The epidermal growth factor receptor- (EGFR-) directed antibody, cetuximab, was FDA-approved for the treatment of squamous cell carcinoma of the head and neck (SCCHN) in 2006. Additional EGFR-targeting agents in clinical development for SCCHN include other EGFR-directed antibodies, tyrosine kinase inhibitors and antisense DNA. Although the majority of SCCHN overexpress EGFR, SCCHN clinical responses to EGFR-targeting agents have been modest. Molecular predictors for SCCHN response to EGFR-targeted therapies have not been identified. However, molecular correlate studies in lung cancer and colon cancer, which have EGFR-targeted therapeutics FDA-approved for treatment, may provide insights. We describe candidate predictive markers for SCCHN response to EGFR-targeted therapies and their prevalence in SCCHN. Clinical response will likely be improved by targeted therapy combination treatments. Src family kinases mediate EGFR-dependent and -independent tumor progression pathways in many cancers including SCCHN. Several Src-targeting agents are in clinical development for solid malignancies. Molecular correlate studies for Src-targeting therapies are few and biomarkers correlated with patient response are limited. Identifying SCCHN patients who will respond to combined EGFR- and Src-targeting will require further characterization of molecular correlates. We discuss rationale for EGFR and Src co-targeting for SCCHN treatment and describe recent clinical trials implementing combined Src- and EGFR-targeted therapeutics.

Recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC) is a devastating malignancy with a poor prognosis. Treatment is limited to chemotherapeutic approaches. Cisplatin is an established and effective treatment for R/M HNSCC, and many studies have investigated cisplatin treatment in combination with other agents. Even when being treated with first line therapy (cisplatin + 5-fluorouracil + cetuximab), overall survival is only 10 months, indicating the need for novel chemotherapeutics and treatment regimens. Current research is focused on molecular targeting therapies inhibiting epidermal growth factor receptor, phosphoinositide-3-kinase/Akt/mammalian target of rapamycin, and vascular endothelial growth factor pathways. A variety of clinical trials have been completed and are currently underway with encouraging results. Finally, future directions of cisplatin-based R/M HNSCC treatment may include targeting specific pathways known to induce cisplatin resistance, such as nucleotide excision repair and inhibition of apoptosis, in hopes to enhance response to cisplatin therapy.

OBJECTIVE

To estimate the distribution of head and neck squamous cell carcinoma (HNSCC) recurrence after definitive chemoradiation therapy (CRT) among patients who underwent 18F-fluorodeoxyglucose positron-emission tomography and computed tomography (PET/CT) surveillance.

METHODS

Retrospective review.

METHODS

HNSCC patients who underwent definitive CRT from 2001 to 2008 were evaluated for recurrence with serial PET/CT. Patients were excluded if they were previously treated for recurrent disease, were treated with surgery as the primary therapeutic modality, or had inadequate clinical follow-up. Recurrence was defined by histopathologic evidence of tumor.

RESULTS

Three hundred eighty-eight patients were studied. Patients in whom recurrence was not detected were followed clinically and radiographically for a median of 27 months. Tumor recurrence was detected in 110 patients. For 37 patients, recurrence was heralded by clinical signs. Among the 73 asymptomatic patients who had a confirmed recurrence, disease was detected by PET/CT between 2 and 43 months, median of 6 months. Forty-five percent of observed asymptomatic recurrences were detected during the first 6 months of surveillance (95% confidence interval [CI], 34%-57%), 79% within the first 12 months (95% CI, 68%-88%), 95% within the first 24 months (95% CI, 87%-98%), and 100% within the first 48 months (95% CI, 95%-100%).

CONCLUSIONS

Among HNSCC patients followed with PET/CT surveillance, 95% of observed asymptomatic recurrences were detected within 24 months after completing CRT. For patients without clinical signs of recurrence, routine PET/CT surveillance beyond the first 24 months may be of limited value and may not be cost effective.

BACKGROUND

In head and neck squamous cell carcinoma (HNSCC), expression levels of the epidermal growth factor receptor (EGFR) correlate with poor prognosis and decreased survival rates. As the mechanisms responsible for cellular immune response to EGFR in vivo remain unclear, the frequency and function of EGFR-specific cytotoxic T cells (CTL) was determined in HNSCC patients.

METHODS

The frequency of CTL specific for the HLA-A2.1-restricted EGFR-derived YLN peptide (YLNTVQPTCV) and KLF peptide (KLFGTSGQKT) was determined in 16 HLA-A2.1+ HNSCC patients and 16 healthy HLA-A2.1+ individuals (NC) by multicolor flow cytometry. Patients' results were correlated to EGFR expression obtained by immunohistochemistry in corresponding tumor sections. Proliferation and anti-tumor activity of peptide-specific CTL was demonstrated by in vitro stimulation with dendritic cells pulsed with the peptides.

RESULTS

Frequency of EGFR-specific CTL correlated significantly with EGFR expression in tumor sections (p = 0.02, r2 = 0.6). Patients with elevated EGFR scores >> 7) had a significantly higher frequency of EGFR-specific CTL than NC and patients with low EGFR scores (< 7). EGFR-specific CTL from cancer patients were expanded ex vivo and produced IFN-γ upon recognition of EGFR+ target cells.

CONCLUSIONS

EGFR expressed on HNSCC cells induces a specific immune response in vivo. Strategies for expansion of EGFR-specific CTL may be important for future immunotherapy of HNSCC patients.

Over the past few decades, it has become increasingly clear that the lethality of cancers depends on more than the malignant cells themselves. The environment those malignant cells are exposed to is just as important a determinant of their behavior. Head and neck squamous cell carcinoma (HNSCC) is both common and deadly. It is the 6th most frequently occurring cancers, and prognosis is still generally poor. Recent evidence indicates that activated fibroblasts residing within the tumor stroma play a significant role in promoting the aggressive spread often seen in head and neck cancer. Tumor associated fibroblasts (TAFs) have also been implicated in facilitating angiogenesis and suppressing the normal anti-tumor function of immune cells. Studying the signaling molecules involved in these processes will facilitate the development of promising targets and inhibitors to prevent tumor-associated fibroblasts from exerting their reinforcing effects on the tumor. In this article, we review the recent literature on the signals used in tumor associated fibroblast communication, with a focus on potential therapeutic targets. Further, we highlight the lead candidates for TAF-targeted therapeutic interventions. Future anti-cancer strategies may achieve better results than current approaches by targeting the support cells in tumor stroma in addition to the cancerous cells.

Structure-activity relationship studies of a 1,2,4-triazolo-[3,4-b]thiadiazine scaffold, identified in an HTS campaign for selective STAT3 pathway inhibitors, determined that a pyrazole group and specific aryl substitution on the thiadiazine were necessary for activity. Improvements in potency and metabolic stability were accomplished by the introduction of an α-methyl group on the thiadiazine. Optimized compounds exhibited anti-proliferative activity, reduction of phosphorylated STAT3 levels and effects on STAT3 target genes. These compounds represent a starting point for further drug discovery efforts targeting the STAT3 pathway.

The incidence of human papillomavirus-positive oropharyngeal cancer (HPV/OPSCC) is rapidly increasing, which will represent a major public health burden for decades to come. Although HPV/OPSCC is generally associated with a better prognosis than HPV-negative OPSCC, the survival rate of individuals with higher-risk clinical and pathologic features remains unchanged. Emerging evidence suggests that HPV/OPSCC is pathologically and molecularly distinct from HPV-negative OPSCC. This review focuses on summarizing treatment strategies for HPV/OPSCC by reviewing the peer-reviewed literature and noting ongoing and planned clinical trials in this disease. We also discuss the potential of designing targeted therapy based on the recent genomic findings of HPV/OPSCC.

Given the potential for long-term toxicities from concurrent chemoradiation, there is great interest in surgery as a primary treatment modality for head and neck cancers, particularly in the younger HPV-positive oropharyngeal cancer patient. Transoral robotic surgery (TORS) has proven to be an effective technique to safely treat oropharyngeal and select supraglottic tumors surgically. Sound, traditional surgical principles are employed using improved endoscopic visualization and precise instrumentation to perform oncologic surgery without the morbidity of transmandibular or transcervical approaches. Although level 1 evidence prospective clinical trials are currently underway for TORS, the literature supports its safety and efficacy based on numerous studies. Currently, prospective randomized trials are underway to provide better evidence for or against TORS in oropharyngeal cancer. Patient selection based on comorbidities, anatomy, and available pathological data is critical in choosing patients for TORS.

BACKGROUND

Expression of gastrin-releasing peptide receptor (GRPR) is elevated in mucosa adjacent to head and neck squamous cell carcinoma (HNSCC) compared with mucosa from cancer-free controls, suggesting elevated GRPR expression may indicate presence of HNSCC.

METHODS

We measured GRPR mRNA levels in histologically normal buccal mucosa from 65 surgical patients with HNSCC and 75 cancer-free control subjects using quantitative polymerase chain reaction (PCR). We tested for association between GRPR expression and HNSCC and evaluated differences in patient progression-free survival (PFS).

RESULTS

Buccal GRPR expression was higher in cases but not controls who were active smokers (p = .04). High GRPR expression was associated with HNSCC (odds ratio [OR] = 3.55; 95% confidence interval [CI] = 1.15-10.93), even after adjustment for age, sex, tobacco use, and sample storage time. PFS did not differ between patients with HNSCC with high versus low GRPR expression (p = .22).

CONCLUSIONS

Elevated buccal GRPR expression was significantly associated with HNSCC independent of known risk factors but was not an indicator of disease prognosis.

OBJECTIVE

The oncogenic transcription factor signal transducer and activator of transcription 3 (STAT3) promotes gene transcription involved in cancer, and its activation by IL-6 is found in head and neck squamous cell carcinoma. Four triazolothiadizine STAT3 pathway inhibitors were evaluated to prioritize a single compound for in vivo examination.

METHODS

Metabolic stability in mouse liver microsome incubation was used to evaluate four triazolothiadizine analogues, and UPCDC-10205 was administered to mice IV as single or multiple doses to evaluate toxicity. Single-dose pharmacokinetics (PK), bioavailability and metabolism were studied after IV 4 mg/kg, PO 4 mg/kg, or PO 30 mg/kg suspension in 1% carboxymethyl cellulose. Mice were euthanized between 5 min to 24 h after dosing, and plasma and tissues were analyzed by LC-MS. Non-compartmental PK parameters were determined.

RESULTS

Of the four triazolothiadizine analogues evaluated, UPCDC-10205 was metabolically most stable. The maximum soluble dose of 4 mg/kg in 10% Solutol™ was not toxic to mice after single and multiple doses. PK analysis showed extensive tissue distribution and rapid plasma clearance. Bioavailability was ~5%. A direct glucuronide conjugate was identified as the major metabolite which was recapitulated in vitro.

CONCLUSIONS

Rapid clearance of UPCDC-10205 was thought to be the result of phase II metabolism despite its favorable stability in a phase I in vitro metabolic stability assay. The direct glucuronidation explains why microsomal stability (reflective of phase I metabolism) did not translate to in vivo metabolic stability. UPCDC-10205 did not demonstrate appropriate exposure to support efficacy studies in the current formulation.