We study hormonal action in multiple tumor types; breast cancer, prostate cancer, endometrial cancer and lung cancer. Our ultimate goal is to better understand hormonal signaling and elucidate therapy resistance in cancer, contributing to personalized clinical decision-making, optimized treatment selection, identification of novel therapeutic options and minimized over-treatment. By enhancing our knowledge on steroid hormone receptor function in cancer and elucidating mechanisms of treatment resistance, our research will be instrumental to fully tailor endocrine treatment selection in the future, selecting the most-suitable therapy for the individual patient.
As hormone receptors are expressed in a wide spectrum of tumor types, we explored wider applicability of hormonal therapies beyond their regular use. We found expression of the glucocorticoid receptor (GR) is associated with favorable outcome in lung cancer patients, with activation of this receptor inducing cellular quiescence in a subset of lung cancer cell lines (Prekovic et al., submitted). By integrating functional genomic studies on GR activity, transcriptomics and CRISPR knockout methods, we identified GR-controlled CDKN1C expression as the key-driver to dictate drug response. A small compound screen revealed a novel drug-drug synergy between GR activation and IGF1R inhibition to eradicate lung cancer cells. In vivo studies are ongoing to explore the therapeutic potential of this novel drug-drug combination in lung cancer treatment.
Prostate cancer is the second-most prevalent malignancy in men, in which the Androgen Receptor (AR) is considered the sole-driving factor in cancer development and progression. In collaboration with the lab of Mathieu Lupien (Princess Margaret Cancer Centre, Toronto), we integrated AR chromatin interactome analyses in healthy prostate tissue and primary tumors with somatic mutation data and prostate cancer risk SNPs. Both somatic and germline variants were enriched in the tumor-specific AR DNA interactome, shared with other prostate cancer driving transcription factors, including FOXA1 and HOXB13. While most variants did not functionally alter AR activity, convergence of somatically acquired and germline risk factors was observed at specific enhancer elements that driver tumor progression (Mazzrooei et al., 2019). We are currently performing analogous studies in two Phase II clinical trials, in which patients receive AR-targeting Enzalutamide treatment in the neo-adjuvant (DARANA; Dynamics of Androgen Receptor Genomics and Transcriptomics After Neoadjuvant Androgen Ablation. NCT03297385. PI: Henk van der Poel) and metastatic (PRESTO; Predicting Response to Enzalutamide as a Second Line Treatment for Metastasized Castration Resistant Prostate Cancer Patients: a biomarker design study. PI: Andre Bergman) setting, aimed elucidate the cellular plasticity of AR function in prostate cancer and treatment resistance, and to better understand the impact of DNA mutations on transcriptional regulation in cancer.
A. GR expression is correlated with lung cancer patient outcome.
- GR activation induces cellular quiescence in vitro (left) and in vivo (right).
- Venn diagrams, illustrating shared and unique DNA binding sites for the three transcription factors in healthy prostate cancer versus primary tumors, in relation to H3K27ac signal.
- Mutation enrichment analyses for sites shared or unique between healthy and tumor prostate tissue. Shown is enrichment (y-axis) relative to the center of the motif (x-axis).