No abstract

Head and neck squamous cell carcinoma (HNSCC) is strongly associated with alcohol and tobacco consumption. Lately, the incidence of human papillomavirus (HPV)-related tumors has shown a significant increase, and HPV-related tumors show distinctive features if compared with the HPV-negative counterpart. Locally advanced HNSCC can be treated with concomitant chemoradiotherapy, but early recurrences sometimes occur. Relapses are often related to an intrinsic radioresistance of the tumors. Alterations in intracellular pathways, primarily involved in cell proliferation, apoptosis, and DNA repair, can lead to radioresistance. Preclinical and clinical evidence highlighted that 3 main pathways, including the epidermal growth factor receptor (EGFR), the phosphotidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR), and the p53 signaling cascades, play a crucial role in radioresistance development. A future approach may consist in the association of radiotherapy (RT) and selective inhibition of the key pathways involved in radioresistance. Phase I, II, and III clinical trials are currently testing these novel treatment strategies.

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P53 is often mutated in solid tumors, in fact, somatic changes involving the gene encoding for p53 (TP53) have been discovered in more than 50% of human malignancies and several data confirmed that p53 mutations represent an early event in cancerogenesis. Main p53 functions consist in cell cycle arrest, DNA repair, senescence and apoptosis induction in response to mutagenic stimuli, and, to exert those functions, p53 acts as transcriptional factor. Recent data have highlighted another very important role of p53, consisting in regulate cell metabolism and cell response to oxidative stress. Majority of tumor suppressor genes, such as adenomatous polyposis coli (APC), retinoblastoma-associated protein (RB) and Von-Hippel-Lindau (VHL) are inactivated by deletion or early truncation mutations in tumors, resulting in the decreased or loss of expression of their proteins.Differently, most p53 mutations in human cancer are missense mutations, which result in the production of fulllength mutant p53 proteins. It has been reported that mutant p53 proteins and wild type p53 proteins often regulate same cellular biological processes with opposite effects. So, mutant p53 has been reported to supply the cancer cells of glucose and nutrients, and, to avoid reactive oxygen species (ROS) mediated damage during oxidative stress. These last features are able to render tumor cells resistant to ionizing radiations and chemotherapy. A future therapeutic approach in tumors bearing p53 mutations may be to deplete cancer cells of their energy reserves and antioxidants.

Recently, “ipilimumab,” an anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) monoclonal antibody, has been demonstrated to improve overall survival in metastatic melanoma. “CTLA-4” is an immune-checkpoint molecule that downregulates pathways of T-cell activation. Ipilimumab, by targeting CTLA-4, is able to remove the CTLA-4 inhibitory signal, allowing the immune system to react to cancer cells. Due to its immune-based mechanism of action, ipilimumab causes the inhibition of CTLA-4-mediated immunomodulatory effects, the enhancement of antitumor specific immune response mediated by the weakening of self-tolerance mechanisms while exacerbating the development of autoimmune diseases and immune-related adverse events, including dermatitis, hepatitis, enterocolitis, hypophysitis, and uveitis.