The development of organ-conserving treatment for locally advanced head and neck cancers shiftedthe paradigm for treatment. A decade ago, we developed the strategy of selecting patients forchemoradiotherapy or for laryngectomy based on their response to a single cycle of chemotherapy. Thisapproach results in 3-year cause-specific survival and laryngeal preservation rates of 87% and 70%,respectively. However, chemoradiation is associated with an increased rate of mucositis and dysphagiacompared with radiotherapy alone. The long-term goal of this application is to preserve a high rate oflarynx preservation while decreasing the toxicity of treatment by using cetuximab-radiation insteadof chemoradiotherapy in patients selected to benefit from this approach. These goals will beachieved through 3 specific aims.
Specific Aim 1 is to decrease the toxicity of larynx-preservingtreatment by using cetuximab-radiation in place of chemoradiation in appropriately selected patients.
In Aim 1 A we propose to extend our current strategy in a phase II study of cetuximab-radiation for patientswho would previously have received chemoradiation: those responding to a cycle of chemotherapy.
In Aim1 B, we propose to assess tumor biopsies in the patients who respond to a cycle of chemotherapy and thenreceive cetuximab for markers of EGFR activation and downstream inhibition as possible predictors ofresponse to cetuximab-radiation.
Specific Aim 2 is to investigate the potential of established markers(Aim 2A) and to discover potential new biomarkers (Aim 2B) by assessment of phosphoproteome topredict response to cetuximab combined with radiation. Our preliminary data suggest that the extentand duration of decrease in the established markers like total EGFR, pEGFR, pSTATS, Bcl-XL, and Ki67correlate with response to the combination of EGFR inhibitors and radiation. In this aim, we propose toextend these studies to a total of 20 head and neck xenografts, 10 responsive and 10 non-responsive.
In Aim 2 B we will assess the effects of cetuximab-radiation on phosphoproteins using proteomic technology.Our preliminary data indicate that this is a promising method of identifying novel phosphoproteins that areaffected by cetuximab treatment.
Specific Aim 3 is to carry out preclinical studies to improve theefficacy of EGFR inhibition with radiochemotherapy.
In Aim 3 A, we focus on the potential importanceof schedule for combining EGFR inhibition with radiochemotherapy.
In Aim 3 B we will focus on a novelapproach toward targeting EGFR via HSP90 inhibition. Our preliminary data show that geldanamycin, aninhibitor of HSP90, accelerates the degradation of EGFR in cisplatin resistant cells, leading to both cellulartoxicity and radiosensitization. We feel our preclinical and clinical team with an extensive track record inthis field makes it likely that these studies will improve patient outcome.
Showing the most recent 10 out of 260 publications
