Correlation of B7-H3 with androgen receptor, immune pathways and poor outcome in prostate cancer: an expression-based analysis

Benzon, Benjamin; Zhao, Shuang G.; Haffner, Michael C.; Takhar, Mandeep; Erho, Nicholas; Yousefi, Kasra; Hurley, Paula J.; Bishop, Jennifer; Tosoian, Jeffrey J.; Ghabili, Kamyar; Alshalalfa, Mohammed; Glavaris, Stephanie; Simons, Brian W.; Tran, Phuoc T.; Davicioni, Elai; Karnes, R. Jeffrey; Boudadi, Karim; Antonarakis, Emmanuel S.; Schaeffer, Edward M.; Drake, Charles G.; Feng, Felix Y.; Ross, Ashley E.

doi:10.1038/pcan.2016.49

Cited by 122 publications

(119 citation statements)

References 37 publications

(39 reference statements)

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“…In the Mayo Clinic Validation study (N = 232), a case-cohort consisting of high risk PCa patients (17) with a median follow-up of 7 years, we found that TOP2A +/ EZH2 + patients had a faster progression to metastatic disease (Figure 2A). This finding was also confirmed in the Thomas Jefferson University dataset (N = 133), a cohort of PCa patients treated with radiation therapy (18) (Figure 2B) and in two Johns Hopkins University case-cohorts consisting of post-RP patients who received no therapy until the onset of metastasis (N = 262) (16) (Figure 2C) or of patients who had developed biochemical recurrence (post-BCR) and again received no therapy until the onset of metastasis (N = 213) (24) (Figure 2D). However, concurrent TOP2A and EZH2 expression in those datasets was not associated to a shorter time to biochemical recurrence (Supplement Figure S4).…”

Section: Resultsmentioning

confidence: 99%

“…A conditional reprogramming method was used to establish cell lines from sKO or dKO PCa mouse models (24). Briefly, tumor samples from the prostate of a 51-week-old sKO mouse or a 38-week-old dKO mouse was chopped into 2-mm fragments followed by digestion in a mixture of Collagenase/Hyaluronidase (Stem Cell Technologies, #7912) at 37 ⁰C for three hours.…”

Section: Methodsmentioning

confidence: 99%

“…Epithelial colonies surrounded by irradiated fibroblast were harvested and trypsinized into single cells, plated in a 96-well plate. sKO and dKO cell lines were established from the homogeneous population in one single well and then continuously maintained in F medium (described previously (24)) with the supplement of 10 μM Y-27632 and 1nM R1881. Both cell lines were finally cultured using DMEM containing 10% fetal bovine serum.…”

Section: Methodsmentioning

confidence: 99%

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TOP2A and EZH2 Provide Early Detection of an Aggressive Prostate Cancer Subgroup

Labbé

Sweeney

Brown

et al. 2017

Clinical Cancer Research

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Purpose Current clinical parameters do not stratify indolent from aggressive prostate cancer (PCa). Aggressive PCa, defined by the progression from localized disease to metastasis, is responsible for the majority of PCa-associated mortality. Recent gene expression profiling has proven successful in predicting the outcome of PCa patients, however they have yet to provide targeted therapy approaches that could inhibit a patient’s progression to metastatic disease. Experimental Design We have interrogated a total of seven primary PCa cohorts (N = 1,900), two metastatic castration resistant PCa datasets (N = 293) and one prospective cohort (N = 1,385) to assess the impact of TOP2A and EZH2 expression on PCa cellular program and patient outcomes. We also performed immunohistochemical staining for TOP2A and EZH2 in a cohort of primary PCa patients (N = 89) with known outcome. Finally, we explored the therapeutic potential of a combination therapy targeting both TOP2A and EZH2 using novel PCa-derived murine cell lines. Results We demonstrate by genome-wide analysis of independent primary and metastatic PCa datasets that concurrent TOP2A and EZH2 mRNA and protein up-regulation selected for a subgroup of primary and metastatic patients with more aggressive disease and notable overlap of genes involved in mitotic regulation. Importantly, TOP2A and EZH2 in PCa cells act as key driving oncogenes, a fact highlighted by sensitivity to combination-targeted therapy. Conclusions Overall, our data supports further assessment of TOP2A and EZH2 as biomarkers for early identification of patients with increased metastatic potential that may benefit from adjuvant or neo-adjuvant targeted therapy approaches.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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TOP2A and EZH2 Provide Early Detection of an Aggressive Prostate Cancer Subgroup

Labbé

Sweeney

Brown

et al. 2017

Clinical Cancer Research

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“…B7-H3 expression is significantly associated with poor outcome in patients with RCC (28–30), lung cancer (31), prostate cancer (32), CRC (33, 34), gallbladder cancer (35), esophageal squamous cancer (36), cervical cancer (37), osteosarcoma (OS) (38) and breast cancer (39). Thus, B7-H3 expression might be a feasible and effective means to predict the prognosis in cancer patients.…”

Section: B7-h3mentioning

confidence: 99%

New B7 Family Checkpoints in Human Cancers

Dong

2017

Molecular Cancer Therapeutics

187

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T cells are the main effector cells in immune response against tumors. The activation of T cells is regulated by the innate immune system through positive and negative costimulatory molecules. Targeting immune checkpoint regulators such as programmed cell death 1 (PD-1)/PD-1 ligand 1 (PD-L1) and cytotoxic T lymphocyte antigen 4 (CTLA-4) has achieved notable benefit in a variety of cancers, which leads to multiple clinical trials with antibodies targeting the other related B7/CD28 family members. Recently five new B7 family ligands, B7-H3, B7-H4, B7-H5, B7-H6 and B7-H7, were identified. Here we review recent understanding of new B7 family checkpoint molecules since they have come to the front of cancer research with the concept that tumor cells exploit them to escape immune surveillance. The aim of this article is to address the structure and expression of the new B7 family molecules as well as their roles in controlling and suppressing immune responses of T cells as well as NK cells. We also discuss clinical significance and contribution of these checkpoint expressions in human cancers.

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“…B7-H3 protein showed broad mRNA expression on many tissues and cell types with proven functions on cellular responses, including proliferation, apoptosis, adhesion, and metastasis [65–67]. While its protein expression is restricted in normal tissues, much higher levels are found in human malignancies [68–75], and because of its association with highly aggressive tumor behavior and poor clinical outcome, B7-H3 has utility as a tumor-associated antigen as well [71,74,76]. …”

Section: Immune Checkpoint Inhibitors and Clinical Trialsmentioning

confidence: 99%

Limitations and opportunities for immune checkpoint inhibitors in pediatric malignancies

Park

Cheung

2017

Cancer Treatment Reviews

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Immune checkpoint inhibitors (ICI) have shown great promise in a wide spectrum of adult solid and hematological malignancies, achieving objective tumor responses and prolonging survival. However, there is limited clinical success amongst pediatric patients. In this review, we summarize the current understanding of ICI and present an up-to-date overview of recent and ongoing clinical trials of ICI in pediatric malignancies. In addition, we will discuss immunologic and clinical difficulties in this young population, as well as future prospects for combination of ICI with other immune-based and conventional treatments.

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Correlation of B7-H3 with androgen receptor, immune pathways and poor outcome in prostate cancer: an expression-based analysis

Abstract: Higher B7-H3 expression correlates with Gleason grade, prostate cancer stage and poor oncologic outcomes in prostatectomy cohorts. B7-H3 expression appears to be related to androgen signaling as well as the immune reactome.

Cited by 122 publications

References 37 publications

TOP2A and EZH2 Provide Early Detection of an Aggressive Prostate Cancer Subgroup

TOP2A and EZH2 Provide Early Detection of an Aggressive Prostate Cancer Subgroup

New B7 Family Checkpoints in Human Cancers

Limitations and opportunities for immune checkpoint inhibitors in pediatric malignancies

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