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Subcellular Localization of ErbB3/HE...

Jathal, Maitreyee Kiran.

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Subcellular Localization of ErbB3/HER3 and its Interactions with the Androgen Receptor In Prostate Cancer.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Subcellular Localization of ErbB3/HER3 and its Interactions with the Androgen Receptor In Prostate Cancer./
作者:	Jathal, Maitreyee Kiran.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2018,
面頁冊數:	178 p.
附註:	Source: Dissertations Abstracts International, Volume: 80-09, Section: B.
Contained By:	Dissertations Abstracts International80-09B.
標題:	Physiology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10981905
ISBN:	9780438930711

Subcellular Localization of ErbB3/HER3 and its Interactions with the Androgen Receptor In Prostate Cancer.
Jathal, Maitreyee Kiran.

Subcellular Localization of ErbB3/HER3 and its Interactions with the Androgen Receptor In Prostate Cancer. - Ann Arbor : ProQuest Dissertations & Theses, 2018 - 178 p.

Source: Dissertations Abstracts International, Volume: 80-09, Section: B.

Thesis (Ph.D.)--University of California, Davis, 2018.

This item must not be sold to any third party vendors.

Prostate cancer (PCa) is the most common type of cancer afflicting men in the Western world and a fast-emerging malignancy in developing nations. Most patients respond to treatment for localized PCa (surgery, radiation) but 15-30% of them experience tumor recurrence within 5 years. All prostate tumors initially rely on the androgen receptor (AR) for growth, so patients are treated by androgen withdrawal (AW) therapy, also known as chemical castration. AW is effective on an average for ~18-24 months, following which patients develop aggressive castration-resistant prostate cancer (CRPC). CRPC does not respond to AW and ultimately all patients succumb to this disease. While in androgen-dependent PCa, the AR is activated by ligand binding, in CRPC the AR is activated by various pathways that regulate AR transcriptional activity, including the receptor tyrosine kinases (RTKs) belonging to the epidermal growth factor (EGFR) family (EGFR, ErbB2, ErbB3 and ErbB4). These RTKs are activated by ligand-binding followed by dimerization with other RTKs of this family. Although prostate tumors express EGFR, ErbB2 and ErbB3 proteins (ErbB4 expression is lost in PCa and plays no known role in tumor progression), clinical trials with established EGFR and ErbB2 inhibitors were unsuccessful and this may be attributed to compensatory ErbB3 signaling. ErbB3 directly binds to the p85 regulatory subunit of PI3K which then activates the major pro-survival protein kinase B/Akt pathway. Akt itself has been reported to either stimulate or inhibit the AR, depending on whether the cells were androgen-dependent or castration-resistant. We have previously shown that ErbB3 signaling is most effectively prevented when EGFR and ErbB2 are inhibited concurrently - inhibiting only EGFR permits ErbB2/ErbB3 signaling while targeting only ErbB2 enables EGFR/ErbB3 activity - and that this 'dual-kinase inhibition' is potentiated in CRPC when it is coupled with AW therapy. Therefore, the overall goal of the proposed study is to determine the effects of ErbB3 regulation of the AR in conditions of androgen-dependence vs castration-resistance. At present, CRPC is fatal. The current standard-of-care is docetaxel-based chemotherapy followed by AR inhibitors abiraterone acetate or enzalutamide, which offers a survival benefit of ∼3-5 months each. Neither treatment results in permanent survival. A large number of clinical trials have been unsuccessful in identifying potential treatments to cure CRPC. We therefore believe it is extremely important to prevent the progression of prostate cancer to CRPC, rather than to attempt to cure CRPC after it has already developed. We will attempt to determine whether co-inhibition of ErbB3 and AR may potentially prolong the effectiveness of AR inhibitors in patients with prostate cancer. Our overall hypothesis is that ErbB3 and AR regulate each other, that inhibition of one upregulates the other, hence both receptors must be simultaneously inhibited to prevent PCa progression to CRPC.

ISBN: 9780438930711Subjects--Topical Terms:

518431
Physiology.

Subcellular Localization of ErbB3/HER3 and its Interactions with the Androgen Receptor In Prostate Cancer.
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