Research
The Diab lab is a cancer biology research laboratory located at the Perelman School of Medicine of the University of Pennsylvania. We study the interplay between high-risk human papilloma viruses, the cell cycle machinery and the tumor microenvironment of head and neck cancer. Our approach is to employ whatever methods are needed to improve our mechanistic understanding of the underlying physiology and pathology. These methods have included biochemistry, live-cell imaging, single-cell transcriptomics, and a combination of human and murine models.
Our previous work has identified the cell cycle checkpoint kinase WEE1, as a candidate therapeutic target for HPV+ head and neck cancer treatment using the first-generation small molecule inhibitor AZD1775. We have defined some of the molecular determinants of AZD1775 sensitivity in HPV+ head and neck cancer. Ongoing work in the lab is exploring tumor-cell extrinsic pathways that sensitize HPV+ tumors to WEE1 inhibition using immunocompetent murine and human models.
HPV infection results in the production of strong viral antigens, which may induce de novo T cell responses and increase CD8 T cell infiltration. In the clinical setting, encouraging data suggest that HPV+ HNSCC patients have significantly improved outcomes with PD-1 pathway-targeting immune checkpoint inhibitor (ICI) therapy, compared to HPV- HNSCC patients. ICIs are currently approved for patients with recurrent/metastatic HNSCC, but the objective response rate is only 15-20%, regardless of HPV status. Since the therapeutic standard for patients who do not benefit from ICIs is not established, our goal is to develop novel immunomodulatory therapy combination regimens that can maximize the antitumor efficacy of cell cycle checkpoint targeting therapies.
There are no current therapies that specifically target HPV+ tumors, and standard multimodal therapies are often associated with severe side effects that that impact quality of life for patients. The TME of HPV+ HNSCC disease is most frequently modeled using the mEER cells, a syngeneic HPV+ HNSCC mouse transplant model derived by stable transduction of mouse tonsil epithelial cells (MTECs) with HPV16 E6 and E7, and hRasG12D . However, H-RAS mutations have not been reported in HPV+ HNSCC. Thus, additional models are needed to more faithfully recapitulate the unique pathobiology of HPV+ HNSCC. Our lab is working to bridge this gap by developing more faithful models of HPV+ head and neck cancer.