The Faye Johnson Laboratory currently has two main projects:
1. Head and neck squamous cell carcinoma (HNSCC) is driven largely by the loss of tumor suppressor genes, including NOTCH1, but lacks a biomarker-driven targeted therapy. Molecular therapies targeting activated oncogenes are common, but rare for cancers driven by the loss of tumor suppressor function. We demonstrated that PI3K inhibition led to apoptosis selectively in NOTCH1 mutant HNSCC cell lines in vitro and in vivo. Our further mechanistic work defined a novel pathway in which Aurora B regulates total AKT levels that subsequently regulate PDK1 selectively in NOTCH1 mutant HNSCC, where these proteins mediate survival in response to PI3K inhibition. These findings may lead to an effective therapeutic approach for NOTCH1 mutant HNSCC while sparing normal cells that lack NOTCH1 mutations. This is the first study to establish a therapeutic vulnerability of NOTCH1-mutant HNSCC to any class of drugs. This R01-funded research led to a clinical trial testing a PI3K/mTOR inhibitor in NOTCH1-mutant HNSCC (NCT03740100).
2. Human papillomavirus (HPV) causes >5% of cancers but no therapies uniquely target HPV-driven cancers. To address the lack of effective molecularly targeted therapies for HNSCC, my laboratory used an unbiased pharmacogenomics approach to integrate drug sensitivity data in molecularly characterized HPV-positive and HPV-negative human squamous cancer cell lines. Aurora kinase inhibitors were more effective in vitro and in vivo in HPV-positive than in HPV-negative models. We defined a novel pathway in which HPV-positive cancer cells maintain a balance of the mitotic checkpoint gene MAD2L1 and its regulator TRIP13 to allow mitotic exit and survival in the absence of retinoblastoma (RB) protein expression. Because it does not affect cells with intact RB function, this novel combination may have a wide therapeutic window, enabling the effective treatment of RB-deficient cancers. Additionally, Aurora kinase in HPV+ cancers leads to immunogenic cell death. These findings are the basis for an R01 and my investigator-initiated clinical trial (NCT04555837) combining the inhibition of Aurora A (alisertib) and PD1 (pembrolizumab).