The Vanderbilt University
Grant: $397,820 - National Institutes of Health - Sep. 29, 2009
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Award Description: Head and neck squamous cell carcinoma (HNSCC) is a devastating disease that is treated aggressively when diagnosed at late stages. Treatment includes at least two and at times all three modalities of surgery, radiation, and chemotherapy. Due to the critical role of structures of the upper aerodigestive tract in speech and swallowing and due to the concentration of cranial nerves and major blood vessels in the neck, standard therapeutic modalities frequently result in unacceptable morbidity including speech and swallowing defects, shoulder dysfunction, accelerated arteriosclerosis of the carotid, xerostomia, trismus, lymphedema and neck muscle fibrosis. Targeted agents and individualized medicine hold the promise of increasing response rates while decreasing treatment related morbidity; however, standard clinical trials to test targeted agents on HNSCC are inadequate for detecting agents that may be effective, especially if efficacy is limited to a small percentage of patients. The expense of clinical trials, the limited number of HNSCC patients eligible, and the expected moderate to low response rate for targeted agents suggest that development of new tools for pre-clinical testing to identify molecular characteristics within tumors that predict response would be useful. We are developing techniques to reliably create a low cost and tractable human-in-mouse model of primary HNSCC that is based on short-term culture (1-5 days) followed by implantation into mice. One advantage of this model is that primary tumors are the source of the cancer cells and since the current success rate with this atypical xenograft model is ~75%, the genetic diversity of HNSCC is likely to be represented. Another advantage is that before modeling, tumors can be engineered to express luciferase so that tumor growth and response can be easily monitored without animal sacrifice. The purpose of the proposed studies is to continue development of this in vivo cancer model that holds the promise to increase the efficiency and decrease the cost of drug development for HNSCC. We will model tissue obtained through an inter-SPORE clinical trial designed to determine molecular characteristics of tumors in response to EGFR inhibitors, src inhibitors, or the combination of EGFR and src inhibitors. Mice harboring modeled tumors will be treated with identical drugs as patients from which the modeled tumors were derived. Molecular characteristics of untreated patient tumors will be compared to derivative modeled tumors with the expectation that the modeled tumors will most closely resemble the parent tumor from which they were derived. The clinical trial is powered to detect molecular alterations associated with EGFR or src inhibition. Modeled tumors will be investigated to determine if they have molecular alterations in response to treatment with identical agents that reflect response of the parent tumors. Validation that molecular and response characteristics of the modeled tumors resemble those of the parent tumor is the next and critical step in development of this model. Once validated, the human-in-mouse model of primary HNSCC will be the most accurate in-vivo model of HNSCC and can be used in a pre-clinical setting to predict response to individual or combinations of targeted therapy. Characteristics of responding tumors from the human-in-mouse model could then be used to inform clinical trials so that patients with tumors most likely to respond would be enrolled. Development of Improved animal models of human cancer that can accurately guide clinical trial patient selection would decrease the abysmal failure rate for investigational cancer therapeutics due to low or no response in clinical trials. We anticipate that this model could be easily expanded to other squamous cancers such as lung, esophagus, and uterine cervix.
Project Description: Head and neck squamous cell carcinoma (HNSCC) is a devastating disease that is treated aggressively when diagnosed at late stages. Treatment includes at least two and at times all three modalities of surgery, radiation, and chemotherapy. The purpose of the proposed studies is to continue development of this in vivo cancer model that holds the promise to increase the efficiency and decrease the cost of drug development for HNSCC. We will model tissue obtained through an inter-SPORE clinical trial designed to determine molecular characteristics of tumors in response to EGFR inhibitors, src inhibitors, or the combination of EGFR and src inhibitors. Mice harboring modeled tumors will be treated with identical drugs as patients from which the modeled tumors were derived. Molecular characteristics of untreated patient tumors will be compared to derivative modeled tumors with the expectation that the modeled tumors will most closely resemble the parent tumor from which they were derived. The clinical trial is powered to detect molecular alterations associated with EGFR or src inhibition. Modeled tumors will be investigated to determine if they have molecular alterations in response to treatment with identical agents that reflect response of the parent tumors. Validation that molecular and response characteristics of the modeled tumors resemble those of the parent tumor is the next and critical step in development of this model. Once validated, the human-in-mouse model of primary HNSCC will be the most accurate in-vivo model of HNSCC and can be used in a pre-clinical setting to predict response to individual or combinations of targeted therapy. Characteristics of responding tumors from the human-in-mouse model could then be used to inform clinical trials so that patients with tumors most likely to respond would be enrolled.
Jobs Summary: Not Applicable at this time. (Total jobs reported: 0)
Project Status: Not Started
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