PROJECT SUMMARY, Overall
The main goal of the Colorado (CO) Head and Neck Cancer (HNC) SPORE is to advance translational research
to improve survival and quality of life for HNC patients. Optimal treatment for HNC patients is critically important
because the head and neck organs support critical functions such as breathing, nourishing and communicating,
and thus HNC can lead to significant morbidity and mortality. The CO HNC SPORE takes advantage of our
expertise in basic and clinical sciences, and uses unique model systems to identify novel molecular and cellular
mechanisms of HNC pathogenesis targetable by therapeutic interventions to treat all cancer types arising from
head and neck anatomic sites. Three projects cover the treatment spectrum of head and neck squamous cell
carcinoma (HNSCC) and include both tobacco-related and human papillomavirus (HPV)-related HNSCC.
Project 1 studies novel immunotherapy mechanisms by inhibiting EphB4-EFNB2 interactions between immune
cells and the endothelium. It will test if blockade of EphB4-EFNB2 signaling at the tumor endothelial barrier
hinders Tregs' and TAMs' ability to infiltrate and promote cancer survival or suppress Teff function. The
applicability of pre-clinical data to clinic will be assessed in samples from HNSCC patients treated with an EphB4-
EFNB2 inhibitor during a window trial. Project 2 investigates if dual inhibition of TGFß/PD-L1 combined with
radiation therapy (RT) induces in situ vaccination, reverses immune suppression, and overcomes RT resistance.
It will translate its findings with a trial of the TGFß/PD-L1 dual inhibitor M7824 combined with RT in locally
recurrent and oligometastatic HNSCC patients. Project 3 will study mechanisms of protein elongation inhibition
in HNSCC, identifying key proteins targeted by the novel inhibitor SVC112 (a drug discovered in Colorado that
is nearing clinical testing), and translating our findings by testing the distribution and prognostic significance of
its target (eEF2) in patient samples. It will use immune relevant models including syngeneic and humanized mice
to study immune-dependent and –independent mechanisms of SVC112 and study if protein elongation inhibition
impacts the tumor microenvironment and enhances RT in HNSCC. The developmental research program (DRP)
is designed to attract current HNC researchers and researchers from other fields to conduct innovative research
in all types of cancers arising from head and neck tissues. The career enhancement program (CEP) is designed
to solicit junior researchers to develop research projects to transition into independent HNC researchers. We
encourage underrepresented minority (URM) and people with disabilities to apply for DRP and CEP projects.
The CO HNC SPORE also includes Biospecimen/Pathology, Data Science, and Administrative Cores. In
sum, the CO HNC SPORE will solidify in-depth HNC translational research and expand our team of dedicated
HNC researchers. These activities will improve the care spanning the entire spectrum of HNC treatment from
improving cures to developing innovative palliation strategies for HNC patients.