title: Clinical and Translational Assessment of VEGFR1 as a Mediator of the Premetastatic Niche in High-Risk Localized Prostate Cancer.
abstract: Preclinical studies have suggested that VEGFR1-positive cells potentially foster the development of metastases by establishing a "premetastatic niche." We sought to test this hypothesis in high-risk localized prostate cancer and assess potential niche modulation by the VEGFR1-targeting drug axitinib. Formalin-fixed, paraffin-embedded tissue derived from benign lymph nodes was collected and VEGFR1-positive cell clustering was assessed in benign lymph nodes via IHC. Recursive partitioning was used to define a threshold for VEGFR1 clustering that could segregate patients based on time to biochemical recurrence (TTBR). Multivariate analyses were used to determine whether VEGFR1 clustering, age, pathologic T-stage, Gleason score, or baseline PSA could independently predict TTBR. A randomized, phase II clinical trial comparing axitinib for 28 days followed by radical prostatectomy and pelvic lymph node dissection (RP/PLND) to RP/LND alone was then conducted, with the primary endpoint of demonstrating downregulation of VEGFR1-positve cell clustering in benign lymph nodes. Our retrospective analysis assessed a cohort of 46 patients. A threshold of 1.65 VEGFR1-positive cells per high power field was identified, below which TTBR was delayed. VEGFR1 clustering was an independent predictor of TTBR in a multivariate analysis. Only 11 out of the planned 44 patients were accrued to the phase II trial. While preoperative axitinib was safe and well tolerated, there was no sign of clinical activity or VEGFR1 downregulation. Our results validate previous findings that suggest VEGFR1-positive cells in benign lymph nodes can predict clinical outcome. Further work is needed to develop a viable clinical strategy for modulating VEGFR1 in these tissues.
authors.affiliation: Department of Medical Oncology and Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, California.
authors.forename: Sumanta Kumar
authors.initials: SK
authors.lastname: Pal
authors.affiliation: Department of Cancer Biology, City of Hope Comprehensive Cancer Center, Duarte, California.
authors.forename: Winston
authors.initials: W
authors.lastname: Vuong
authors.affiliation: GenScript, Nanjing City, Jiangsu, China.
authors.forename: Wang
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Cancer Immunotherapeutics and Tumor Immunology, City of Hope Comprehensive Cancer Center, Duarte, California.
authors.forename: Jiehui
authors.initials: J
authors.lastname: Deng
authors.affiliation: Department of Biostatistics, City of Hope Comprehensive Cancer Center, Duarte, California.
authors.forename: Xueli
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Medical Oncology and Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, California.
authors.forename: Courtney
authors.initials: C
authors.lastname: Carmichael
authors.affiliation: Department of Biostatistics, City of Hope Comprehensive Cancer Center, Duarte, California.
authors.forename: Nora
authors.initials: N
authors.lastname: Ruel
authors.affiliation: Department of Medical Oncology and Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, California.
authors.forename: Manasvi
authors.initials: M
authors.lastname: Pinnamaneni
authors.affiliation: Department of Medical Oncology and Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, California.
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Twardowski
authors.affiliation: Department of Urology, City of Hope Comprehensive Cancer Center, Duarte, California.
authors.forename: Clayton
authors.initials: C
authors.lastname: Lau
authors.affiliation: Department of Cancer Immunotherapeutics and Tumor Immunology, City of Hope Comprehensive Cancer Center, Duarte, California.
authors.forename: Hua
authors.initials: H
authors.lastname: Yu
authors.affiliation: Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Figlin
authors.affiliation: Department of Medicine, Huntsman Cancer Institute, Salt Lake City, Utah.
authors.forename: Neeraj
authors.initials: N
authors.lastname: Agarwal
authors.affiliation: Department of Cancer Biology, City of Hope Comprehensive Cancer Center, Duarte, California. jjones@coh.org.
authors.forename: Jeremy O
authors.initials: JO
authors.lastname: Jones
mesh_terms: D000368:Aged; D000077784:Axitinib; D018572:Disease-Free Survival; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage*; D007191:Indazoles / Q000008:administration & dosage*; D008198:Lymph Nodes / Q000378:metabolism / Q000473:pathology; D008207:Lymphatic Metastasis / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D017430:Prostate-Specific Antigen / Q000235:genetics; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics*
chemical_list: D007093:Imidazoles; D007191:Indazoles; D000077784:Axitinib; D040281:Vascular Endothelial Growth Factor Receptor-1; D017430:Prostate-Specific Antigen