The field of nanotechnology has exploded in recent years with diverse arrays of applications. Cancer therapeutics have recently seen benefit from nanotechnology with the approval of some early nanoscale drug delivery systems. A diversity of novel delivery systems are currently under investigation and an array of newly developed, customized particles have reached clinical application. Drug delivery systems have traditionally relied on passive targeting via increased vascular permeability of malignant tissue, known as the enhanced permeability and retention effect (EPR). More recently, there has been an increased use of active targeting by incorporating cell specific ligands such as monoclonal antibodies, lectins, and growth factor receptors. This customizable approach has raised the possibility of drug delivery systems capable of multiple, simultaneous functions, including applications in diagnostics, imaging, and therapy which is paving the way to improved early detection methods, more effective therapy, and better survivorship for cancer patients. Keywords: drug delivery systems, nanotechnology, cancer, passive targeting, active targeting

HER3 (ErbB3) is a unique member of the human epidermal growth factor receptor (EGFR) family (ErbB family). It functions only through dimerization with other members of the ErbB family and modulates activity and sensitivity to targeted cancer therapies. This paper briefly describes the mechanism of HER3 in signal transduction and its potential role in acquired resistance to EGFR- and HER2-targeted therapies. We also consider recent developments in HER3-targeting therapeutics and their combination with inhibitors of other ErbB members in clinical applications.

Squamous cell carcinoma of head and neck (SCCHN) is the most common neoplasm of the upper aerodigestive tract. In this paper, we attempt to summarize the role and applications of the epidermal growth factor receptor (EGFR) inhibitors monoclonal antibodies (moAbs) and tyrosine kinase inhibitors (TKIs) locally advanced as well as metastatic SCCHN. Targeted therapy in SCCHN is now incorporated in the first-line regimes for advanced disease. Novel targeted agents, including the EGFR antibody, cetuximab, have been approved for use as single agents or in combination with radiation therapy or chemotherapy in treatment of recurrent metastatic or locally advanced SCCHN. Refractory mechanisms that bypass the pathway of EGFR inhibitors activity are identified explaining resistance to targeted therapy. Strategies of cotargeting EGFR and other pathways are under investigation. Examples of targeted therapy being used include mammalian target of rapamycin (mtor) inhibitors, antivascular endothelial growth factor (VEGF) moAb, and other inhibitors. We will be focusing our paper on the preclinical and clinical aspects of EGFR inhibition in SCCHN and touch upon other targeted therapies in application.

E-cigarettes have become increasingly popular in the last decade and are considered less harmful than traditional tobacco products due to the lower content of toxic and carcinogenic compounds. However, this is still a controversial issue. This paper contains a review of previous reports on the composition of e-cigarettes and their impact on the pathogenesis and risk of head and neck cancer (HNC). The objective of the review was to compare the molecular and health effects of e-cigarette use in relation to the effects of traditional cigarette smoking in the upper respiratory tract, and to assess the safety and effect of e-cigarettes on HNC risk. A review for English language articles published until 31 August 2020 was made, using a PubMed (including MEDLINE), CINAHL Plus, Embase, Cochrane Library and Web of Science data. The authors reviewed articles on both toxic and carcinogenic compounds contained in e-cigarettes and their molecular and health effects on the upper respiratory tract in comparison to tobacco cigarettes. The risk of developing head and neck squamous cell carcinoma (HNSCC) remains lower in users of e-cigarettes compared with tobacco smokers. However, more long-term studies are needed to better address the safety of e-cigarettes.

Background: SCLC has limited treatment options and inadequate preclinical models. Promising activity of arsenic trioxide (ASO) recorded in conventional preclinical models of SCLC supported the clinical evaluation of ASO in patients. We assessed the efficacy of ASO in relapsed SCLC patients and in corresponding patient-derived xenografts (PDX). Methods: Single arm, Simon 2-stage, phase II trial to enroll patients with relapsed SCLC who have failed at least one line of therapy. ASO was administered as an intravenous infusion over 1-2h daily for 4days in week 1 and for 2days in weeks 2-6 of an 8-week cycle. Treatment continued until disease progression. Pretreatment tumor biopsy was employed for PDX generation through direct implantation into subcutaneous pockets of SCID mice without in vitro manipulation and serially propagated for five generations. Ex vivo efficacy of cisplatin (3mg/kg i.p. weekly) and ASO (3.75mg/kg i.p. every other day) was tested in PDX representative of platinum sensitive and platinum refractory SCLC. Results: The best response in 17 evaluable patients was stable disease in 2 (12%), progressive disease in 15 (88%) patients and median time-to-progression of seven (range 1-7) weeks. PDX was successfully grown in 5 of 9 (56%) transplanted biopsy samples. Serially-propagated PDXs preserved characteristic small cell histology and genomic stability confirmed by immunohistochemistry, short tandem repeat (STR) profiling and targeted sequencing. ASO showed in vitro cytotoxicity but lacked in vivo efficacy against SCLC PDX tumor growth. Conclusions: Cisplatin inhibited growth of PDX derived from platinum-sensitive SCLC but was ineffective against PDX from platinum-refractory SCLC. Strong concordance between clinical and ex vivo effects of ASO and cisplatin in SCLC supports the use of PDX models to prescreen promising anticancer agents prior to clinical testing in SCLC patients.

HNC (head and neck cancer) remains the 6th most common carcinoma worldwide. The suboptimal survival and toxicities observed with conventional approaches warrant exploration of novel therapeutic strategies such as targeted therapies. Although targeting EGFR (epidermal growth factor receptor) with cetuximab demonstrated clinical promise, HER (human epidermal growth factor receptor) or ERBB (erythroblastic leukemia viral oncogene homolog) targeted therapy in HNC has overall been suboptimal to date in clinical settings. Overcoming the resistance as well as identifying new strategies therefore remains a significant challenge. In this review, we will discuss the emerging roles of HER members besides EGFR. A comprehensive "three-dimensional" view of HER signaling pathway from the importance of EGFR nuclear translocation to our maturing concept of receptors' "spatial regulation", as well as the interdependence and interaction among different HER members will also be addressed to complete an essential update of HER signaling in HNC.

OBJECTIVES: The eighth edition American Joint Committee on Cancer (AJCC) Staging incorporates significant changes to the seventh edition in the staging of oropharyngeal squamous cell carcinomas (OPSCC). An important change was the inclusion of OPSCC associated with the human papilloma virus (HPV). Our goal is to compare the performance of both staging systems for patients with HPV-selected and unselected clinical characteristics for OPSCC. METHODS: Using the Surveillance, Epidemiology, and End Results (SEER) database, 2004-2016, we identified patients with likely HPV-associated OPSCC based on surrogate markers (white males aged <65 years old with squamous cell carcinomas of the tonsil and base of tongue), excluding those who underwent surgery. We re-classified these patients using seventh and eighth edition staging for HPV-selected OPSCC and compared the prediction performance of both staging editions for overall survival (OS) and disease-specific survival (DSS). We performed the same analysis for clinically unselected patients with OPSCC. RESULTS: Our analysis included 9554 patients with a median follow-up of 67 months. Comparing the eighth versus seventh edition for our HPV-selected cohort, clinical staging changed for 92.3% of patients and 10-year OS was 62.2%, 61.2%, 35.3%, and 15.5% for Stage I, II, III, and IV, versus 52.9%, 59.2%, 61.6%, 55.1%, 38.3%, and 15.5% for stage I, II, III, IVA, IVB, and IVC, respectively. A similar pattern was observed for 10-year DSS. The concordance statistics for our HPV-selected cohort were improved for both AJCC 7 (0.6260) and AJCC 8 (0.6846) compared with the unselected cohort, 0.5860 and 0.6457 for AJCC 7 and 8, respectively. CONCLUSION: The overall performance of discrimination improved from AJCC 7 to AJCC 8 for both clinically selected and unselected patients, but more notably for our HPV-selected cohort. Despite the lack of statistically significant differentiation between Stages I and II in AJCC 8 in either groups, markedly improved discrimination was observed between Stages I/II, III, and IV in the HPV-selected cohort.

Background Alterations in metabolism are one of the emerging hallmarks of cancer cells and targeting dysregulated cancer metabolism provides a new approach to developing more selective therapeutics. However, insufficient blockade critical metabolic dependencies of cancer allows the development of metabolic bypasses, thus limiting therapeutic benefits. Methods A series of head and neck squamous cell carcinoma (HNSCC) cell lines and animal models were used to determine the efficacy of CPI-613 and CB-839 when given alone or in combination. Glutaminase 1 (GLS1) depletion was achieved by lentiviral shRNAs. Cell viability and apoptosis were determined in HNSCC cells cultured in 2D culture dish and SeedEZ™ 3D scaffold. Molecular alterations were examined by Western blotting and immunohistochemistry. Metabolic changes were assessed by glucose uptake, lactate production, glutathione levels, and oxygen consumption rate. Results We show here that HNSCC cells display strong addiction to glutamine. CPI-613, a novel lipoate analog, redirects cellular activity towards tumor-promoting glutaminolysis, leading to low anticancer efficacy in HNSCC cells. Mechanistically, CPI-613 inhibits the tricarboxylic acid cycle by blocking the enzyme activities of pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase, which upregulates GLS1 and eventually promotes the compensatory role of glutaminolysis in cancer cell survival. Most importantly, the addition of a GLS1 inhibitor CB-839 to CPI-613 treatment abrogates the metabolic dependency of HNSCC cells on glutamine, achieving a synergistic anticancer effect in glutamine-addicted HNSCC. Conclusions These findings uncover the critical role of GLS1-mediated glutaminolysis in CPI-613 treatment and suggest that the CB-839 and CPI-613 combination may potentiate synergistic anticancer activity for HNSCC therapeutic gain.

Acute myeloid leukemia (AML) is a myeloid disorder with several established treatment regimens depending on patient and leukemic factors. Cisplatin is known to have strong leukemogenic potential and is rarely used even as salvage therapy in relapsed or refractory AML. We present a patient simultaneously diagnosed with AML and squamous cell carcinoma of the larynx, who was found to be in complete remission from AML following treatment with cisplatin based chemoradiotherapy for his laryngeal cancer.