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Circulating Lipid Profiles Associated With Resistance to Androgen Deprivation Therapy in Localized Prostate Cancer
Hui-Ming Lin1,2, Xiaoyu Yang3, Margaret M Centenera4,5
1Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
Purpose:
Intense androgen deprivation therapy (ADT) with androgen receptor pathway inhibitors (ARPIs) before radical prostatectomy (RP) produced favorable pathologic responses in approximately 20% of patients. The molecular reason for the low rate of response remains unclear. Lipid metabolism is known to influence androgen receptor signaling and ARPI efficacy. The aim of the study was to identify circulating lipid profiles associated with ADT/ARPI resistance in localized prostate cancer.
Materials And Methods:
Two independent experimental approaches were used. Experiment 1: Post hoc analysis of the association between plasma lipidomic profiles and ADT/ARPI response was performed on patients (n = 104) from two phase II trials of neoadjuvant ADT/ARPI. Response to ADT/ARPI was defined by pathologic response. Experiment 2: Patient-derived tumor explants from RP (n = 105) were cultured in enzalutamide for 48 hours. Explant response to enzalutamide was evaluated against pre-RP plasma lipidomic profiles (n = 105) and prostate tissue lipidomic profiles (n = 36). Response was defined by Ki67 (cell proliferation marker) fold difference between enzalutamide and vehicle-treated explants. In both experiments, associations between lipid profiles and ADT/ARPI response were analyzed by latent class analysis.
Results:
Pretreatment plasma lipid profiles classified each experimental cohort into two groups with differences in ADT/ARPI response rates. The response rates of the groups were 9.6% versus 29% in experiment 1 (chi-squared test P = .012) and 49% versus 70% in experiment 2 (chi-squared test P = .037). In both experiments, the group with a higher incidence of ADT/ARPI resistance had higher plasma levels of sphingomyelin, glycosylceramides, free fatty acids, acylcarnitines, cholesterol esters, and alkyl/alkenyl-phosphatidylcholine and lower plasma levels of triacylglycerols, diacylglycerols, and phosphoethanolamine (t-test P < .05).
Conclusion:
Pretreatment circulating lipid profiles are associated with ADT/ARPI resistance in localized cancer in both human cohorts and explant models.
Insights
Circulating lipid profiles before treatment can predict resistance to androgen deprivation therapy (ADT) and androgen receptor pathway inhibitors (ARPIs) in prostate cancer patients. Identifying these lipid profiles may improve treatment strategies for localized prostate cancer.
Area of Science:
- Oncology
- Metabolomics
- Prostate Cancer Research
Background:
- Androgen deprivation therapy (ADT) combined with androgen receptor pathway inhibitors (ARPIs) shows limited pathologic response rates (approx. 20%) in localized prostate cancer before surgery.
- The molecular mechanisms underlying resistance to ADT/ARPI remain largely unknown.
- Lipid metabolism is increasingly recognized for its role in modulating androgen receptor signaling and treatment efficacy.
Purpose of the Study:
- To identify specific circulating lipid profiles associated with resistance to ADT/ARPI in localized prostate cancer.
- To explore the relationship between lipid metabolism and treatment response in prostate cancer patients undergoing neoadjuvant ADT/ARPI therapy.
Main Methods:
- Two independent experiments were conducted using patient cohorts and patient-derived tumor explants.
- Experiment 1 involved post hoc analysis of plasma lipidomic profiles from 104 patients in phase II trials of neoadjuvant ADT/ARPI, correlating lipids with pathologic response.
- Experiment 2 analyzed lipidomic profiles from 105 patient-derived tumor explants treated with enzalutamide, comparing them with pre-treatment plasma and tissue lipid profiles from 105 and 36 patients, respectively, using Ki67 as a response marker.
Main Results:
- Pretreatment plasma lipid profiles stratified patients into distinct groups with significantly different ADT/ARPI response rates (Experiment 1: 9.6% vs. 29%, P=.012; Experiment 2: 49% vs. 70%, P=.037).
- Patients exhibiting higher resistance to ADT/ARPI showed elevated plasma levels of sphingomyelin, glycosylceramides, free fatty acids, acylcarnitines, cholesterol esters, and alkyl/alkenyl-phosphatidylcholine.
- Conversely, resistant groups displayed lower plasma levels of triacylglycerols, diacylglycerols, and phosphoethanolamine.
Conclusions:
- Pretreatment circulating lipid profiles are significantly associated with resistance to ADT/ARPI in localized prostate cancer.
- These findings were consistent across both human patient cohorts and in vitro tumor explant models.
- The study highlights the potential of lipidomic profiling for predicting treatment response and guiding therapeutic strategies in prostate cancer.
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