Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.775309
Title: Identifying and targeting LIM-domain loss in clear cell renal cell carcinoma
Author: Smith, K. J.
Awarding Body: Queen Mary, University of London
Current Institution: Queen Mary, University of London
Date of Award: 2018
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Abstract:
Sequential use of targeted therapies has significantly improved overall survival in metastatic clear cell renal cell carcinoma (ccRCC) but durable responses remain rare. Improved prognostic and predictive algorithms are required. 3p loss is near ubiquitous in ccRCC. Functions of LIMD1 include regulation of hypoxia-inducible factors and microRNA-mediated gene silencing. LIMD1 loss/deregulation contributes to lung tumour formation and is associated with poor prognosis in breast cancer. The closely related family members, WTIP and Ajuba also regulate the hypoxic response and mediate micro-RNA silencing. Ajuba regulates the Hippo signaling pathway, controlling cell cycle and proliferation. In vivo, loss of LIMD1 was observed in 49% of ccRCC samples. 76% of ccRCC tumours demonstrated reduced Ajuba staining and nuclear WTIP staining was reduced in 73% of tumours compared to matched control. Co-loss of LIMD1/Ajuba/WTIP was common. Using patient-derived tumour tissue from two prospective clinical trials, LIMD1, Ajuba and WTIP staining was correlated with clinico-pathological outcome data. With the exception of loss of Ajuba staining and tumour stage, staining and outcome data did not correlate. The effects of LIMD1 loss on tumourigenesis were investigated using a paired lentiviral transduction system in ccRCC lines. LIMD1 loss did not affect cell migration, or cell cycle, however loss of LIMD1 was associated with greater hypoxic deregulation. A CRISPR-Cas-9 gene editing system was used to successfully knockout LIMD1 and Ajuba in a renal primary cell line. Using a drug-screening platform, the topoisomerase-I inhibitor irinotecan was identified as a potentially synthetically lethal drug in association with LIMD1 loss. This was validated in a further ccRCC line and in non-renal lines. Exploiting synthetic lethal approaches in ccRCC treatment has not been widely explored. Our data suggests that loss of LIMD1/Ajuba/WTIP is common and could represent a predictive biomarker such that tumours with loss/low expression could be selectively targeted.
Supervisor: Not available Sponsor: Cancer Research UK
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.775309  DOI: Not available
Keywords: LIM-domain loss ; Barts Cancer Institute ; clear cell renal cell carcinoma
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