scholarly journals Correction to: Transcriptional inhibition by CDK7/9 inhibitor SNS-032 abrogates oncogene addiction and reduces liver metastasis in uveal melanoma

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Jing Zhang ◽  
Shenglan Liu ◽  
Qianyun Ye ◽  
Jingxuan Pan
Keyword(s):  
Liver Metastasis ◽  
Uveal Melanoma ◽  
Oncogene Addiction ◽  
Transcriptional Inhibition

scholarly journals Transcriptional inhibition by CDK7/9 inhibitor SNS-032 abrogates oncogene addiction and reduces liver metastasis in uveal melanoma

2019 ◽  
Vol 18 (1) ◽  
Author(s):  
Jing Zhang ◽  
Shenglan Liu ◽  
Qianyun Ye ◽  
Jingxuan Pan
Keyword(s):  
Liver Metastasis ◽  
Cell Motility ◽  
Uveal Melanoma ◽  
Actin Polymerization ◽  
Cellular Proliferation ◽  
Xenograft Model ◽  
Transcriptional Inhibition ◽  
Mouse Xenograft Model ◽  
Induced Apoptosis ◽  
Organotropic Metastasis

Abstract Background Life of patients with uveal melanoma (UM) is largely threatened by liver metastasis. Little is known about the drivers of liver organotropic metastasis in UM. The elevated activity of transcription of oncogenes is presumably to drive aspects of tumors. We hypothesized that inhibition of transcription by cyclin-dependent kinase 7/9 (CDK7/9) inhibitor SNS-032 diminished liver metastasis by abrogating the putative oncogenes in charge of colonization, stemness, cell motility of UM cells in host liver microenvironment. Methods The effects of SNS-032 on the expression of the relevant oncogenes were examined by qRT-PCR and Western blotting analysis. Proliferative activity, frequency of CSCs and liver metastasis were evaluated by using NOD-SCID mouse xenograft model and NOG mouse model, respectively. Results The results showed that CDK7/9 were highly expressed in UM cells, and SNS-032 significantly suppressed the cellular proliferation, induced apoptosis, and inhibited the outgrowth of xenografted UM cells and PDX tumors in NOD-SCID mice, repressed the cancer stem-like cell (CSC) properties through transcriptional inhibition of stemness-related protein Krüppel-like factor 4 (KLF4), inhibited the invasive phonotypes of UM cells through matrix metalloproteinase 9 (MMP9). Mechanistically, SNS-032 repressed the c-Myc-dependent transcription of RhoA gene, and thereby lowered the RhoA GTPase activity and actin polymerization, and subsequently inhibited cell motility and liver metastasis. Conclusions In conclusion, we validate a set of transcription factors which confer metastatic traits (e.g., KLF4 for CSCs, c-Myc for cell motility) in UM cells. Our results identify SNS-032 as a promising therapeutic agent, and warrant a clinical trial in patients with metastatic UM.

scholarly journals Prospective validation in epithelial tumors of a gene expression predictor of liver metastasis derived from uveal melanoma

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Petros Tsantoulis ◽  
Mauro Delorenzi ◽  
Ivan Bièche ◽  
Sophie Vacher ◽  
Pascale Mariani ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Colorectal Cancer ◽  
Liver Metastasis ◽  
Uveal Melanoma ◽  
Meta Analysis ◽  
Prognostic Score ◽  
Penalized Regression ◽  
Breast Cancer Patients ◽  
Public Data

AbstractPredicting the risk of liver metastasis can have important prognostic and therapeutic implications, given the availability of liver-directed therapy. Uveal melanoma has a striking predisposition for liver metastasis despite the absence of anatomical proximity. Understanding its biology may uncover factors promoting liver metastasis in other malignancies. We quantified gene expression by RNAseq in 76 uveal melanomas and combined with public data in a meta-analysis of 196 patients. The meta-analysis of uveal melanoma gene expression identified 63 genes which remained prognostic after adjustment for chromosome 3 status. Two genes, PTP4A3 and JPH1, were selected by L1-penalized regression and combined in a prognostic score. The score predicted liver-specific relapse in a public pan-cancer dataset and in two public colorectal cancer datasets. The score varied between colorectal consensus molecular subtypes (CMS), as did the risk of liver relapse, which was lowest in CMS1. Additional prospective validation was done by real-time PCR in 463 breast cancer patients. The score was significantly correlated with liver relapse in hormone receptor positive tumors. In conclusion, the expression of PTP4A3 and JPH1 correlates with risk of liver metastasis in colorectal cancer and breast cancer. The underlying biological mechanism is an interesting area for further research.

Are liver function tests relevant for early detection of liver metastasis of uveal melanoma?

2011 ◽  
Vol 89 (s248) ◽  
pp. 0-0
Author(s):  
F MOURIAUX ◽  
C DIORIO ◽  
D BERGERON ◽  
C BERCHI ◽  
A ROUSSEAU
Keyword(s):  
Liver Metastasis ◽  
Early Detection ◽  
Liver Function ◽  
Uveal Melanoma ◽  
Liver Function Tests ◽  
Function Tests

scholarly journals Development and optimization of orthotopic liver metastasis xenograft mouse models in uveal melanoma

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Takahito Sugase ◽  
Bao Q. Lam ◽  
Meggie Danielson ◽  
Mizue Terai ◽  
Andrew E. Aplin ◽  
...  
Keyword(s):  
Liver Metastasis ◽  
Mouse Models ◽  
Uveal Melanoma

scholarly journals An Outcome Assessment of a Single Institution’s Longitudinal Experience with Uveal Melanoma Patients with Liver Metastasis

Cancers ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 117 ◽  
Author(s):  
Rino S. Seedor ◽  
David J. Eschelman ◽  
Carin F. Gonsalves ◽  
Robert D. Adamo ◽  
Marlana Orloff ◽  
...  
Keyword(s):  
Liver Metastasis ◽  
Uveal Melanoma ◽  
Chart Review ◽  
University Hospital ◽  
Treatment Modalities ◽  
Consecutive Series ◽  
Systemic Treatments ◽  
Melanoma Patients ◽  
Develop Liver Metastasis ◽  
Systemic Therapies

There is no FDA-approved treatment for metastatic uveal melanoma (UM) and overall outcomes are generally poor for those who develop liver metastasis. We performed a retrospective single-institution chart review on consecutive series of UM patients with liver metastasis who were treated at Thomas Jefferson University Hospital between 1971–1993 (Cohort 1, n = 80), 1998–2007 (Cohort 2, n = 198), and 2008–2017 (Cohort 3, n = 452). In total, 70% of patients in Cohort 1 received only systemic therapies as their treatment modality for liver metastasis, while 98% of patients in Cohort 2 and Cohort 3 received liver-directed treatment either alone or with systemic therapy. Median Mets-to-Death OS was shortest in Cohort 1 (5.3 months, 95% CI: 4.2–7.0), longer in Cohort 2 (13.6 months, 95% CI: 12.2–16.6) and longest in Cohort 3 (17.8 months, 95% CI: 16.6–19.4). Median Eye Tx-to-Death OS was shortest in Cohort 1 (40.8 months, 95% CI: 37.1–56.9), and similar in Cohort 2 (62.6 months, 95% CI: 54.6–71.5) and Cohort 3 (59.4 months, 95% CI: 56.2–64.7). It is speculated that this could be due to the shift of treatment modalities from DTIC-based chemotherapy to liver-directed therapies. Combination of liver-directed and newly developed systemic treatments may further improve the survival of these patients.

Characterization of the typical multidrug resistance profile in human uveal melanoma cell lines and in mouse liver metastasis derivatives

2005 ◽  
Vol 15 (4) ◽  
pp. 257-266 ◽  
Author(s):  
St??phane Labialle ◽  
Guila Dayan ◽  
Jo??l Gambrelle ◽  
Landry Gayet ◽  
St??phane Barakat ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Liver Metastasis ◽  
Cell Lines ◽  
Uveal Melanoma ◽  
Melanoma Cell ◽  
Mouse Liver ◽  
Resistance Profile ◽  
Uveal Melanoma Cell ◽  
Melanoma Cell Lines

Patterns of hepato-pulmonary metastasis and their impact on clinical outcomes in uveal melanoma.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e22052-e22052
Author(s):  
Asad Javed ◽  
Abdullah S. Al Saleh ◽  
Matthew Stephen Block ◽  
Robert R. McWilliams ◽  
Yiyi Yan ◽  
...  
Keyword(s):  
Liver Metastasis ◽  
Clinical Outcomes ◽  
Uveal Melanoma ◽  
Lung Metastasis ◽  
Pulmonary Metastasis ◽  
Metastatic Disease ◽  
Univariate Analysis ◽  
Primary Diagnosis ◽  
Group 2 ◽  
Group 1

e22052 Background: Metastatic Uveal Melanoma (MUM) is a rare tumor with poor prognosis following development of liver metastasis. We hypothesized that patterns of metastasis in Uveal Melanoma correlate with clinical outcomes. Methods: We retrospectively reviewed patients with MUM at Mayo Clinic, Rochester from January 1999 to August 2019. Patients were stratified into two groups based on the pattern of hepatic and pulmonary metastasis at the time of diagnosis of metastatic disease: Group 1 (≤5 liver metastasis or lung metastasis) and Group 2 ( > 5 liver metastasis without lung metastasis). Baseline characteristics were compared between both groups. Survival analysis was performed using the Kaplan Meier method. Univariate and multivariate analysis were performed for Overall Survival (OS). Results: 147 patients were included in the study (n = 67 Group 1; n = 80 Group 2). In Group 1, 49/67 patients presented with ≤5 liver metastasis and 18/67 had lung metastasis without liver metastasis. Median OS for Group 1 was significantly longer than Group 2 (38 vs. 15 months; p < 0.0001) (Table). On univariate analysis, predictors for OS were: Pattern of Metastasis, ECOG PS > 0, Time to metastasis > 60 months, and Surgical metastatectomy. Pattern of Metastasis was an independent predictor for OS in a multivariate model that included these predictors (p = 0.0004). Group 1 patients were more likely to undergo surgical metastatectomy compared to group 2 (21.5% vs. 1.3%; p < 0.0001). Interestingly, the median time to metastasis from diagnosis of UM was significantly longer for Group 1 as compared to Group 2 (67 vs. 24.5 months; p < 0.0001). Conclusions: Limited (≤5) liver metastasis or lung metastasis (without liver metastasis) at diagnosis predict favorable clinical outcomes in MUM. The occurrence of such metastasis following a significantly longer time from primary diagnosis suggests the existence of a distinct sub-type of metastatic disease with relatively indolent behavior. [Table: see text]

scholarly journals Uveal Melanoma Metastatic to the Liver: Treatment Trends and Outcomes

2019 ◽  
Vol 5 (5) ◽  
pp. 323-332 ◽  
Author(s):  
Lucy T. Xu ◽  
Pauline F. Funchain ◽  
James F. Bena ◽  
Manshi Li ◽  
Ahmad Tarhini ◽  
...  
Keyword(s):  
Liver Metastasis ◽  
Uveal Melanoma ◽  
Survival Data ◽  
Checkpoint Inhibitors ◽  
Local Treatment ◽  
Local Therapy ◽  
First Line ◽  
Significant Difference ◽  
Time Periods ◽  
Treatment Trends

Objective: To describe treatment trends and outcomes of liver metastasis from uveal melanoma. Methods: Retrospective case series of 73 patients with uveal melanoma liver metastasis. Patients were treated first-line with systemic therapy (not including checkpoint inhibitors), checkpoint inhibitors, local therapy or no treatment. Time to metastasis, detection method, and survival data were collected. Time periods were divided between 2004–2011 and 2012–2016. Cox proportional hazards models were used to compare progression-free survival (PFS) and overall survival (OS). Results: Median PFS and OS for the entire cohort was 4 months (95% CI 3–5) and 15 months (95% CI 11–18), respectively. There was no statistically significant difference in PFS and OS across the two time periods. Patients who received no treatment had the shortest OS (median 4.9 months), whereas those treated with local therapy had the longest PFS (median 4.6 months) and OS (median 18.7 months). Having liver metastasis diagnosed by symptoms was associated with a greater risk of mortality (p < 0.001). Conclusion: Patients who received first-line local treatment had the longest PFS and OS, while patients who received no treatment had the shortest OS. Survival outcomes did not improve for patients including those receiving check point inhibitors.

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