The embryonic Brachyury transcription factor is a novel biomarker of GIST aggressiveness and poor survival

Pinto, Filipe; Campanella, Nathália C.; Abrahão-Machado, Lucas Faria; Scapulatempo‐Neto, Cristovam; Oliveira, Antonio Talvane de; Brito, María José; Andrade, Raquel P.; Guimarães, Denise Peixoto; Reis, Rui Manuel

doi:10.1007/s10120-015-0505-0

Cited by 18 publications

(21 citation statements)

References 50 publications

(75 reference statements)

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“…Tumor cells undergoing this phenotypic transition exhibit enhanced motility and invasiveness in vitro , a propensity to metastasize in vivo , and features of tumor stemness (16), including resistance to a range of therapeutics such as chemotherapy, radiation, small molecule therapies, and, potentially, immunotherapy (17–20). In agreement with a role for brachyury in the progression of carcinomas, multiple studies have now shown that the level of brachyury in the primary tumor correlates with poor patient prognosis in carcinomas of the lung (21), colon (6), breast (9), triple-negative breast (10), and gastrointestinal stromal tumor (GIST) (22). Brachyury expression has also been shown to be correlated with advanced-stage prostate cancer (8).…”

Section: Introductionmentioning

confidence: 64%

Phase I Study of a Poxviral TRICOM-Based Vaccine Directed Against the Transcription Factor Brachyury

Heery

Palena

McMahon

et al. 2017

Clinical Cancer Research

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Purpose The transcription factor brachyury has been shown in preclinical studies to be a driver of the epithelial-to-mesenchymal transition (EMT) and resistance to therapy of human tumor cells. This study describes the characterization of a Modified Vaccinia Ankara (MVA) vector-based vaccine expressing the transgenes for brachyury and three human costimulatory molecules (B7.1, ICAM-1, and LFA-3, designated TRICOM) and a phase I study with this vaccine. Experimental Design Human dendritic cells (DCs) were infected with MVA-brachyury-TRICOM to define their ability to activate brachyury-specific T cells. A dose escalation phase I study (NCT02179515) was conducted in advanced cancer patients (n = 38) to define safety and to identify brachyury-specific T-cell responses. Results MVA-brachyury-TRICOM-infected human DCs activated CD8+ and CD4+ T cells specific against the self-antigen brachyury in vitro. No dose-limiting toxicities were observed due to vaccine in cancer patients at any of the three dose levels. One transient grade 3 adverse event (AE) possibly related to vaccine (diarrhea) resolved without intervention and did not recur with subsequent vaccine. All other AEs related to vaccine were transient and ≤ grade 2. Brachyury-specific T-cell responses were observed at all dose levels and in most patients. Conclusions The MVA-brachyury-TRICOM vaccine directed against a transcription factor known to mediate EMT can be administered safely in patients with advanced cancer and can activate brachyury-specific T cells in vitro and in patients. Further studies of this vaccine in combination therapies are warranted and planned.

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Section: Introductionmentioning

confidence: 64%

Phase I Study of a Poxviral TRICOM-Based Vaccine Directed Against the Transcription Factor Brachyury

Heery

Palena

McMahon

et al. 2017

Clinical Cancer Research

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“…In this regard, we and others have shown that the presence of high levels of brachyury in the primary tumor can predict poor prognosis in a range of human carcinomas including lung (Haro et al 2013), hepatocellular (Du, et al 2014), GIST (Pinto, et al 2015), prostate (Pinto et al 2014), colorectal (Kilic et al 2011; Sarkar, et al 2012) and hormone receptor positive breast cancer (Palena et al 2014b). In agreement, here we have observed that high levels of brachyury in primary TNBC tumors associate with poor survival.…”

Section: Discussionmentioning

confidence: 98%

Brachyury, a vaccine target, is overexpressed in triple-negative breast cancer

Hamilton

Roselli

Ferroni

et al. 2016

Endocrine-Related Cancer

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Patients diagnosed with triple negative breast cancer (TNBC) have a high rate of tumor metastasis and a poor prognosis. The treatment option for these patients is currently chemotherapy, which results in very low response rates. Strategies that exploit the immune system for the treatment of cancer have now shown the ability to improve survival in several tumor types. Identifying potential targets for immune therapeutic interventions is an important step in developing novel treatments for TNBC. In this study, in-silico analysis of publicly available datasets and immunohistochemical analysis of primary and metastatic tumor biopsies from TNBC patients were conducted to evaluate the expression of the transcription factor brachyury, a driver of tumor metastasis and resistance and a target for cancer vaccine approaches, in TNBC. Analysis of breast cancer datasets demonstrated a predominant expression of brachyury mRNA in TNBC and in basal vs. luminal or HER2 molecular breast cancer subtypes. At the protein level, variable levels of brachyury expression were detected both in primary and metastatic TNBC lesions, and a strong association was observed between nuclear brachyury protein expression and the stage of disease, with nuclear brachyury being more predominant in metastatic vs. primary tumors. Survival analysis also demonstrated an association between high levels of brachyury in the primary tumor and poor prognosis. Two brachyury-targeting cancer vaccines are currently undergoing clinical evaluation; the data presented here provides rationale for utilizing brachyury-targeting immunotherapy approaches for the treatment of TNBC.

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“…Brachyury ( T ) is a T‐box transcription factor family with a central role in notochord and mesoderm specification (Herrmann et al ., ). In the last years, Brachyury has been described by us and others to be upregulated in several solid tumors, including chordoma (Vujovic et al ., ), lung (Roselli et al ., ), breast (Palena et al ., ), colorectal (Kilic et al ., ), prostate (Pinto et al ., ) cancer, and GIST (Pinto et al ., ,b). Importantly, in these tumors, Brachyury has been reported as an independent biomarker of poor prognosis (Kilic et al ., ; Haro et al ., ; Palena et al ., ; Pinto et al ., , ,b).…”

Section: Introductionmentioning

confidence: 99%

Brachyury oncogene is a prognostic factor in high‐risk testicular germ cell tumors

et al. 2018

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The T-box transcription factor Brachyury has been considered a cancer-specific marker and a novel oncotarget in solid tumors. Brachyury overexpression has been described in various cancers, being associated with epithelial-mesenchymal transition, metastasis, and poor prognosis. However, its clinical association with testicular germ cell tumor is unknown. We analyzed the expression of Brachyury by immunohistochemistry in a series of well-characterized testicular germ cell tumor samples and at transcript level by in silico analysis. Additionally, we aimed to investigate the clinical significance of Brachyury in testicular germ cell tumor. Brachyury cytoplasm immunostaining was present in 89.6% (86/96) of cases with nuclear staining observed in 24% (23/96) of testicular germ cell tumor. Bioinformatics microarray expression analysis of two independent cohorts of testicular germ cell tumors showed similar results with increased levels of Brachyury in testicular germ cell tumors and metastasis compared with normal testis. Clinically, Brachyury nuclear staining was statistically associated with lower event-free survival (p = 0.04) and overall survival (p = 0.01) in intermediate/high-risk testicular germ cell tumors. Univariate analysis showed that Brachyury nuclear subcellular localization was a predictor of poor prognosis (p = 0.02), while a tendency was observed by multivariate analysis (HR: 3.56, p = 0.06). In conclusion, these results indicate that Brachyury plays an oncogenic role in testicular germ cell tumors and its subcellular localization in the nucleus may constitute a novel biomarker of poor prognosis and a putative oncotarget for intermediate/high-risk testicular germ cell tumor patients.

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The embryonic Brachyury transcription factor is a novel biomarker of GIST aggressiveness and poor survival

Cited by 18 publications

References 50 publications

Phase I Study of a Poxviral TRICOM-Based Vaccine Directed Against the Transcription Factor Brachyury

Phase I Study of a Poxviral TRICOM-Based Vaccine Directed Against the Transcription Factor Brachyury

Brachyury, a vaccine target, is overexpressed in triple-negative breast cancer

Brachyury oncogene is a prognostic factor in high‐risk testicular germ cell tumors

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