecules seem to be able to block this tumor activity, such as PD-1 or PD-L1 inhibitors. Nivolumab significantly improved overall survival vs investigator’s choice (IC) of chemotherapy in patients with recurrent or metastatic HNSCC(19). Further, overall survival benefit with nivolumab vs IC was also noted among patients who received first-line treatment for recurrent/metastatic HNSCC after progressing on platinum therapy for locally advanced disease in the adjuvant or primary (i.e., with radiation) setting(19). In a trial, pembrolizumab or Keytruda is was twice as effective than standard therapy with cetuximab in HNSCC, obtaining a disease control rate of approximately 50% and a tumor shrinkage in 57% of the patients(20). Conclusions There are several new classes of drugs useful in the HNSCC treatment, but all these molecules are not free by adverse reactions, in fact targeted therapy can still cause significant toxicity to non-cancer cells(21).

References

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Keywords: head neck cancer,, Immune check point inhibitor, mTOR inhibitors, tyrosine kinase inhibitors, Monoclonal antibodies (cetuximab, panitumumab)

Conference: 5th National and 1st International Symposium of Italian Society of Oral Pathology and Medicine., Ancona, Italy, 19 Oct - 20 Oct, 2018.

Presentation Type: oral presentation

Topic: Oral Diseases

Citation: Lo Muzio L (2019). Targeted therapy in head neck tumours. Front. Physiol. Conference Abstract: 5th National and 1st International Symposium of Italian Society of Oral Pathology and Medicine.. doi: 10.3389/conf.fphys.2019.27.00012

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Received: 26 Jan 2019; Published Online: 09 Dec 2019.

* Correspondence: Prof. Lorenzo Lo Muzio, University of Foggia, Foggia, Italy, lorenzo.lomuzio@unifg.it