?A reasoned approach to combination therapy development in head and neck cancer? Clinical Context: More than 55,000 head and neck cancers were diagnosed in 2014, making it the seventh most-common solid tumor. Head and neck squamous cell carcinoma (HNSCC) is the most common histologic subtype, comprising approximately 90% of all cases. Treatment for HNSCC may include surgical resection, radiation therapy, chemotherapy, or a combination of these modalities. The preponderance of HNSCC mortality is due to locoregional recurrence in 20-40% of patients and 5-20% developing distant metastases at 2 years. Compared with similarly prevalent tumors, HNSCC has had relatively stagnant survival rates over the last twenty years. Cetuximab, a monoclonal antibody against endothelial growth factor receptor, is the only new agent to gain FDA approval for HNSCC in the last 10 years. Background: A specific, uncommon subpopulation of cancer stem-like cells (CSCs) in HNSCC tumors has been identified that are highly tumorigenic and have a propensity to migrate. Head and neck CSCs have been described as 1-10% of the cell population, and exhibit enhanced tumorigenicity and metastatic potential compared to non-CSCs. These cells are identified as having high expression of aldehyde dehydrogenase (ALDH) and the surface marker CD44 (ALDH+/CD44+). Recently published in-vivo experiments performed in our lab have shown that treatment with cisplatin induces phenotypic changes in HNSCC tumors including upregulation of stem-cell markers and an increasing fraction of CSCs. We have also generated preliminary data which suggests that tumor xenograft re-growth rates following treatment with cisplatin are no slower than the growth of untreated HNSCC tumors. Gene expression analysis we performed revealed that the IL6/STAT3 pathway was upregulated in head and neck cancer cells following cisplatin treatment. Project Approach: In order to determine the reproductive changes made to HNSCC cells by cisplatin, we will directly observe the offspring quantity and state of both CSC and bulk tumor cells. We will employ single-cell capture microfluidics culture devices which allow us to monitor the cellular division patterns of HNSCC cells and determine CSC status using live cell flourochrome staining for ALDH and CD44. We will confirm these findings in vivo, using a series of short studies to confirm in the proportion of CSCs, as well as STAT3 and IL6R changes following treatment. Next, we will attempt to interrupt the post-cisplatin treatment tumor growth by administering the FDA approved IL6 receptor inhibitor tocilizumab with cisplatin in a series of translational in vivo experiments. Finally, we will use the data we generate to refine a series of mathematical and statistical models. We have developed a computational sampling algorithm to determine how single cell observations predict shifts in the populations of cells within tumors. Preliminary work with this computational platform has shown excellent agreement with in-vitro and in-vivo cellular validation data sets (correlation coefficient r= 0.98, p<0.0001) at predicting the quantity of stem- and non-stem cells within a validation population. We plan to merge laboratory data with these novel quantitative approaches in order to predict an optimum dosing strategy for HNSCC treatment with cisplatin and tocilizumab. Training Plan: As a PhD trained theoretical statistician, my training plan and mentorship committee will focus on dramatically increasing my basic science skill set with the goal of translating my quantitative skills into bench science innovation. My specific training needs include a variety of bench science techniques as well as a select few advanced mathematical modeling techniques through mentorship with an applied mathematician.
A significant body of literature has recently emerged in a number of cancers including head and neck squamous cell carcinoma that detail phenotypic changes in carcinoma cells following exposure to chemotherapy. While both molecular pathway-level and tumor-level changes have been described, less data exist at the cellular level to link these findings. This project will employ single cell observations, laboratory studies, and mathematical modeling to characterize the chemotherapy related modifications of head and neck cancer stem-like cell phenotypes, and propose new therapeutic strategies to improve treatment.
| Nazari, Fereshteh; Pearson, Alexander T; Nör, Jacques Eduardo et al. (2018) A mathematical model for IL-6-mediated, stem cell driven tumor growth and targeted treatment. PLoS Comput Biol 14:e1005920 |
| Pearson, Alexander T; Ingram, Patrick; Bai, Shoumei et al. (2017) Sampling from single-cell observations to predict tumor cell growth in-vitro and in-vivo. Oncotarget 8:111176-111189 |
| Kerk, Samuel A; Finkel, Kelsey A; Pearson, Alexander T et al. (2017) 5T4-Targeted Therapy Ablates Cancer Stem Cells and Prevents Recurrence of Head and Neck Squamous Cell Carcinoma. Clin Cancer Res 23:2516-2527 |
| Nör, Felipe; Warner, Kristy A; Zhang, Zhaocheng et al. (2017) Therapeutic Inhibition of the MDM2-p53 Interaction Prevents Recurrence of Adenoid Cystic Carcinomas. Clin Cancer Res 23:1036-1048 |
| Bai, Shoumei; Ingram, Patrick; Chen, Yu-Chih et al. (2016) EGFL6 Regulates the Asymmetric Division, Maintenance, and Metastasis of ALDH+ Ovarian Cancer Cells. Cancer Res 76:6396-6409 |
