Rewiring oncogenic signaling to therapeutic viral activation for treatment of metastatic cancer
Abstract/Contents
- Abstract
- Despite recent advances in cancer treatments, improvements to long-term survival in metastatic solid tumors, such as pancreatic or ovarian cancer, remain limited. Current medical therapies suppress growth-promoting biochemical signals or activate immune responses to tumor-associated antigens (TAAs). However, these approaches are limited by toxicity to normal cells that utilize the same signaling pathways or express the same antigens. Previously we developed a method for Rewiring Aberrant Signaling to Effector Release (RASER) to selectively redirect hyperactive ErbB signaling, found in many solid tumors but not normal tissues, to programmable responses. Here in my thesis, I report the engineering of viral vectors that express and are regulated by RASER, resulting in the selective ablation of cancer cells exhibiting hyperactive ErbB signaling. In mice, RASER-restricted vesicular stomatitis virus (VSV) exhibited 10000-fold less toxicity per dose than parental VSV, and 10-fold less than the attenuated VSV-∆M51 variant. RASER-restricted VSV conferred a larger survival benefit in non-immune mouse models of peritoneally disseminated ErbB-hyperactive pancreatic and ovarian cancers. Thus, RASER-restricted viral activation may represent a new approach for treating ErbB-hyperactive metastatic cancers that is independent of adaptive immunity. I also successfully extended the RASER concept to additional signals caused by oncogene mutations including hyperactive c-Met and KRAS and successfully developed Ad and VSV controlled by c-Met and KRAS RASER. With its generalizability and application in vivo, RASER controlled viruses will thus build a completely new type of cancer therapy, in which synthetic proteins are engineered to specifically identify and destroy cancer cells.
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource. |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2023; ©2023 |
| Publication date | 2023; 2023 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Zou, Xinzhi |
|---|---|
| Degree supervisor | Lin, Michael Z |
| Thesis advisor | Lin, Michael Z |
| Thesis advisor | Qi, Lei, (Professor of Bioengineering) |
| Thesis advisor | Wang, Bo, (Researcher in bioengineering) |
| Degree committee member | Qi, Lei, (Professor of Bioengineering) |
| Degree committee member | Wang, Bo, (Researcher in bioengineering) |
| Associated with | Stanford University, School of Engineering |
| Associated with | Stanford University, Department of Bioengineering |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Xinzhi Zou. |
|---|---|
| Note | Submitted to the Department of Bioengineering. |
| Thesis | Thesis Ph.D. Stanford University 2023. |
| Location | https://purl.stanford.edu/sw016fr9351 |
Access conditions
- Copyright
- © 2023 by Xinzhi Zou
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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