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Intrathecal AAV9.Trastuzumab Tumor Prophylaxis and Treatment in a Murine Xenograft Model of HER2+ Breast Cancer Brain Metastases / William Thomas Rothwell.
- Format:
- Book
- Thesis/Dissertation
- Author/Creator:
- Rothwell, William Thomas, author.
- Language:
- English
- Subjects (All):
- Cellular biology.
- Molecular biology.
- Oncology.
- Cell and Molecular Biology--Penn dissertations.
- Penn dissertations--Cell and Molecular Biology.
- Local Subjects:
- Cellular biology.
- Molecular biology.
- Oncology.
- Cell and Molecular Biology--Penn dissertations.
- Penn dissertations--Cell and Molecular Biology.
- Genre:
- Academic theses.
- Physical Description:
- 1 online resource (117 pages)
- Contained In:
- Dissertation Abstracts International 79-07B(E).
- Place of Publication:
- [Philadelphia, Pennsylvania]: University of Pennsylvania ; Ann Arbor : ProQuest Dissertations & Theses, 2017.
- Language Note:
- English
- System Details:
- Mode of access: World Wide Web.
- text file
- Summary:
- Breast cancer brain metastases (BCBM) are a deadly sequela of breast tumors that overexpress human epidermal growth factor receptor 2 (HER2). HER2+ BCBM affects approximately 17,000 women in the US every year. Median survival is 10-13 months from the time of diagnosis of central nervous system (CNS) disease. Current therapeutic interventions are invasive, toxic, and largely ineffective, leaving a clear, unmet need for targeted HER2+ BCBM treatments. Trastuzumab(HerceptinRTM) is a monoclonal antibody used to treat HER2+ breast cancer successfully, but systemic trastuzumab cannot bypass the blood-brain barrier (BBB). To solve this problem, we have developed an adeno-associated virus serotype 9 (AAV9) vector to express trastuzumab in vivo after a single intrathecal (IT) injection. IT vector administration in an orthotopic Rag1--/-- murine xenograft model of HER2+ BCBM led to a significant increase in median survival and attenuated brain tumor growth. We also report preservation of both the HER2 antigen specificity and the natural killer (NK) cell-associated mechanism of action of trastuzumab. Finally, we demonstrate increased median survival when IT AAV9.trastuzumab is administered as tumor treatment. Our results indicate that IT AAV9.trastuzumab may provide significant anti-tumor activity in patients with HER2+ BCBM.
- Notes:
- Source: Dissertation Abstracts International, Volume: 79-07(E), Section: B.
- Advisors: James M. Wilson; Lewis A. Chodosh; Committee members: Jose R. Conejo-Garcia; Chi V. Dang; Laura A. Johnson.
- Department: Cell and Molecular Biology.
- Ph.D. University of Pennsylvania 2017.
- Local Notes:
- School code: 0175
- ISBN:
- 9780355619836
- Access Restriction:
- Restricted for use by site license.
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