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Targeting Fibronectin to Modulate the Breast Tumor Microenvironment: A Preclinical Evaluation of PEG-FUD as a Dual Imaging and Therapeutic Agent
Targeting Fibronectin to Modulate the Breast Tumor Microenvironment: A Preclinical Evaluation of PEG-FUD as a Dual Imaging and Therapeutic Agent
상세정보
- 자료유형
- 학위논문 서양
- 최종처리일시
- 20260202103628
- ISBN
- 9798315781202
- DDC
- 615
- 서명/저자
- Targeting Fibronectin to Modulate the Breast Tumor Microenvironment: A Preclinical Evaluation of PEG-FUD as a Dual Imaging and Therapeutic Agent
- 발행사항
- [Sl] : The University of Wisconsin - Madison, 2025
- 발행사항
- Ann Arbor : ProQuest Dissertations & Theses, 2025
- 형태사항
- 261 p
- 주기사항
- Source: Dissertations Abstracts International, Volume: 86-12, Section: B.
- 주기사항
- Advisor: Ponik, Suzanne.
- 학위논문주기
- Thesis (Ph.D.)--The University of Wisconsin - Madison, 2025.
- 초록/해제
- 요약In breast cancer (BC), the extracellular matrix (ECM) plays a central role in disease progression by regulating cell signaling pathways that promote proliferation, migration, and invasion. High ECM protein expression within tumors contributes to fibrosis and increased tissue stiffness, forming physical barriers that impede drug delivery and immune infiltration while enhancing tumor aggressiveness. Fibronectin (FN), a major scaffolding ECM protein, is a key driver of tumor fibrosis and ECM remodeling, facilitating tumor progression and resistance to therapy. Clinical studies have shown that FN is significantly upregulated in BC tissues compared to normal breast tissue, with elevated levels correlating with poor prognosis and increased mortality. Due to its abundant expression, FN serves as a promising biomarker for cancer imaging and therapy. However, efforts to target the ECM in BC have been limited by toxicity and poor specificity, and to date, no FDA-approved therapies directly target FN. To address this therapeutic gap, a FN-binding peptide derived from the F1 adhesin of Streptococcus pyogenes, known as PEGylated Functional Upstream Domain (PEG-FUD), was evaluated. PEG-FUD is a potent inhibitor of FN assembly that binds with high affinity to the 70 kDa N-terminal region of FN. The hypothesis is that PEG-FUD will localize to tumors, disrupt FN assembly, alter cell adhesion, and thereby suppress tumor growth. Additionally, PEG-FUD is expected to enhance chemotherapy response by modulating the tumor microenvironment. This thesis employed triple-negative BC models, namely 4T1 and E0771, due to the limited availability of targeted therapies for this aggressive and clinically challenging subtype. Multimodal imaging confirmed PEG-FUD accumulation in 4T1 mammary tumors in vivo. Therapeutic studies demonstrated that PEG-FUD treatment reduced tumor volume by approximately 30% in 4T1 tumors and up to 85% in E0771 tumors, with no detectable systemic toxicity. Mechanistic analysis revealed that PEG-FUD impaired FN signaling, disrupted cell adhesion, and promoted tumor cell death. Furthermore, PEG-FUD enhanced the anti-cancer efficacy of the standard-of-care chemotherapy drug, doxorubicin, when used in combination therapy. These findings establish PEG-FUD as both a targeted imaging and a therapeutic agent capable of modulating the tumor microenvironment. By overcoming FN-driven barriers, PEG-FUD demonstrates strong translational potential for improving outcomes in BC, other FN-enriched malignancies, and fibrotic diseases.
- 일반주제명
- Pharmacology
- 일반주제명
- Oncology
- 일반주제명
- Cellular biology
- 일반주제명
- Medical imaging
- 키워드
- Breast cancer
- 키워드
- Fibronectin
- 키워드
- Cancer imaging
- 키워드
- Therapy
- 기타저자
- The University of Wisconsin - Madison Molecular & Cellular Pharmacology
- 기본자료저록
- Dissertations Abstracts International. 86-12B.
- 전자적 위치 및 접속
- 로그인 후 원문을 볼 수 있습니다.
MARC
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■006m o d
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■020 ▼a9798315781202
■035 ▼a(MiAaPQ)AAI32046635
■040 ▼aMiAaPQ▼cMiAaPQ
■0820 ▼a615
■1001 ▼aGari, Metti Kefyalew.
■24510▼aTargeting Fibronectin to Modulate the Breast Tumor Microenvironment: A Preclinical Evaluation of PEG-FUD as a Dual Imaging and Therapeutic Agent
■260 ▼a[Sl]▼bThe University of Wisconsin - Madison▼c2025
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2025
■300 ▼a261 p
■500 ▼aSource: Dissertations Abstracts International, Volume: 86-12, Section: B.
■500 ▼aAdvisor: Ponik, Suzanne.
■5021 ▼aThesis (Ph.D.)--The University of Wisconsin - Madison, 2025.
■520 ▼aIn breast cancer (BC), the extracellular matrix (ECM) plays a central role in disease progression by regulating cell signaling pathways that promote proliferation, migration, and invasion. High ECM protein expression within tumors contributes to fibrosis and increased tissue stiffness, forming physical barriers that impede drug delivery and immune infiltration while enhancing tumor aggressiveness. Fibronectin (FN), a major scaffolding ECM protein, is a key driver of tumor fibrosis and ECM remodeling, facilitating tumor progression and resistance to therapy. Clinical studies have shown that FN is significantly upregulated in BC tissues compared to normal breast tissue, with elevated levels correlating with poor prognosis and increased mortality. Due to its abundant expression, FN serves as a promising biomarker for cancer imaging and therapy. However, efforts to target the ECM in BC have been limited by toxicity and poor specificity, and to date, no FDA-approved therapies directly target FN. To address this therapeutic gap, a FN-binding peptide derived from the F1 adhesin of Streptococcus pyogenes, known as PEGylated Functional Upstream Domain (PEG-FUD), was evaluated. PEG-FUD is a potent inhibitor of FN assembly that binds with high affinity to the 70 kDa N-terminal region of FN. The hypothesis is that PEG-FUD will localize to tumors, disrupt FN assembly, alter cell adhesion, and thereby suppress tumor growth. Additionally, PEG-FUD is expected to enhance chemotherapy response by modulating the tumor microenvironment. This thesis employed triple-negative BC models, namely 4T1 and E0771, due to the limited availability of targeted therapies for this aggressive and clinically challenging subtype. Multimodal imaging confirmed PEG-FUD accumulation in 4T1 mammary tumors in vivo. Therapeutic studies demonstrated that PEG-FUD treatment reduced tumor volume by approximately 30% in 4T1 tumors and up to 85% in E0771 tumors, with no detectable systemic toxicity. Mechanistic analysis revealed that PEG-FUD impaired FN signaling, disrupted cell adhesion, and promoted tumor cell death. Furthermore, PEG-FUD enhanced the anti-cancer efficacy of the standard-of-care chemotherapy drug, doxorubicin, when used in combination therapy. These findings establish PEG-FUD as both a targeted imaging and a therapeutic agent capable of modulating the tumor microenvironment. By overcoming FN-driven barriers, PEG-FUD demonstrates strong translational potential for improving outcomes in BC, other FN-enriched malignancies, and fibrotic diseases.
■590 ▼aSchool code: 0262.
■650 4▼aPharmacology
■650 4▼aOncology
■650 4▼aCellular biology
■650 4▼aMedical imaging
■653 ▼aBreast cancer
■653 ▼aFibronectin
■653 ▼aCancer imaging
■653 ▼aTherapy
■653 ▼aTumor microenviroment
■690 ▼a0419
■690 ▼a0992
■690 ▼a0379
■690 ▼a0574
■71020▼aThe University of Wisconsin - Madison▼bMolecular & Cellular Pharmacology.
■7730 ▼tDissertations Abstracts International▼g86-12B.
■790 ▼a0262
■791 ▼aPh.D.
■792 ▼a2025
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T17357996▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
