Targeting non-oncogene addiction in small cell lung cancer
Abstract/Contents
- Abstract
- Therapeutic strategies for cancers often revolve around targeting pathways downstream of an activated oncogene. This strategy has yielded life-saving, efficacious therapies, but focusing solely on this approach excludes patients with cancers which are not characterized by oncogene addiction pathways. Non-oncogene addiction (NOA) refers to the pathways upon which tumors are dependent for tumor maintenance and survival, but which are not necessary for tumor initiation. Here, we describe multiple NOA-based strategies to exploit pathway dependencies of small cell lung cancer (SCLC), the most aggressive type of lung cancer. SCLC is an aggressive neuroendocrine carcinoma which accounts for about 15 percent of all lung cancers, and has a dire diagnosis of a mere 5% 5-year survival. FDA-approved therapies for this disease are incredibly limited. Despite global sequencing efforts, few activating mutations have been discovered in SCLC tumors, and targetable alterations account for very small subsets of patients. Due to this lack of a strong oncogenic driver for conventional targeted therapy, SCLC has the potential to benefit from NOA-based therapeutic approaches. SCLC has a high mutational burden, which we hypothesized places stress on the tumor to evade the immune system as it progresses. Together with collaborators, we describe the efficacy of immunotherapy in SCLC via interruption of CD47 -- SIRPα binding, which increases macrophagemediated phagocytosis of tumor cells and in vivo tumor inhibition. We also describe a novel immune-competent system in which to investigate clinically relevant therapeutic strategies, including immunotherapies, for SCLC. Additionally, we hypothesized that SCLC is highly dependent on the G2-M cell cycle checkpoint for DNA damage repair signaling, since virtually all SCLC tumors lose TP53 and RB1, two significant mediators of the G1-S checkpoint. With collaborators, we investigated inhibition of the G2-M checkpoint regulator CHK1 in our endogenous SCLC mouse model and showed its stunning efficacy in reducing overall tumor burden. Finally, we focused on finding novel non-mutated targetable pathways SCLC. We elucidated the active kinome of SCLC and investigated the role of the MEK5-ERK5 kinase axis in SCLC. We found that reduction of this axis in both human and murine SCLC cells causes increased susceptibility to apoptosis and decreased subcutaneous tumor growth in vivo. Transcriptomic analysis of MEK5 and ERK5-knockdown cells showed downregulation of lipid metabolism pathways, and targeted lipidomics analyses of these same cells showed downregulated cholesteryl ester species. An HMG-CoA-Reductase inhibitor was efficacious in human SCLC cells, and knockdown of MEK5 and ERK5 in the most resistant cell line sensitized it to cholesterol synthesis inhibition. In these studies, we provide evidence of SCLC dependencies with potential to be become efficacious NOA-based therapeutic approaches for patients with this disease.
Description
Type of resource | text |
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Form | electronic resource; remote; computer; online resource |
Extent | 1 online resource. |
Place | California |
Place | [Stanford, California] |
Publisher | [Stanford University] |
Copyright date | 2018; ©2018 |
Publication date | 2018; 2018 |
Issuance | monographic |
Language | English |
Creators/Contributors
Author | Cristea, Sandra |
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Degree supervisor | Sage, Julien |
Thesis advisor | Sage, Julien |
Thesis advisor | Gozani, Or Pinchas |
Thesis advisor | Mallick, Parag, 1976- |
Thesis advisor | Winslow, Monte |
Degree committee member | Gozani, Or Pinchas |
Degree committee member | Mallick, Parag, 1976- |
Degree committee member | Winslow, Monte |
Associated with | Stanford University, Cancer Biology Program. |
Subjects
Genre | Theses |
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Genre | Text |
Bibliographic information
Statement of responsibility | Sandra Cristea. |
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Note | Submitted to the Cancer Biology Program. |
Thesis | Thesis Ph.D. Stanford University 2018. |
Location | electronic resource |
Access conditions
- Copyright
- © 2018 by Sandra Cristea
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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