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Optimizing the Therapeutic Index for Medulloblastoma by Targeting Apoptosis- [electronic resource]
Optimizing the Therapeutic Index for Medulloblastoma by Targeting Apoptosis- [electronic resource]
상세정보
- 자료유형
- 학위논문파일 국외
- 최종처리일시
- 20240214101706
- ISBN
- 9798380848886
- DDC
- 574
- 서명/저자
- Optimizing the Therapeutic Index for Medulloblastoma by Targeting Apoptosis - [electronic resource]
- 발행사항
- [S.l.]: : Harvard University., 2023
- 발행사항
- Ann Arbor : : ProQuest Dissertations & Theses,, 2023
- 형태사항
- 1 online resource(123 p.)
- 주기사항
- Source: Dissertations Abstracts International, Volume: 85-05, Section: B.
- 주기사항
- Advisor: Sarosiek, Kristopher A.
- 학위논문주기
- Thesis (Ph.D.)--Harvard University, 2023.
- 사용제한주기
- This item must not be sold to any third party vendors.
- 초록/해제
- 요약Medulloblastoma (MB) is the most common central nervous system (CNS) malignancy affecting children, accounting for 20% of all childhood brain tumors. While current treatments, which include surgery, chemotherapy, and external beam radiation therapy, are effective at eliminating tumors in the majority of patients, there are long term consequences of these treatments. Namely, the use of ionizing radiation in the CNS of pediatric patients has been shown to lead to loss of cognitive function and neurodevelopmental delay, in addition to neurosensory impairment and pituitary-hypothalamic dysfunction. While there are multiple proposed mechanisms behind this radiation induced brain injury, the apoptotic death of healthy brains cells has been shown to be a large contributing factor. Previous studies have demonstrated that genetic knock out of BAX, a protein necessary for initiating mitochondrial apoptosis, protects neural cells from radiation induced apoptosis. However, clinically relevant pharmacological inhibitors of BAX have yet to be developed and are unlikely to be useful in this setting due to potential reductions in cure rates. We therefore sought alternative approaches to reducing BAX levels in healthy brain tissue. BAX expression in the immature brain is mediated by the growth-associated transcription factor MYC, which is also dysregulated in a majority of cancers and is a demonstrated driver of pediatric MB. We therefore hypothesized that targeting the transcription of BAX in young brain tissues by inhibiting the transcription factor MYC may protect healthy neural cells from ionizing radiation, while still eliminating MB cells.As such, BET inhibitors JQ1 and BMS-986158 were used to treat human MB cell lines, primary murine neural cells, and C57BL/6 mice (healthy and tumor bearing). The resulting effects in combination with ionizing radiation (from a Cs-137 source or from a constant voltage X-ray source) were assessed. We found that BET inhibition led to a decrease in BCL-XL in Group 3 MB cells, and a subsequent increase in dependence on MCL-1. On the other hand, we found that BET inhibition decreases apoptotic sensitivity of healthy neural cells by downregulating BAX and BAK. These divergent effects broadened the therapeutic window for radiation treatment, leading to increased loss of MB viability while protecting healthy neural cells from radiation induced apoptosis. Together, these data provide insight on the differing mechanistic effects of BET inhibition on cancerous MB cells and healthy brain cells, and the enhancement of the therapeutic window for treatment of pediatric patients diagnosed with medulloblastoma.
- 일반주제명
- Biology.
- 일반주제명
- Cellular biology.
- 일반주제명
- Neurosciences.
- 키워드
- Medulloblastoma
- 키워드
- Neural cells
- 키워드
- Brain tissue
- 키워드
- Brain cells
- 기타저자
- Harvard University Biological Sciences in Public Health
- 기본자료저록
- Dissertations Abstracts International. 85-05B.
- 기본자료저록
- Dissertation Abstract International
- 전자적 위치 및 접속
- 로그인 후 원문을 볼 수 있습니다.
MARC
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■00520240214101706
■006m o d
■007cr#unu||||||||
■020 ▼a9798380848886
■035 ▼a(MiAaPQ)AAI30636169
■040 ▼aMiAaPQ▼cMiAaPQ
■0820 ▼a574
■1001 ▼aYu, Stacey Jessica.▼0(orcid)0000-0001-5540-4027
■24510▼aOptimizing the Therapeutic Index for Medulloblastoma by Targeting Apoptosis▼h[electronic resource]
■260 ▼a[S.l.]:▼bHarvard University. ▼c2023
■260 1▼aAnn Arbor :▼bProQuest Dissertations & Theses, ▼c2023
■300 ▼a1 online resource(123 p.)
■500 ▼aSource: Dissertations Abstracts International, Volume: 85-05, Section: B.
■500 ▼aAdvisor: Sarosiek, Kristopher A.
■5021 ▼aThesis (Ph.D.)--Harvard University, 2023.
■506 ▼aThis item must not be sold to any third party vendors.
■520 ▼aMedulloblastoma (MB) is the most common central nervous system (CNS) malignancy affecting children, accounting for 20% of all childhood brain tumors. While current treatments, which include surgery, chemotherapy, and external beam radiation therapy, are effective at eliminating tumors in the majority of patients, there are long term consequences of these treatments. Namely, the use of ionizing radiation in the CNS of pediatric patients has been shown to lead to loss of cognitive function and neurodevelopmental delay, in addition to neurosensory impairment and pituitary-hypothalamic dysfunction. While there are multiple proposed mechanisms behind this radiation induced brain injury, the apoptotic death of healthy brains cells has been shown to be a large contributing factor. Previous studies have demonstrated that genetic knock out of BAX, a protein necessary for initiating mitochondrial apoptosis, protects neural cells from radiation induced apoptosis. However, clinically relevant pharmacological inhibitors of BAX have yet to be developed and are unlikely to be useful in this setting due to potential reductions in cure rates. We therefore sought alternative approaches to reducing BAX levels in healthy brain tissue. BAX expression in the immature brain is mediated by the growth-associated transcription factor MYC, which is also dysregulated in a majority of cancers and is a demonstrated driver of pediatric MB. We therefore hypothesized that targeting the transcription of BAX in young brain tissues by inhibiting the transcription factor MYC may protect healthy neural cells from ionizing radiation, while still eliminating MB cells.As such, BET inhibitors JQ1 and BMS-986158 were used to treat human MB cell lines, primary murine neural cells, and C57BL/6 mice (healthy and tumor bearing). The resulting effects in combination with ionizing radiation (from a Cs-137 source or from a constant voltage X-ray source) were assessed. We found that BET inhibition led to a decrease in BCL-XL in Group 3 MB cells, and a subsequent increase in dependence on MCL-1. On the other hand, we found that BET inhibition decreases apoptotic sensitivity of healthy neural cells by downregulating BAX and BAK. These divergent effects broadened the therapeutic window for radiation treatment, leading to increased loss of MB viability while protecting healthy neural cells from radiation induced apoptosis. Together, these data provide insight on the differing mechanistic effects of BET inhibition on cancerous MB cells and healthy brain cells, and the enhancement of the therapeutic window for treatment of pediatric patients diagnosed with medulloblastoma.
■590 ▼aSchool code: 0084.
■650 4▼aBiology.
■650 4▼aCellular biology.
■650 4▼aNeurosciences.
■653 ▼aMedulloblastoma
■653 ▼aNeural cells
■653 ▼aBrain tissue
■653 ▼aMitochondrial apoptosis
■653 ▼aBrain cells
■690 ▼a0306
■690 ▼a0379
■690 ▼a0317
■71020▼aHarvard University▼bBiological Sciences in Public Health.
■7730 ▼tDissertations Abstracts International▼g85-05B.
■773 ▼tDissertation Abstract International
■790 ▼a0084
■791 ▼aPh.D.
■792 ▼a2023
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T16934870▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
■980 ▼a202402▼f2024
