Shahriar Koochekpour, MD, PhD
Shahriar Koochekpour, MD, PhD
Dr. Koochekpour joined the staff of Roswell Park Cancer Institute (RPCI) as an Associate Professor of Cancer Genetics, Urology and Oncology in 2011. Dr. Koochekpour graduated from Shiraz Medical School, Shiraz University of Health Sciences Center (Iran), with an MD degree and followed that with a short-term residency in General Pathology. Dr. Koochekpour obtained his PhD in cellular and molecular oncology from Kings College School of Medicine, University of London; London, UK. He continued his postdoctural training at the National Cancer Institute-Advanced Bioscience Laboratories, Frederick Cancer Research and Development Center, Frederick, Maryland. Dr. Koochekpour has comprehensive training and experience in cellular and molecular biology of cancer, analyzing gene expression and functions, oncogenes and tumor suppressors, genetics, health disparity and translational cancer research.
To define the clinical significance of tissue expression of GRM1 or serum-glutamate levels as a marker of prostate cancer (PCa) progression or aggressiveness: Using a large pool of serum samples from European American and African-American patients with organ-confined, locally-invasive, or metastatic tumors and a highly sensitive sandwich-ELISA assay, and biostatistical analysis, Dr. Koochekpour examined the association between serum-Glutamate levels and the progression or aggressiveness of PCa that is based on clinical stage, prognostic, or risk factors (e.g., age, race, PSA, Gleason’s score). Serum glutamate levels were measured in normal men (n = 60) and patients with primary PCa (n = 197) or mCRPCa (n = 109). Univariate and multivariate analyses demonstrated significantly higher serum glutamate levels in Gleason score ≥ 8 than in the Gleason sscore ≤ 7 and in African Americans than in the Caucasian Americans. AAs with mCRPCa had significantly higher serum glutamate levels than those with primary PCa or benign prostate. However, in Caucasian Americans, serum glutamate levels were similar in normal research subjects and patients with mCRPC. Glutamate deprivation or blockade decreased PCa cells’ proliferation, migration, and invasion and led to apoptotic cell death. Glutamate expression appears to be mechanistically associated with and may provide a biomarker of PCa aggressiveness. In addition, in a pilot study, immunohistochemical analyses demonstrated weak or no expression of GRM1 in luminal acinar epithelial cells of normal or hyperplastic glands, but high expression in primary or metastatic PCa tissues. These studies will be extended to a large cohort of archived tissues derived from European and African American patients with primary, metastatic, or castrate-recurrent (resistant) prostate cancer (mCRPCa).
Next, we determined the relationship between CRM1 and AR, PSA, and tumor growth, remission, and recurrence in CWR22 (n=59) and LuCaP 35AS/CR (n=12) preclinical PCa models. We discovered that GRM1 transcript and tissue expression directly correlated with growth and AR and PSA expression in hormone-sensitive (HS), castrated, and CR tumor xenografts. GRM1 overexpression or silencing directly correlated with PCs cell proliferation, migration, and invasion. DHT increased GRM1 expression via an AR-dependent manner in HS- and CR-PCa cell lines. This was the first report of GRM1 as an androgen and AR- target gene. GRM1 expression directly correlated with tumor growth, regression,and recurrence and may contribute to CR-progressionof PCa in preclinical models.Additional studies are underway to define the utility of GRM1 as a druggable target or biomarker for PCa.
To determine the association between GRM1 and invasive and metastatic phenotypes in GRM1-overexpressed or -silenced PCa cells: To study the cause-and-effect relationship between GRM1 tissue expression and invasive and metastatic phenotypes in PCa progression models, we will use the PCa cell lines established from European Americans (e.g., LNCaP, C4-2, VCaP, LAPC4, 22Rv1) and the three available authentic PCa cell lines derived from African-American patients (the non-metastatic E006AA cell line, the invasive and highly tumorigenic cell line, E006AA-hT, and the metastatic MDA PCa 2b cell line). We will test how alterations in GRM1 expression levels will affect tumor growth rate and invasive and metastatic abilities using subcutaneous and orthotopic xenograft implantation in athymic nude mice and NOD-SCID mice and humanized CWR22 castrate-recurrent progression model.
To develop methods for decreasing or inhibiting the expression of androgen receptor (AR) and AR-variants (e.g., AR-v7) in mCRPCa.
Targeting wild-type, mutated, or variants of AR has been at the center of modern therapeutic objectives in patients with castrate-recurrent PCa. We are currently testing a variety of biological or medicinal approaches to decrease or inhibit the AR expression at protein levels.
- Cao Z, Koochekpour S, Strup SE, Kyprianou N, Pharmacologic Reversion of Epithelial Mesenchymal Transition in Prostate Cancer Cells via IGF binding protein-3. Oncotarget. https://doi.org/10.18632/oncotarget.19659. 2017.
- Liu S, Kumari S, Hu Q, Senapati D, Venkadakrishnan VB, Wang D, DePriest AD, Schlanger SE, Ben-Salem S, Valenzuela MM, Willard B, Mudambi S, Swetzig WM, Das GM, Shourideh M, Koochekpour S, Falzarano SM, Magi-Galluzzi C, Yadav N, Chen X, Lao C, Wang J, Billaud JN, Heemers HV. A comprehensive analysis of coregulator recruitment, androgen receptor function and gene expression in prostate cancer. Elife: pii: e28482. doi: 10.7554/eLife.28482, 2017.
- Wadosky KM, Koochekpour S. Androgen receptor splice variants and prostate cancer: From bench to bedside. Oncotarget: 8(11):18550-18576, 2017.
- Wadosky KM, Koochekpour S. Molecular mechanisms underlying resistance to androgen deprivation therapy in prostate cancer. Oncotarget: 27;7(39):64447-64470. doi: 10.18632/oncotarget.10901, 2016.
- Shourideh M, DePriest A, Mohler JL, Wilson EM, Koochekpour S. Characterization of fibroblast-free CWR-R1ca castration-recurrent prostate cancer cell line. Prostate: 76(12):1067-77, 2016.