Addressing Thoracic Cancers: Biomarker and Pre-Clinical Drug Discovery in Non-Small Cell Lung Cancer and Thymic Carcinoma

Abstract

Thoracic cancer is a term that encompasses numerous malignancies within the thoracic cavity; the term includes malignancies such as lung cancers and thymic epithelial tumors. Lung cancers are the leading cause of cancer death in the United States and worldwide, resulting in the need for more effective therapeutics. Likewise, systemic treatments for thymic carcinoma, a type of thymic epithelial tumor, are not very effective. This dissertation will address the need for more effective therapeutics by investigating a potential mechanism of drug resistance in non-small cell lung carcinoma in the first chapter. In the second chapter, mesothelin will be investigated as a drug delivery target in thymic carcinoma.

Adenocarcinoma, which is the most common subtype of non-small cell lung cancer (NSCLC), often harbors oncogenic driver mutations in the epidermal growth factor receptor (EGFR). Osimertinib (AZD9291), a third generation EGFR tyrosine kinase inhibitor (TKI), has replaced earlier generation EGFR TKIs for the first-line treatment of EGFR mutant lung cancer. However, like earlier generation EGFR TKIs, not all patients respond, indicating an unknown mechanism of intrinsic resistance for the non-responders. It has been demonstrated that CRIPTO expression is a potential mechanism of intrinsic resistance to first and second generation EGFR TKIs. Therefore, we wanted to determine if CRIPTO could also promote drug resistance against third generation EGFR TKIs like osimertinib. We found that CRIPTO is unable to elicit resistance against third generation EGFR TKI osimertinib, despite previous research indicating CRIPTO’s role in resistance against earlier generation EGFR TKIs; however, we also found that CRIPTO is a potentially useful biomarker in tracking cancer progression in NSCLC patients.

Thymic epithelial tumors (TETs) are rare cancers with an incidence rate of 0.32 per 100,000 persons. Being a rare malignancy, the biology of these tumors is not well understood, and there are currently no FDA approved therapies. Of all TETs, thymic carcinoma is the most aggressive, with a 5-year survival rate of 30%, compared to 90% in thymomas. We investigated utilizing mesothelin (MSLN), a cell surface glycoprotein that is expressed in TETs but has limited expression elsewhere in the body, as a drug delivery target for thymic carcinoma. We found that anetumab ravtansine, an antibody drug conjugate, was able to bind and be internalized by MSLN expressing thymic carcinoma. We also found that anetumab ravtansine was effective at inhibiting mesothelin expressing thymic carcinoma in vitro and in vivo, despite our findings that MSLN increases drug resistance against cytotoxic therapies such as cisplatin.