Predictive biomarkers

Treatment decisions for cancer have historically been based on tissue of origin and other pathologic and clinical variables which give prognostic information on the overall level of aggressiveness of a tumor. Predictive biomarkers on the other hand are used to predict response to specific treatments, rather than overall prognosis. For example, we have developed the prostate cancer radiation therapy outcomes score (PORTOS) which has been validated in multiple randomized clinical trials (e.g. SAKK 09/10, NRG/RTOG 0126). Likewise, we characterized luminal and basal subtypes of prostate cancer, which have similarly been investigated in randomized clinical trials (e.g. ENACT, CHAARTED). Our laboratory seeks to leverage advances in molecular medicine to identify new predictive biomarkers for standard and emerging cancer therapies.

• SG Zhao^*, SL Chang^*, …, PL Nguyen^†, FY Feng^†.The development and validation of a 24-gene predictor of response to post-operative radiation therapy in prostate cancer: a matched retrospective analysis. Lancet Oncology. PMID 27743920.
• A Dal Pra*, P Ghadjar*, …, PT Tran^†, SG Zhao^†. Predicting dose-response to radiotherapy: a radiation signature in the randomized phase III NRG/RTOG 0126 and SAKK 09/10 trials. Annals of Oncology. PMID 39986927.
• SG Zhao^*, SL Chang^*, …, DE Spratt^†, FY Feng^†. Associations of luminal and basal subtyping of prostate cancer with prognosis and response to androgen deprivation therapy. JAMA Oncology. PMID 28494073.
• R Aggarwal*, NR Rydzewski*, …, EJ Small^†, FY Feng^†, SG Zhao^†. Prognosis associated with luminal and basal subtypes of metastatic prostate cancer. JAMA Oncology. PMID 34554200.
• SG Zhao, …, DR Wahl. Development and validation of xenograft-based platform-independent gene signatures that predict response to alkylating chemotherapy, radiation, and combination therapy in patients with glioblastoma. Neuro-Oncology. PMID 31121035.
• NM White^*, SG Zhao^*, …, CA Maher. Multi-institutional analysis shows low PCAT-14 expression associates with poor outcome in prostate cancer. European Urology. PMID 27460352.

Multi-omic discovery

Integrated multi-omic next-generation sequencing (NGS) on clinical samples allows for a global view of the landscape of molecular alterations that drive cancer progression and treatment resistance. Our lab analyzes DNA, RNA, and epigenetic sequencing data from clinical cohorts and trials to better understand the molecular underpinnings of the phenotypic behavior of tumors.

• SG Zhao^*, M Bootsma^*, S Zhou^*, …, D Quigley^†, M Lupien^†, FY Feng^†. Interactions between the 3D-genome and DNA, RNA, and epigenomic alterations in metastatic prostate cancer. Nature Genetics. PMID 39020220.
• SG Zhao^*, W Chen^*, H Li^*, …, AM Chinnaiyan^†, CA Maher^†, EJ Small^†, DA Quigley^†, FY Feng^†. Hallmarks of epigenomic regulation in advanced prostate cancer. Nature Genetics. PMID 32661416.
• DA Quigley*, HX Dang*, SG Zhao*, …, AM Chinnaiyan^†, CA Maher^†, EJ Small^†, FY Feng^†. Genomic hallmarks and structural variation in metastatic prostate cancer. Cell. PMID 30033370.
• SG Zhao*, WS Chen*, …, FY Feng. Clinical and genomic implications of luminal and basal subtypes across carcinomas. Clinical Cancer Research. PMID 30573691.
• E Feng*, NR Rydzewski*, …, M Sjöström^†, SG Zhao^†. Intrinsic molecular subtypes of metastatic castration-resistant prostate cancer. Clinical Cancer Research. PMID 36260524.
• M Sjöström*, SG Zhao*, S Levy*, M Zhang*, …, HH He^†, AW Wyatt^†, DA Quigley^†, FY Feng^†. The 5-hydroxymethylcytosine landscape of prostate cancer. Cancer Research. PMID 36251389.

Liquid biomarkers

Obtaining tissue specimens from cancer patients for molecular analysis is logistically challenging to perform at scale, especially in metastatic cancer. In collaboration with the UWCCC Circulating Biomarker Core, we work on developing liquid biopsy approaches for circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), and other non-invasive assays for institutional and national trials.

• KT Helzer^*, M Sharifi^*, JM Sperger^*, …, JM Lang^†, SG Zhao^†. Fragmentomic analysis of circulating tumor DNA targeted cancer panels. Annals of Oncology. PMID 37330052.
• M Bootsma^*, RR McKay^*, H Emamekhoo^*, …, TK Choueiri^†, JM Lang^†, SG Zhao^†. Longitudinal molecular profiling of circulating tumor cells in metastatic renal cell carcinoma J Clin Oncol. PMID 35617646.
• SG Zhao^*, JM Sperger^*, JL Schehr^*, …, JM Lang. A clinical-grade liquid biomarker to detect neuroendocrine differentiation in prostate cancer. J Clin Invest. PMID 36317634.
• MN Sharifi*, JM Sperger*, …, SG Zhao^†, Joshua M. Lang^†. High-purity CTC RNA sequencing identifies prostate cancer lineage phenotypes prognostic for clinical outcomes. Cancer Discovery. PMID 39912912.
• JR Prensner^*, S Zhao^*, …, FY Feng. RNA biomarkers associated with metastatic progression in prostate cancer: a multi-institutional high-throughput analysis of SChLAP1. Lancet Oncology. PMID 25456366.
• JM Sperger^*, H Emamekhoo^*, RR McKay^*, …, SG Zhao, JM Lang. Prospective evaluation of clinical outcomes utilizing a multi-plex liquid biopsy targeting diverse resistance mechanisms in metastatic prostate cancer. J Clin Oncol. PMID 34197212.

Computational and machine-learned approaches

High-throughput sequencing techniques can generate an enormous amount of data. Machine-learning is the branch of computer science specifically focused on identifying important patterns that are too complex for humans to independently explore. Our laboratory seeks to leverage machine learning and other advanced computational approaches to develop models for clinical and biological endpoints.

• SG Zhao, …, FY Feng. The immune landscape of prostate cancer and nomination of PD-L2 as a potential therapeutic target. J Natl Cancer Inst. PMID 30321406.
• SG Zhao^*, JR Evans^*, …, FY Feng. The landscape of prognostic outlier genes in high-risk prostate cancer. Clinical Cancer Research. PMID 26631616.
• JR Evans^*, SG Zhao^*, …, FY Feng. Patient-level DNA damage and repair pathway profiles and prognosis after prostatectomy for High-Risk Prostate Cancer. JAMA Oncology. PMID 26746117.
• C Speers^*, S Zhao^*, …, LJ Pierce^†, FY Feng^†. Development and validation of a novel radiosensitivity signature in human breast cancer. Clinical Cancer Research. PMID 25904749.
• NR Rydzewski, …, FY Feng^†, SG Zhao^†. Predicting Cancer Drug TARGETS – TreAtment Response Generalized Elastic-neT Signatures NPJ Genom Med. PMID 34548481.
• H Bakhtiar^*, KT Helzer^*, …, SG Zhao. Identification of phenocopies improves prediction of targeted therapy response over DNA mutations alone. NPJ Genom Med. PMID 36253482.
• NR Rydzewski, …, SG Zhao. A Platform-Independent AI Tumor Lineage and Site (ATLAS) Classifier. Communications Biology. PMID 38480799.
• H Bakhtiar*, MN Sharifi, …, SG Zhao. A phenocopy signature of TP53 loss predicts response to chemotherapy. NPJ Precision Oncology. PMID 39358429.
• MN Sharifi*, Y Shi*, …, SG Zhao. Clinical cell surface targets in metastatic and primary solid cancers. JCI Insight. PMID 39315546.

^*Co-first authorship, ^†Co-senior authorship

Selected funding

• NIH DP2 Director’s New Innovator Award (Principal Investigator)
• NIH R01 (Principal Investigator)
• NIH Prostate Cancer SPORE (Biostatistics & Bioinformatics Core Co-director)
• DoD Prostate Cancer Research Program Physician Research Award (Principal Investigator)
• DoD Prostate Cancer Research Program Idea Award (Principal Investigator)
• DoD Prostate Cancer Research Program Translational Science Award (Partnering Principal Investigator)
• NCCN Young Investigator Award (Principal Investigator)
• Prostate Cancer Foundation Young Investigator Award (Principal Investigator)