Development and Characterization of HPV-Positive and HPV-Negative Head and Neck Squamous Cell Carcinoma Tumorgrafts

Abstract

Purpose To develop a clinically relevant model system to study head and neck squamous cell carcinoma (HNSCC), we have established and characterized a direct-from-patient, tumorgraft model of Human Papillomavirus (HPV)-positive and HPV-negative cancers. Experimental Design Patients with newly diagnosed or recurrent HNSCC were consented for donation of tumor specimens. Surgically obtained tissue was implanted subcutaneously into immunodeficient mice. During subsequent passages, both formalin-fixed/paraffin embedded as well as flash frozen tissues were harvested. Tumors were analyzed for a variety of relevant tumor markers. Tumor growth rates and response to radiation, cisplatin, or cetuximab were assessed and early passage cell strains were developed for rapid testing of drug sensitivity. Results Tumorgrafts have been established in 22 of 26 patients to date. Significant diversity in tumorgraft tumor differentiation was observed with good agreement in degree of differentiation between patient tumor and tumorgraft (Kappa 0.72). Six tumorgrafts were HPV-positive on the basis of p16 staining. A strong inverse correlation between tumorgraft p16 and p53 or Rb was identified (Spearman correlations p=0.085 and p=0.002, respectively). Significant growth inhibition of representative tumorgrafts was demonstrated with cisplatin, cetuximab or radiation treatment delivered over a two-week period. Early passage cell strains showed high consistency in response to cancer therapy between tumorgraft and cell strain. Conclusions We have established a robust human tumorgraft model system for investigating HPV-positive and HPV-negative HNSCC. These tumorgrafts show strong correlation with the original tumor specimens and provide a powerful resource for investigating mechanisms of therapeutic response as well as preclinical testing.

Pan-HER Inhibitor Augments Radiation Response in Human Lung and Head and Neck Cancer Models

“…These data confirm the capacity of Pan-HER to overcome acquired resistance to cetuximab and radiation in similar fashion to that previously demonstrated in vitro. Finally, we examined the capacity of Pan-HER to augment the radiation response of xenografted tumors from a patient-derived human tumor using a previously described method (27). Remarkably, a single dose of Pan-HER demonstrated a profound capacity to sensitize cells to a single fraction of radiation (PX), resulting in a robust regrowth delay (>153 days to reach 500 mm 3 ) when compared with PBS-treated mice (50 days) and mice that were treated with either a single dose of Pan-HER (94 days) or a single fraction of radiation (95 days; P < 0.001; Fig.…”

Targeting the HER family with Pan-HER effectively overcomes resistance to cetuximab

“…Tumor volume measurements were evaluated by digital calipers and calculated by the formula (p)/6 x (large diameter) x (small diameter) 2 . The patient-derived xenograft (PDX) model was established as previously described (23).…”

In vitro3-dimensional tumor model for radiosensitivity of HPV positive OSCC cell lines

“…7,8 Various OSCC cell lines have been established but only a few HPV positive OSCC cell lines are available for in vitro study. [9][10][11] In this study, we established and characterized cell lines from the HPV positive OSCC of 2 patients. Corresponding HPV positive cell lines were subsequently generated from nodal metastases following xenografting of these cell lines into nude mice.…”