Over 50% of patients with advanced Oral cavity Squamous Cell Carcinomas (OSCCs) seen at major tertiary centers die within five years of diagnosis following relapse from frontline therapy. We believe that improvements to overall survival will be made by improving our ongoing precision medicine trials, in which the right therapies are given at the right time, but this requires a comprehensive understanding of molecular subsets of the disease. Despite the knowledge that has been gained from publicly available OSCC sequencing data and because of the diversity of drivers and lost suppressors, too few cases have been sequenced to molecularly stratify the disease on an integrated genomic and transcriptomic level. Importantly, several targeted therapies have been advanced for common molecular alterations including EGFR, FGFR1/3, PIK3CA, NOTCH, etc.; however, these often perform poorly as monotherapies due to innate genetic or compensatory resistance creating a strong need for rational combination therapy. In fact, various members of the NOTCH pathway are mutated in ~50% of all OSCCs, and while we and others have recently advanced WNT pathway inhibitors to clinical trials for this molecular subset, NOTCH-deficient tumors frequently harbor additional lesions that can confound the therapeutic benefits of targeted monotherapy. We have collected a unique set of surgically treated responsive and relapsed OSCC tumors, which we propose to study for the frequency of co-altered lesions using integrative genetic and transcriptomic sequencing. Through preliminary pooled CRISPR and small molecule screening of genetically defined OSCC cell line models, we will validate a strategy that defines targets for combination therapy. Further, we show preliminary results using surgically excised, ex vivo OSCC tissue as a model system to evaluate novel combination therapies. Leveraging these tools and techniques, we will test our central hypothesis that innate or compensatory pathways, which drive resistance to targeted monotherapies, can be identified through our integrative approach and exploited to develop effective combination protocols that overcome resistance. We will address this hypothesis with the following Aims: 1) Identify co-dependent molecular targets for combination therapy through integrative next generation sequencing in surgically non-responsive OSCC, 2) Define the combinations of genes and pathways pivotal for cell proliferation in OSCC cell lines using lentiviral CRISPR and small molecule libraries, 3) Develop combination treatment strategies for genetically defined OSCC using in vivo models. Our primary goal is to develop novel combination strategies to improve the survival of patients with OSCC through identification of co-dependent therapeutic targets.

Public Health Relevance

Oral cancers are a set of highly aggressive diseases with extremely poor 5-year overall survival rates, of which oral squamous cell carcinoma (OSCC) is the most common. The studies proposed in this application seek to logically discover and evaluate therapeutic strategies to disrupt co-dependent pathways in OSCC that can be immediately advanced to precision medicine trials. We will develop genetic and functional information to define the co-dependent pathways that drive both innate and compensatory resistance to targeted monotherapies and perform pre-clinical studies to immediately advance novel combination strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01DE025184-03
Application #
9271962
Study Section
Special Emphasis Panel (ZDE1)
Program Officer
Wang, Chiayeng
Project Start
2015-07-01
Project End
2019-04-30
Budget Start
2017-05-01
Budget End
2018-04-30
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Gingerich, Morgan A; Smith, Joshua D; Michmerhuizen, Nicole L et al. (2018) Comprehensive review of genetic factors contributing to head and neck squamous cell carcinoma development in low-risk, nontraditional patients. Head Neck 40:943-954
Hoesli, Rebecca; Birkeland, Andrew C; Rosko, Andrew J et al. (2018) Proportion of CD4 and CD8 tumor infiltrating lymphocytes predicts survival in persistent/recurrent laryngeal squamous cell carcinoma. Oral Oncol 77:83-89
Mann, Jacqueline E; Smith, Joshua D; Birkeland, Andrew C et al. (2018) Analysis of tumor-infiltrating CD103 resident memory T-cell content in recurrent laryngeal squamous cell carcinoma. Cancer Immunol Immunother :
VanKoevering, Kyle K; Marchiano, Emily; Walline, Heather M et al. (2018) An Algorithm to Evaluate Suspected Lung Metastases in Patients with HPV-Associated Oropharyngeal Cancer. Otolaryngol Head Neck Surg 158:118-121
Smith, Joshua; Kulkarni, Aditi; Birkeland, Andrew C et al. (2018) Whole-Exome Sequencing of Sinonasal Small Cell Carcinoma Arising within a Papillary Schneiderian Carcinoma In Situ. Otolaryngol Head Neck Surg 159:859-865
Ludwig, Megan L; Kulkarni, Aditi; Birkeland, Andrew C et al. (2018) The genomic landscape of UM-SCC oral cavity squamous cell carcinoma cell lines. Oral Oncol 87:144-151
Spector, Matthew E; Farlow, Janice L; Haring, Catherine T et al. (2018) The potential for liquid biopsies in head and neck cancer. Discov Med 25:251-257
Swiecicki, Paul L; Brennan, Julia R; Mierzwa, Michelle et al. (2018) Head and Neck Squamous Cell Carcinoma Detection and Surveillance: Advances of Liquid Biomarkers. Laryngoscope :
Hoesli, R C; Ludwig, M L; Michmerhuizen, N L et al. (2017) Genomic sequencing and precision medicine in head and neck cancers. Eur J Surg Oncol 43:884-892
Smith, Joshua D; Birkeland, Andrew C; Goldman, Edward B et al. (2017) Immortal Life of the Common Rule: Ethics, Consent, and the Future of Cancer Research. J Clin Oncol 35:1879-1883

Showing the most recent 10 out of 28 publications