Daniel Johnson, PhD
Work in our lab employs multiple model systems to investigate the biology and therapy of head and neck squamous cell carcinoma (HNSCC), including isogenic cell lines, organoids, patient-derived xenograft tumors, genetically engineered mice, and primary patient specimens.
Our research is focused on understanding the molecular mechanisms that contribute to the origin and progression of HNSCC, and the development of novel therapeutic agents and strategies for this disease. We are particularly interested in combating the intrinsic and acquired resistance to anti-cancer agents that characterizes the majority of HNSCC patient tumors. Work from our lab has shown that overexpression of anti-apoptotic Bcl-2 family members and/or hyperactivation of STAT3 transcription factor contribute to HNSCC drug resistance. We have employed small molecule inhibitors of Bcl-2/Bcl-XL/Mcl-1, as well as proteasome inhibitors, to develop synergistic co-targeting strategies to overcome resistance arising for overexpression of Bcl-2 family members. To combat the effects of STAT3 hyperactivation, we co-invented an highly novel decoy oligonucleotide inhibitor for this previously undruggable oncogene. Current efforts are focused on moving the STAT3 decoy to clinical evaluation in patients with HNSCC. Additional studies in our lab have shown that mutations in caspase-8 protease, which occur frequently in HNSCC tumors, contribute to disease progression by abrogating cell death mediated by death ligands such as TRAIL and TNF. Ongoing studies are aimed at developing further in vivo and organoid models of HNSCC for investigation of drug resistance mechanisms and evaluation of novel precision medicine therapeutic strategies.
Current laboratory goals include:
- To determine the impact of STAT3 inhibition on HNSCC tumors and immune components in the tumor microenvironment.
- To determine the mechanistic impact of caspase-8 mutations in HNSCC.
- To determine the molecular mechanisms underlying the unique vulnerability of Fanconi Anemia patients to development of HNSCC.