The Prostate Cancer Foundation Scholar-in-Training Awards recognize promising young cancer researchers presenting outstanding proffered papers relating to advanced prostate cancer at the American Association for Cancer Research (AACR) Annual Meeting. The Prostate Cancer Foundation is one of 17 organizations sponsoring this highly competitive awards program in conjunction with the AACR. The 2019 AACR Annual Meeting will be held from March 29 to April 3 at the Georgia World Congress Center in Atlanta, Georgia.
Andi K. Cani, MS
University of Michigan, Ann Arbor, MI
Development of a whole-urine, next-generation sequencing-based assay for early detection of aggressive prostate cancer
Andi K. Cani, Kevin Hu, Javed Siddiqui, Sumin Han, Daniel H. Hovelson, Chia-Jen Liu, Simpa S. Salami, Ganesh S. Palapattu, Todd M. Morgan, John T. Wei, Arul M. Chinnaiyan, Scott A. Tomlins. University of Michigan, Ann Arbor, MI
Despite advances in biomarker development, early detection of aggressive prostate cancer (PCa) remains challenging. Existing biomarkers show modest improvement over models based on serum prostate specific antigen (PSA). We have previously developed a clinical-grade laboratory-developed test, named MiProstate Score (MiPS), for individualized risk prediction of aggressive prostate cancer. It uses transcription-mediated amplification to quantify the gene-fusion TMPRSS2:ERG (T2:ERG) (T1E4 splice isoform) and the lncRNA PCA3 from whole-urine obtained after a digital rectal exam (DRE), combined with serum PSA. To improve MiPS, we describe here the pre-clinical development and validation of a targeted next generation sequencing assay (NGS-MiPS) using post-DRE urine RNA to asses ~90 PCa transcriptomic biomarkers. These include those in MiPS as well as many isoforms of common PCa gene fusions, mRNA, and lncRNA candidate biomarkers nominated by our large-scale PCa tissue RNAseq and other sources. We have obtained a 98% informative sample rate from 2.5 mL of urine and high technical reproducibility (Pearson r=0.99). Risk scores for having PCa [or high-grade PCa (Gleason Score >6)] on biopsy, as determined by clinical MiPS vs. the clinical MiPS model using NGS data, were highly concordant, Pearson’s r=0.74 (and r=0.81). Urine from patients with benign or Gleason 6 vs. Gleason ≥ 4+3=7 cancer on biopsy (extreme design) showed expected differences in the levels of T2:ERG T1E4 (p=0.00003) and PCA3 (p=0.07), with additional T2:ERG splice isoforms and other biomarkers also being significantly different between low vs. high grade cancer. Feature selection and logistic regression trained in an extreme design cohort (n=73) yielded a 29-transcript model that outperformed MiPS and serum PSA in two validation cohorts: 1. A held-out set from the extreme design cohort n=36, AUC 0.81 vs. 0.76 and 0.63 respectively; 2. A separate active surveillance cohort n=45, AUCs 0.66 vs. 0.56 and 0.53 respectively. These results support the potential utility of our urine based targeted NGS assay to supplement serum PSA for the early detection of aggressive prostate cancer.
This abstract will be presented in a Minisymposium entitled “Biomarkers for Early Detection and Biologic Assessment of Cancer” on Sunday, March 31, 2019, 3:00 pm – 5:00 pm located in Room B302 – Georgia World CC.
Zoila Areli Lopez Bujanda, MSc
Johns Hopkins, Baltimore, MD
Zoila A. Lopez Bujanda1, Michael C. Haffner1, Matthew G. Chaimowitz2, Nivedita Chowdhury1, Paula J. Hurley1, Angela M. Christiano2, Charles G. Drake2. 1Johns Hopkins, Baltimore, MD; 2Columbia University, New York, NY
Androgen deprivation therapy (ADT) results in castration-resistant prostate cancer (CRPC) in a significant fraction of patients. We have previously reported that the protein levels of interleukin-8 (IL-8) were inversely correlated with disease progression in men with biochemical recurrent prostate cancer treated with Lenalidomide. Recently, polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) were implicated as potential drivers of CRPC. Here we show that IL-8 expression is upregulated as a consequence of ADT and mediates the recruitment of PMN-MDSCs to the tumor microenvironment. We found that IL-8 expression is regulated by both an inflammatory stimulus (NF-kβ mediated) and loss of androgen receptor (AR) signaling following ADT. We confirmed direct binding of both the p65 subunit of NF-kβ and AR to the IL-8 promoter, and their respective effects on promoter activity. The suppressive activity of AR was further supported by a reduction in active transcription markers at the chromatin level surrounding the IL-8 promoter. Accordingly, intratumoral infiltration of PMN-MDSCs correlated with IL-8 expression, and was reduced in IL-8 knockouts. Taken together, these results suggest an innate inflammatory response, loss of AR suppressive activity, and subsequent chemokine upregulation as a potential mechanism that regulates the infiltration of PMN-MDSCs to the tumor microenvironment of CRPC after ADT. These findings open a window of opportunity for therapeutic interventions aiming to improve responses to checkpoint blockade in prostate cancer.
This abstract will be presented in a Poster Session entitled “Suppressive Myeloid Cells” on Monday, April 1, 2019, 8:00 am – 12:00 noon located in Section 24, Board 6.
Naveen Ramesh, MS
The University of Texas MD Anderson Cancer Center, Houston, TX
Plasma genome sequencing identifies prostate cancer patients that are sensitive to platinum-based therapy
Naveen Ramesh, Emi Sei, Pei Ching Tsai, Christopher Logothetis, Paul Corn, Ana Aparicio, Amado J. Zurita, Nicholas E. Navin. MD Anderson Cancer Center, Houston, TX
Castration-resistant prostate cancer (CRPC) is a lethal disease. A subset of these patients present with atypical clinical characteristics and aggressive disease behavior. These patients, classified as Aggressive Variant Prostate Cancer (AVPC), may derive benefit from platinum-based chemotherapy. However, the identification of AVPC patients is often challenging due to heterogeneity in clinical presentations and potentially in biological drivers, which may not be fully reflected in a biopsy obtained from a single tumor site. To address these challenges, we developed an unbiased genome sequencing method called PEGASUS (Plasma Exome and Genome Analysis by Size-Selection and Unbiased Sequencing) that enables the simultaneous detection of copy number aberrations and exome mutations from circulating-tumor DNA (ctDNA). We applied this method to plasma specimens obtained from 160 CRPC patients with and without AVPC participating in a randomized trial of cabazitaxel alone or in combination with carboplatin. We were able to successfully isolate ctDNA (>2 ng) for genomic profiling using PEGASUS in 91/160 (57%) CRPC patients. Among these 91 CRPC patients, we detected common prostate cancer mutations as well as genomic copy number changes in genes such as RB1, PTEN and TP53 and several other genes associated with DNA repair. One of the most salient features that distinguished the patients’ outcomes was whether they had diploid or aneuploid genomes detected by whole genome profiling of the ctDNA. Patients with aneuploid ctDNA had worse progression-free and overall survival. Overall, our data shows the feasibility of performing whole- genome and exome profiling of ctDNA in CRPC patients to characterize the molecular features associated with distinct clinical presentations. Candidate markers associated to benefit from platinum-based chemotherapy are being evaluated. These results pave the way for future clinical applications in biomarker discovery to assist treatment decisions in prostate cancer patients.
This abstract will be presented in a Poster Session entitled “Current Developments in Non-invasive Biomarkers for Assessment of Cancer 1” on Sunday, March 31, 2019, 1:00 pm – 5:00 pm located in Section 18, Board 18.