While mutations affecting protein-coding regions have been examined across many cancers, structural variants at the genome-wide level are still poorly defined. Through integrative deep whole-genome and -transcriptome analysis of 101 castration-resistant prostate cancer metastases (109X tumor/38X normal coverage), we identified structural variants altering critical regulators of tumorigenesis and progression not detectable by exome approaches.
Understanding the genomic landscape of aggressive prostate cancer
The Feng laboratory has performed a number of studies to discover genomic events that contribute to prostate cancer development and progression. We have performed landmark studies that have defined the genomic landscape of metastatic prostate cancer (Quigley et al, Cell 2018), and have identified that specific DNA repair alterations result in unique genomic scars and that structural variants play a major role in inactivating tumor suppressor genes and activating oncogenes such as the androgen receptor (AR). We have also interrogated the transcriptomes of thousands of localized prostate cancers to delineate the immune landscape (Zhao et al, JNCI 2012) and the non-coding landscape (Prensner et al, Lancet Oncology 2015) of this disease.
One of our goals is to develop biomarker tools to personalize patient care. In line with this goal, we have developed the first clinical-grade biomarker panels that predict response to hormone therapy (Zhao et al, JAMA Oncology 2017) and radiation therapy (Zhao et al, Lancet Oncology 2016). Additionally, we have interrogated circulating tumor DNA from patient blood samples to identify early determinants of resistance to PARP inhibitors (Quigley et al, Cancer Discovery 2017). The biomarkers that we have developed have been incorporated into a number of ongoing national clinical trials.
PCAT-1 expression leads to defective HR in prostate cells. A, left, expression level of PCAT-1 by quantitative PCR in three isogenic cell lines with overexpression (Du145, RWPE) or knockdown (LNCaP) of PCAT-1. B, expression of PCAT-1 and BRCA2 in a cohort of patients with prostate cancer. C, left, quantification of RAD51 foci in isogenic Du145 and LNCaP cell lines following 2 Gy of radiation or treatment with 25 μmol/L olaparib. D, I-SceI–mediated GFP HR assay in PC3-PCAT-1 cells compared with matched control cells. Error bars, SEM.
Functionally investigating molecular drivers of prostate cancer
One of our major research emphases is to understand how certain genomic or molecular aberrations drive aggressive prostate cancer. We have utilized our genomically-profiled clinical samples to identify driver kinases, such as DNA-dependent protein kinase (DNAPK). Previous studies performed with collaborators determined that DNAPK transcriptionally activates a number of oncogenic pathways resulting in metastases (Goodwin et al, Cancer Cell 2015). We also helped identify a positive-feedback loop between DNAPK and the androgen receptor (AR), which results in a hormone-driven circuit that repairs damage from genotoxic stress (Goodwin et al, Cancer Discovery 2013).
In addition to studying protein drivers of prostate cancer, we have also investigated the role of noncoding RNAs in prostate cancer progression. We have identified SChLAP1 as a noncoding gene that antagonizes the SWI/SNF complex to rewire the prostate cancer transcriptome towards a metastatic phenotype (Zhao et al, Lancet Oncology 2016; Prensner et al, Nature Genetics 2013). We also determined that PCAT1 mediates prostate carcinogenesis via a dual mechanism of downregulating BRCA2 (Prensner et al, Cancer Research 2011) and upregulating c-MYC (Prensner et al, Neoplasia 2014).
S9346 (INT- 0162) study schema. D2, metastatic; PSA, prostate-specific antigen; ADT, androgen-deprivation therapy.
Developing targeted therapy strategies for prostate cancer
We have partnered with a number of collaborators to develop new therapeutic strategies for advanced prostate cancer. Based on initial preclinical data demonstrating that the DNA repair enzyme PARP1 can serve as a transcriptional co-activator of androgen receptor (AR) and the ETS transcription factor ERG (Schiewer et al, Cancer Discovery 2012; Brenner et al, Cancer Cell 2011), we initiated one of the first biomarker-driven trials for patients with metastatic prostate cancer (Hussain et al, Journal of Clinical Oncology 2006); we also helped establish the relationship between DNA repair alterations and response to PARP inhibitors in prostate cancer patients (Mateo et al, New England Journal of Medicine 2015). Our laboratory studies identifying DNAPK as a driver of prostate cancer resulted in a first-in-patient study combining a DNAPK inhibitor with AR-directed therapy for patients with metastatic disease (Goodwin et al, Cancer Discovery 2013). In addition, we helped determine that the bromodomain protein BRD4 recruits AR to its target gene loci, and based on the preclinical efficacy of bromodomain inhibitors in prostate cancer models, we have initiated one of the first trials of bromodomain inhibition in prostate cancer patients.