[Show abstract][Hide abstract] ABSTRACT: This phase 2 trial evaluated the tolerability and clinical efficacy of the combination of oxaliplatin and pemetrexed as an induction chemotherapy regimen in locally advanced head and neck squamous cell carcinoma (HNSCC).
Forty-two patients were enrolled in the study. Patients received pemetrexed 300 mg/m(2) intravenously (IV) and oxaliplatin 85 mg/m(2) IV every 14 days for a total of 4 cycles. A subset of patients consented to correlative studies including tumor tissue for human papillomavirus (HPV) detection and expression of DNA repair genes that may be predictive of response or resistance to oxaliplatin or pemetrexed.
Response data were available for 40 patients. Eighteen had a partial response, and 1 had a complete response, for a response rate of 47.5%. Patients with HPV(+) disease demonstrated superior response rates, progression-free survival, and overall survival. The regimen was well tolerated, with predominantly grade 1 or 2 alanine aminotransferase/aspartate aminotransferase elevation. One patient had grade 5 toxicity with neutropenia and sepsis. The authors did not identify genes predictive of response or toxicity, although HPV(+) tumors demonstrated a unique gene expression signature.
Although the response rate of oxaliplatin and pemetrexed proved less than anticipated, the combination remains an active induction regimen in HNSCC. This regimen should be evaluated further in combination with targeted agents, such as cetuximab, especially in the HPV(+) patient population.
Cancer 02/2012; 118(4):1007-13. DOI:10.1002/cncr.26364 · 4.89 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We hypothesized that chronic inhibition of epidermal growth factor receptor (EGFR) by cetuximab, a monoclonal anti-EGFR antibody, induces up-regulation of its ligands resulting in resistance and that microRNAs (miRs) play an important role in the ligand regulation in head and neck squamous cell carcinoma (HNSCC).
Genome-wide changes in gene and miR expression were determined in cetuximab-sensitive cell line, SCC1, and its resistant derivative 1Cc8 using DNA microarrays and RT-PCR. The effects of differentially expressed EGFR ligands and miRs were examined by MTS, colony formation, ELISA, and western blot assays. Heparin-binding EGF-like growth factor (HB-EGF) and its regulator, miR-212, were differentially expressed with statistical significance when SCC1 and 1Cc8 were compared for gene and miR expression. Stimulation with HB-EGF induced cetuximab resistance in sensitive cell lines. Inhibition of HB-EGF and the addition of miR-212 mimic induced cetuximab sensitivity in resistant cell lines. MicroRNA-212 and HB-EGF expression were inversely correlated in an additional 33 HNSCC and keratinocyte cell lines. Six tumors and 46 plasma samples from HNSCC patients were examined for HB-EGF levels. HB-EGF plasma levels were lower in newly diagnosed HNSCC patients when compared to patients with recurrent disease.
Increased expression of HB-EGF due to down-regulation of miR-212 is a possible mechanism of cetuximab resistance. The combination of EGFR ligand inhibitors or miR modulators with cetuximab may improve the clinical outcome of cetuximab therapy in HNSCC.
PLoS ONE 09/2010; 5(9):e12702. DOI:10.1371/journal.pone.0012702 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To develop a reliable modeling system for head and neck squamous cell carcinoma (HNSCC).
Laboratory-based translational study.
HNSCC tissue was obtained from patients at biopsy/resection, cultured, and implanted into mice. In vivo, tumor growth, and survival was monitored by bioluminescence imaging. Histology and immunohistochemistry (IHC) were used to confirm HNSCC and human origin.
Short-term culture techniques were optimized allowing survival of primary HNSCC cells more than 7 days in 76% of tumors. The size of the tumor biopsy collected did not correlate with the success of short-term culture or xenograft establishment. Xenograft modeling was attempted in primary HNSCCs from 12 patients with a success rate of 92%. Immunostaining confirmed human origin of epithelial tumor cells within the modeled tumor. Bioluminescence and Ki67 IHC suggested tumor proliferation within the model. Luciferase expression was maintained for as long as 100 days in modeled tumors.
The techniques developed for short-term primary tumor culture followed by xenograft modeling provide a low-cost and tractable model for evaluation of HNSCC response to standard and novel therapies. The high success rate of human-in-mouse tumor formation from primary HNSCC suggests that selection pressures for tumor growth in this model may be less than those observed for establishment of cell lines. Bioluminescent imaging provides a useful tool for evaluating tumor growth and could be expanded to measure response of the modeled tumor to therapy. This model could be adapted for xenograft modeled growth of other primary tumor types.
The Laryngoscope 12/2009; 119(12):2315-23. DOI:10.1002/lary.20607 · 2.14 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To examine the role of HPV status in the etiology, prognosis, and treatment of head and neck squamous cell carcinoma in early larynx malignancies.
Thirty-eight cases of T1 or carcinoma in situ (CIS) laryngeal lesions were examined for the presence of human papilloma virus (HPV) using an inclusive polymerase chain reaction (PCR)/hybridization technique capable of identifying 37 HPV subtypes.
HPV DNA was detected in 6 (16%) of the 38 lesions, representing HPV types 16, 26, 31, 39, and 52, and p16 tumor suppressor protein expression was confirmed in 10 representative cases. This HPV prevalence is higher than that noted in many previous laryngeal cancer studies, possibly due to the relatively large panel of subtypes screened for in this study. Identification of HPV-26, which has been associated with uterine cervical cancer, in an early laryngeal cancer specimen represents the first evidence of this subtype in a laryngeal carcinoma. Consistent with reports focusing on head and neck squamous cell carcinoma (HNSCC) arising from other subsites within the upper aerodigestive tract, patients with HPV-positive laryngeal carcinomas were of younger age and were somewhat less likely to have a history of tobacco use, although the latter of the two findings did not reach statistical significance.
Our findings emphasize the presence of a broad spectrum of HPV types in a relevant proportion of early laryngeal cancers, and together with evidence of an association of HPV tumor status with a more favorable clinical course, provide a rationale for the routine HPV testing of small larynx lesions.
The Laryngoscope 08/2009; 119(8):1531-7. DOI:10.1002/lary.20509 · 2.14 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Imaging mass spectrometry is becoming a key technology for the investigation of the molecular content of biological tissue sections in direct correlation with the underlying histology. Much of our work has been done with fresh-frozen tissue sections that has undergone minimal protein degradation between the time a tissue biopsy is sampled and the time it is snap-frozen so that no preserving or fixing agents need to be added to the frozen biopsy. However, in many sampling environments, immediate flash freezing may not be possible and so we have explored the use of ethanol-preserved, paraffin-embedded tissue specimens for proteomic analyses. Solvent-only preserved tissue specimens provide long-term preservation at room temperature, generation of high quality histological sections and little if any chemical alteration of the proteins. Using mouse organs, several key steps involved in the tissue dehydration process have been investigated to assess the potential of such preserved specimens for profiling and imaging mass spectrometry investigations.
Journal of Proteome Research 08/2008; 7(8):3543-55. DOI:10.1021/pr800286z · 4.25 Impact Factor