ORCID ID

0000-0002-8128-613X

Graduation Date

Summer 8-13-2021

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Cancer Research

First Advisor

Dr. Ashley Wysong MD MS

Second Advisor

Dr. Justin Mott MD PhD

Abstract

Cutaneous squamous cell carcinoma (SCC) is the second most common skin cancer, affecting 1,000,000 people in the United States annually and causing approximately 9,000 deaths. SCC and basal cell carcinoma are the most common types of skin cancer arising in the superficial squamous cells or deeper basal cells of the epidermis, respectively. SCC is more likely to invade and metastasize, while basal cell cancer tends to grow locally. While the majority of cases of SCC are cured by surgery alone, approximately 2-5% of SCCs metastasize, at which point outcomes may be poor. Specific patient groups, particularly immunosuppressed patients, have a 60-250-times increased risk of SCC and an elevated risk of metastasis of up to 8%. There are also gene mutations known to affect SCC pathogenesis, however, less is known about the impact of mutations on metastasis.

Current staging systems for SCC include the Brigham and Women’s Hospital (BWH) system and the American Joint Committee on Cancer (AJCC) 8th edition staging systems. While these staging systems help to risk stratify patients, the sensitivity (proportion of positives correctly identified) of AJCC8 and BWH for patients who will experience nodal metastasis or disease-specific death is only 0.78 and 0.73, respectively, and the specificity (proportion of negatives correctly identified) of each is 0.85 and 0.93, respectively. With this knowledge, one aim of this project was to identify and quantify additional risk factors for SCC metastasis utilizing a large database of institutional data.

Treatment options for metastatic SCC are limited and often consist of excision followed by radiation and/or systemic therapy. Utilized systemic therapies include traditional cytotoxic chemotherapy, cetuximab (off-label), cemiplimab and pembrolizumab. However, overall response rates (ORRs) are currently low (34-78%). Therefore, additional therapeutic targets are needed to expand and improve treatment options. To identify additional therapeutic targets, next-generation sequencing was performed on a cohort of localized primary SCCs (n=10), metastatic primary SCCs (n=10), and matched nodal metastases from SCC (n=10). The localized primary SCCs were obtained from 10 unique patients and the metastatic primary SCCs and nodal metastases were obtained from an additional 10 unique patients, with each patient providing a primary tumor and metastatic sample, allowing for sample matching by patient. In addition to identifying actionable somatic mutations to further investigate, analyses of germline polymorphisms and mutational patterns in subsets of patient groups were performed.

To validate findings from the sequencing data, a comprehensive literature search was completed for all manuscripts that performed next-generation sequencing in SCC and had patient-level mutational data available. The data generated were used to confirm our previous findings and to identify additional mutational targets in SCC. For a two-tiered approach to identifying actionable targets, a literature review was performed to identify immunohistochemistry studies that found proteins that are differentially expressed in metastatic and localized SCC. Combining all approaches led to the investigation of ALK and LRP1B in the laboratory, where these findings were validated and explored further. Notably, we identified a new therapeutic target, ALK, explored the mechanism by which it promotes SCC progression, and identified ceritinib, a commercially available molecular inhibitor, as a possible therapy for ALK-mutated SCC.

Download

Included in

Dermatology Commons

Share

COinS