소장자료
LDR | 03629nam 2200505 4500 | ||
001 | 0100800564▲ | ||
005 | 20240322141250▲ | ||
006 | m o d ▲ | ||
007 | cr#unu||||||||▲ | ||
008 | 240116s2023 us |||||||||||||||c||eng d▲ | ||
020 | ▼a9798379951993▲ | ||
035 | ▼a(MiAaPQ)AAI30567684▲ | ||
040 | ▼aMiAaPQ▼cMiAaPQ▲ | ||
082 | 0 | ▼a615▲ | |
100 | 1 | ▼aWhite, Ralph Edward, III.▲ | |
245 | 1 | 0 | ▼aSaracatinib Synergizes With Enzalutamide in Castration-Resistant Prostate Cancer▼h[electronic resource]▲ |
260 | ▼a[S.l.]: ▼bUniversity of Minnesota. ▼c2023▲ | ||
260 | 1 | ▼aAnn Arbor : ▼bProQuest Dissertations & Theses, ▼c2023▲ | |
300 | ▼a1 online resource(121 p.)▲ | ||
500 | ▼aSource: Dissertations Abstracts International, Volume: 85-01, Section: B.▲ | ||
500 | ▼aAdvisor: Drake, Justin M.▲ | ||
502 | 1 | ▼aThesis (Ph.D.)--University of Minnesota, 2023.▲ | |
506 | ▼aThis item must not be sold to any third party vendors.▲ | ||
520 | ▼aProstate cancer (PCa) remains the most diagnosed non-skin cancer amongst the American male population. Treatment for localized prostate cancer consists of androgen deprivation therapies (ADTs), which typically inhibit androgen production and the androgen receptor (AR). Though initially effective, a subset of patients will develop resistance to ADTs and the tumors will transition to castration-resistant prostate cancer (CRPC). Second generation hormonal therapies such as abiraterone acetate and particularly enzalutamide, which inhibits AR full-length (AR-FL), are typically given to men with CRPC. However, these treatments are not curative and typically prolong survival only by a few months. Several resistance mechanisms contribute to this lack of efficacy such as the emergence of AR mutations, AR amplification, lineage plasticity, AR splice variants (AR-Vs) and increased kinase signaling. Having identified SRC kinase as a key tyrosine kinase enriched in CRPC patient tumors from our previous work, we evaluated whether inhibition of SRC kinase synergizes with enzalutamide or chemotherapy in several prostate cancer cell lines expressing variable AR isoforms. We observed robust synergy between the SRC kinase inhibitor, saracatinib, and enzalutamide, in the AR-FL+/AR-V+ CRPC cell lines, LNCaP95 and 22Rv1. We also observed that saracatinib significantly decreased AR Y534 phosphorylation, a key SRC kinase substrate residue, on AR-FL and AR-Vs, along with the AR regulome, supporting key mechanisms of synergy with enzalutamide. Lastly, we also found that the saracatinib-enzalutamide combination reduced DNA replication compared to the saracatinib-docetaxel combination, resulting in marked increased apoptosis. By elucidating this combination strategy, we provide pre-clinical data that suggests combining SRC kinase inhibitors with enzalutamide in select patients that express both AR-FL and AR-Vs.▲ | ||
590 | ▼aSchool code: 0130.▲ | ||
650 | 4 | ▼aPharmacology.▲ | |
650 | 4 | ▼aMolecular biology.▲ | |
650 | 4 | ▼aBiochemistry.▲ | |
653 | ▼aProstate cancer▲ | ||
653 | ▼aAndrogen deprivation therapies▲ | ||
653 | ▼aSRC kinase▲ | ||
653 | ▼aTumors▲ | ||
653 | ▼aHormonal therapies▲ | ||
690 | ▼a0419▲ | ||
690 | ▼a0487▲ | ||
690 | ▼a0307▲ | ||
710 | 2 | 0 | ▼aUniversity of Minnesota.▼bPharmacology.▲ |
773 | 0 | ▼tDissertations Abstracts International▼g85-01B.▲ | |
773 | ▼tDissertation Abstract International▲ | ||
790 | ▼a0130▲ | ||
791 | ▼aPh.D.▲ | ||
792 | ▼a2023▲ | ||
793 | ▼aEnglish▲ | ||
856 | 4 | 0 | ▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T16933926▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.▲ |
Saracatinib Synergizes With Enzalutamide in Castration-Resistant Prostate Cancer[electronic resource]
자료유형
국외eBook
서명/책임사항
Saracatinib Synergizes With Enzalutamide in Castration-Resistant Prostate Cancer [electronic resource]
발행사항
[S.l.] : University of Minnesota. 2023 Ann Arbor : ProQuest Dissertations & Theses , 2023
형태사항
1 online resource(121 p.)
일반주기
Source: Dissertations Abstracts International, Volume: 85-01, Section: B.
Advisor: Drake, Justin M.
Advisor: Drake, Justin M.
학위논문주기
Thesis (Ph.D.)--University of Minnesota, 2023.
요약주기
Prostate cancer (PCa) remains the most diagnosed non-skin cancer amongst the American male population. Treatment for localized prostate cancer consists of androgen deprivation therapies (ADTs), which typically inhibit androgen production and the androgen receptor (AR). Though initially effective, a subset of patients will develop resistance to ADTs and the tumors will transition to castration-resistant prostate cancer (CRPC). Second generation hormonal therapies such as abiraterone acetate and particularly enzalutamide, which inhibits AR full-length (AR-FL), are typically given to men with CRPC. However, these treatments are not curative and typically prolong survival only by a few months. Several resistance mechanisms contribute to this lack of efficacy such as the emergence of AR mutations, AR amplification, lineage plasticity, AR splice variants (AR-Vs) and increased kinase signaling. Having identified SRC kinase as a key tyrosine kinase enriched in CRPC patient tumors from our previous work, we evaluated whether inhibition of SRC kinase synergizes with enzalutamide or chemotherapy in several prostate cancer cell lines expressing variable AR isoforms. We observed robust synergy between the SRC kinase inhibitor, saracatinib, and enzalutamide, in the AR-FL+/AR-V+ CRPC cell lines, LNCaP95 and 22Rv1. We also observed that saracatinib significantly decreased AR Y534 phosphorylation, a key SRC kinase substrate residue, on AR-FL and AR-Vs, along with the AR regulome, supporting key mechanisms of synergy with enzalutamide. Lastly, we also found that the saracatinib-enzalutamide combination reduced DNA replication compared to the saracatinib-docetaxel combination, resulting in marked increased apoptosis. By elucidating this combination strategy, we provide pre-clinical data that suggests combining SRC kinase inhibitors with enzalutamide in select patients that express both AR-FL and AR-Vs.
주제
ISBN
9798379951993
관련 인기대출 도서