Dataset Information

IGF-1R associates with adverse outcomes after radical radiotherapy for prostate cancer.

ABSTRACT:

Background

Activated type 1 insulin-like growth factor receptors (IGF-1Rs) undergo internalisation and nuclear translocation, promoting cell survival. We previously reported that IGF-1R inhibition delays DNA damage repair, sensitising prostate cancer cells to ionising radiation. Here we tested the clinical relevance of these findings.

Methods

We assessed associations between IGF-1R and clinical outcomes by immunohistochemistry in diagnostic biopsies of 136 men treated with 55-70?Gy external beam radiotherapy for prostate cancer, comparing results with publicly available transcriptional data in surgically treated patients.

Results

Following radiotherapy, overall recurrence-free survival was shorter in patients whose tumours contained high total, cytoplasmic and internalised (nuclear/cytoplasmic) IGF-1R. High total IGF-1R associated with high primary Gleason grade and risk of metastasis, and cytoplasmic and internalised IGF-1R with biochemical recurrence, which includes patients experiencing local recurrence within the radiation field indicating radioresistance. In multivariate analysis, cytoplasmic, internalised and total IGF-1R were independently associated with risk of overall recurrence, and cytoplasmic IGF-1R was an independent predictor of biochemical recurrence post radiotherapy. Insulin-like growth factor receptors expression did not associate with biochemical recurrence after radical prostatectomy.

Conclusions

These data reveal increased risk of post-radiotherapy recurrence in men whose prostate cancers contain high levels of total or cytoplasmic IGF-1R.

SUBMITTER: Aleksic T

PROVIDER: S-EPMC5729437 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

IGF-1R associates with adverse outcomes after radical radiotherapy for prostate cancer.

Aleksic Tamara T Verrill Clare C Bryant Richard J RJ Han Cheng C Worrall Andrew Ross AR Brureau Laurent L Larré Stephane S Higgins Geoff S GS Fazal Fahad F Sabbagh Ahmad A Haider Syed S Buffa Francesca M FM Cole David D Macaulay Valentine M VM

British journal of cancer 20171003 11

<h4>Background</h4>Activated type 1 insulin-like growth factor receptors (IGF-1Rs) undergo internalisation and nuclear translocation, promoting cell survival. We previously reported that IGF-1R inhibition delays DNA damage repair, sensitising prostate cancer cells to ionising radiation. Here we tested the clinical relevance of these findings.<h4>Methods</h4>We assessed associations between IGF-1R and clinical outcomes by immunohistochemistry in diagnostic biopsies of 136 men treated with 55-70 G ...[more]

PMID: 28972962

Similar Datasets

Project description:BackgroundObservational data has indicated improved survival after radical prostatectomy (RP) compared with definitive radiotherapy (RT) in men with high-risk prostate cancer (PCa).ObjectiveTo compare PCa-specific mortality (PCSM) and overall mortality (OM) in men with high-risk PCa treated with RP or RT, providing information on target doses and fractionations.Design setting and participantsThis is an observational study from the Cancer Registry of Norway. Patients were diagnosed with high-risk PCa during 2006-2015, treated with RP ≤12 mo or RT ≤15 mo after diagnosis, and stratified according to RP or RT modality; external beam radiotherapy (EBRT; 70-<74, 74-<78, or 78 Gy), hypofractionated RT or EBRT combined with brachytherapy (BT-RT).Outcome measurements and statistical analysisCompeting risk and Kaplan-Meier methods estimated PCSM and OM, respectively. Multivariable Cox regression models evaluated hazard ratios (HRs) for PCSM and OM.Results and limitationsIn total, 9254 patients were included (RP 47%, RT 53%). RT patients were older, had poorer performance status and more unfavorable disease characteristics. With a median follow-up time of seven and eight yrs, the overall 10-yr PCSM was 7.2% (95% confidence interval [CI] 6.4-8.0) and OM was 22.9% (95% CI 21.8-24.1). Compared with RP, EBRT 70-<74 Gy was associated with increased (HR 1.88, 95% CI 1.33-2.65, p < 0.001) and BT-RT with decreased (HR 0.49, 95% CI 0.24-0.96, p = 0.039) 10-yr PCSM. Patients treated with EBRT 70-78 Gy had higher adjusted 10-yr OM than those treated with RP.ConclusionsIn men with high-risk PCa, treatment with EBRT <74 Gy was associated with increased adjusted 10-yr PCSM and OM, and BT-RT with decreased 10-yr PCSM, compared with RP.Patient summaryIn this study, we compared mortality after radical prostatectomy (RP) and radiotherapy (RT) in men with high-risk prostate cancer (PCa); the results suggest that men receiving lower-dose RT have higher, and patients receiving brachytherapy may have lower, risk of death from PCa than patients treated with prostatectomy.

Project description:The type I insulin-like growth factor-1 receptor is a well-described target in breast cancer and multiple clinical trials examining insulin-like growth factor-1 receptor have been completed. Unfortunately, monoclonal antibodies and tyrosine kinase inhibitors targeting insulin-like growth factor-1 receptor failed in phase III breast clinical trials for several reasons. First, insulin-like growth factor-1 receptor antibody therapy resulted in hyperglycemia and metabolic syndrome most likely due to disruption of insulin-like growth factor-1 homeostasis and subsequent growth hormone elevation. Growth hormone elevation induces insulin resistance, hence a subsequent elevation of insulin and the potential for activation of insulin receptor. Second, the insulin-like growth factor-1 receptor and insulin receptor are highly homologous in amino acid sequence, structure, and function. These two receptors bind insulin, insulin-like growth factor-1 and insulin-like growth factor-2, to regulate glucose uptake and other cellular functions. Hybrid receptors composed of one chain of insulin-like growth factor-1 receptor and insulin receptor also participate in signaling. Third, since all the monoclonal antibodies were specific for insulin-like growth factor-1 receptor, any pathophysiologic role for insulin receptor was not inhibited. While the insulin-like growth factor-1 receptor tyrosine kinase inhibitors effectively inhibited both insulin-like growth factor-1 receptor and insulin receptor, these drugs are not being further developed likely due to their metabolic toxicities. Insulin-like growth factor-1/2 neutralizing antibodies are still being studied in early phase clinical trials. Perhaps a more comprehensive strategy of targeting the insulin-like growth factor-1 receptor network would be successful. For example, targeting receptor, ligand and downstream signaling molecules such as phosphatidylinositol 3'-kinase or particularly the insulin receptor substrate adapter proteins might result in a complete blockade of insulin-like growth factor-1 receptor/insulin receptor biological functions.

Dataset Information

IGF-1R associates with adverse outcomes after radical radiotherapy for prostate cancer.

Background

Methods

Results

Conclusions

Publications

IGF-1R associates with adverse outcomes after radical radiotherapy for prostate cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets