Date of Award

2013

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Molecular Biology

Abstract

Lung cancer is the leading cause of cancer death in the U.S. and worldwide. The most frequent type of lung cancer is non-small cell lung cancer (NSCLC). NSCLC is mostly diagnosed at advanced stages (stage IIIB 18% of cases, stage IV 40% of cases) due to the lack of effective early detection methods. Thus, the discovery of alternative therapeutic strategies is of extreme importance.

Others and we have previously found that Notch signaling plays a crucial role in NSCLC. Our preliminary results indicate that Notch-1 provides necessary survival signals to NSCLC cells by positively regulating IGF-1R to activate the Akt-1 pathway. Therefore, the overall hypothesis is that an inhibitor of Notch activation, such as γ-secretase inhibitor (GSI) MRK-003; or a fully humanized antibody against the human IGF-1R that promotes the receptor degradation (IGF-1R inhibitory antibody) MK-0646; or a pan-Akt inhibitor MK-2206, alone or in combinations, could improve the efficacy of chemotherapy for advanced NSCLC by specifically targeting hypoxic NSCLC tumor environment. We tested this hypothesis in mouse preclinical models of orthotopic, advanced (metastatic) NSCLC. Our results indicate that all treatments (with the exception of MK-2206, which caused lethal glucose intolerance), significantly improved the survival of mice compared to controls. The expression levels of hypoxic markers were reduced in GSI treated mice lungs, indicating that GSI treatment caused specific cell death of hypoxic tumor areas. GSI treatment also significantly reduced cancer metastasis to the liver and brain. We found that tumor evasion from MK-0646 treatment was mediated by over-activated epidermal growth EGF-R signaling pathway. Of relevance, the sensitivity of NSCLC cells to erlotinib (EGF-R inhibitor) was increased after MK-0646 treatment. Sequential therapy of MK-0646 followed by erlotinib significantly prolonged survival of the mice compared to each single agent or simultaneous administration of two drugs.

Together, these data indicate: Notch inhibition seems to specifically target tumor hypoxic regions and to significantly inhibit tumor metastasis. We also found serendipitously that the administration of IGF-1R inhibitory antibody sensitizes NSCLC to erlotinib, a second-line therapeutic agent whose sensitivity is difficult to predict, with the notable exception of NSCLC with activating mutations in the EGF-R itself.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.

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