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Published on: September 8, 2017
IGF-1 axis changes with ADT and docetaxel in metastatic prostate cancer
Praful Ravi1, Victoria Wang2, Raina N Fichorova3
1Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Abstract:
Androgen deprivation therapy (ADT) forms the cornerstone of treatment in locally advanced and metastatic prostate cancer (PCa). Since the growth hormone-insulin-like growth factor (GH-IGF-1) axis has been implicated in prostate tumorigenesis, we aimed to evaluate the association between IGF-1 and its binding proteins on outcomes in men with metastatic PCa treated with ADT, with or without docetaxel (D). We analyzed serum samples for IGF-1 and its family proteins from baseline, 6 months post-randomization, and at the time of progression in men enrolled to receive ADT +/- D in the phase 3 CHAARTED trial. The key outcomes were time to the development of castrate-resistant prostate cancer and overall survival (OS). About 560 patients had samples available for analysis. At 6 months, significant increases in IGF-BP1 (mean Δ+27.4%, P = 0.033), IGF-BP3 (mean Δ+10.3%, P < 0.001), and IGF-BP4 (mean Δ+31.1%, P < 0.001) were seen in the ADT + D group, while the ADT group showed an increase in IGF-BP3 (mean Δ+5.5%, P = 0.015). A higher IGF-1:IGF-BP1 ratio at baseline and after 6 months was associated with improved OS in both the ADT (baseline: hazard ratio (HR) = 0.77, P = 0.026; 6 months: HR = 0.83, P = 0.036) and ADT + D groups (baseline: HR = 0.78, P = 0.04; 6 months: HR = 0.81, P = 0.018). Patients with a log10IGF-1:IGF-BP1 ratio >1.3 at baseline had improved OS when meta-analyzed with data from a prior cohort (HR = 0.71). A higher baseline and 6-month IGF-1:IGF-BP1 ratio was associated with better OS. Further exploration of the IGF-1 axis will be important to assess its role as a predictive biomarker and to target this axis in therapeutic trials.
Insights
A higher insulin-like growth factor-1 (IGF-1) to IGF binding protein 1 (IGF-BP1) ratio in men with metastatic prostate cancer treated with androgen deprivation therapy (ADT) correlates with improved overall survival (OS). This ratio may serve as a predictive biomarker for treatment outcomes.
Area of Science:
- Endocrinology
- Oncology
- Molecular Biology
Background:
- Androgen deprivation therapy (ADT) is a primary treatment for advanced prostate cancer (PCa).
- The growth hormone-insulin-like growth factor (GH-IGF-1) axis is implicated in prostate cancer development.
- The role of the GH-IGF-1 axis in treatment response for metastatic PCa is not fully understood.
Purpose of the Study:
- To investigate the association between insulin-like growth factor-1 (IGF-1) and its binding proteins with treatment outcomes in metastatic prostate cancer (PCa) patients receiving ADT.
- To evaluate the potential of the IGF-1 axis as a predictive biomarker for overall survival (OS) and time to castrate-resistant prostate cancer (CRPC).
Main Methods:
- Serum samples from 560 patients in the phase 3 CHAARTED trial (ADT +/- docetaxel) were analyzed for IGF-1 and IGF binding proteins (IGF-BP1, IGF-BP3, IGF-BP4) at baseline, 6 months, and progression.
- Statistical analysis assessed the relationship between IGF-1 axis proteins and key outcomes: time to CRPC and OS.
Main Results:
- Significant increases in IGF-BP1, IGF-BP3, and IGF-BP4 were observed at 6 months in the ADT + docetaxel group.
- A higher IGF-1:IGF-BP1 ratio at baseline and 6 months was significantly associated with improved OS in both ADT and ADT + docetaxel groups.
- Meta-analysis with prior data confirmed that a higher baseline IGF-1:IGF-BP1 ratio predicts improved OS.
Conclusions:
- The IGF-1:IGF-BP1 ratio shows promise as a predictive biomarker for overall survival in metastatic prostate cancer patients undergoing ADT.
- Further research into the IGF-1 axis is warranted to explore its therapeutic potential and role in predicting treatment response.
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