P2, N=42, Active, not recruiting, University of Southern California | Phase classification: P2a --> P2 | Trial completion date: Mar 2025 --> Mar 2026 | Trial primary completion date: Mar 2024 --> Mar 2025

8 months ago

Phase classification • Trial completion date • Trial primary completion date • Combination therapy • IO biomarker

PD-L1 (Programmed death ligand 1) • BRAF (B-raf proto-oncogene) • ALK (Anaplastic lymphoma kinase) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • PD-1 (Programmed cell death 1)

PD-L1 expression

Keytruda (pembrolizumab) • sEphB4-HSA

9ms

Multicohort Phase II Trial of sEphB4-HSA+Pembrolizumab in Solid Tumors (clinicaltrials.gov)

P2, N=170, Recruiting, University of Southern California | Trial completion date: Nov 2024 --> Nov 2026 | Trial primary completion date: Nov 2023 --> Nov 2025

9 months ago

Trial completion date • Trial primary completion date • Combination therapy

Keytruda (pembrolizumab) • sEphB4-HSA

over1year

sEphB4-HSA in Treating Participants With BCG-Unresponsive or Refractory Bladder Cancer (clinicaltrials.gov)

P2, N=0, Withdrawn, University of Southern California | N=36 --> 0 | Not yet recruiting --> Withdrawn

over 1 year ago

Enrollment change • Trial withdrawal

sEphB4-HSA

over1year

Comprehensive bioinformatics and experimental analysis of SH3PXD2B reveals its carcinogenic effect in gastric carcinoma. (PubMed, Life Sci)

Our study strongly suggests that SH3PXD2B is a carcinogenic molecule that can be used as a biomarker for GC detection, prognosis, treatment design, and follow-up.

over 1 year ago

Journal

ADAM15 (ADAM Metallopeptidase Domain 15) • SH3PXD2B (SH3 And PX Domains 2B)

sirolimus • sotrastaurin (AEB071) • BHG712

over1year

sEphB4-HSA in Treating Participants With BCG-Unresponsive or Refractory Bladder Cancer (clinicaltrials.gov)

P2, N=36, Not yet recruiting, University of Southern California | Trial completion date: Apr 2025 --> Aug 2025 | Trial primary completion date: Apr 2024 --> Aug 2024

over 1 year ago

Trial completion date • Trial primary completion date

sEphB4-HSA

over1year

Optimization of the Lead Compound NVP-BHG712 as Colorectal Cancer Inhibitor. (PubMed, Chemistry)

Testing in up to seven colon cancer cell lines that express EPHA2 reveals that several derivatives feature promising effects for control of human colon carcinoma. Thus, we have developed a set of powerful tool compounds for fundamental new research on the interplay of EPH receptors in a cellular context.

over 1 year ago

Journal

EPHA2 (EPH receptor A2)

BHG712

almost2years

Divergent Roles of Ephrin-B2/EphB4 Guidance System in Pulmonary Hypertension. (PubMed, Hypertension)

In sum, pulmonary vascular remodeling was dependent on ephrin-B2-induced Eph receptor (erythropoietin-producing hepatocellular carcinoma receptor) forward signaling in SMC, while EphB4 receptor activity was necessary for RhoA expression in SMC, interaction with endothelial cells and vasoconstrictive components of pulmonary hypertension.

almost 2 years ago

Journal

RHOA (Ras homolog family member A) • EPHB4 (EPH receptor B4)

EFNB2 expression • EPHB4 expression • RHOA mutation

almost2years

Robust identification of common genomic biomarkers from multiple gene expression profiles for the prognosis, diagnosis, and therapies of pancreatic cancer. (PubMed, Comput Biol Med)

Finally, we suggested KGs-guided five repurposable drug molecules (Linsitinib, CX5461, Irinotecan, Timosaponin AIII, and Olaparib) and a new molecule (NVP-BHG712) against PC by molecular docking. The cross-validation and some literature reviews also supported our findings. Therefore, the finding of this study might be useful resources to the researchers and medical doctors for diagnosis, prognosis and therapies of PC by the wet-lab validation.

almost 2 years ago

Journal • Gene Expression Profile • PARP Biomarker

ADAM10 (ADAM Metallopeptidase Domain 10) • ITGB1 (Integrin Subunit Beta 1) • ITGB5 (Integrin Subunit Beta 5)

Lynparza (olaparib) • irinotecan • pidnarulex (CX-5461) • linsitinib (ASP7487) • BHG712

almost2years

sEphB4-HSA With RT+Chemo or Cetux in Patients With Intermediate to High Risk LAHNSCC (clinicaltrials.gov)

P1, N=3, Completed, University of Colorado, Denver | Active, not recruiting --> Completed

almost 2 years ago

Trial completion • Combination therapy • Metastases

EGFR (Epidermal growth factor receptor)

EGFR expression • CDKN2A negative

Erbitux (cetuximab) • cisplatin • carboplatin • sEphB4-HSA

almost2years

P30CA014089: Recombinant EphB4-HSA Fusion Protein and Pembrolizumab, MK-3475 (clinicaltrials.gov)

P2a, N=42, Active, not recruiting, University of Southern California | Trial completion date: Mar 2024 --> Mar 2025 | Trial primary completion date: Mar 2023 --> Mar 2024

almost 2 years ago

Trial completion date • Trial primary completion date • Combination therapy • IO biomarker

PD-L1 (Programmed death ligand 1) • BRAF (B-raf proto-oncogene) • ALK (Anaplastic lymphoma kinase) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS)

PD-L1 expression

Keytruda (pembrolizumab) • sEphB4-HSA

2years

A Study of sEphB4-HSA in Kaposi Sarcoma (clinicaltrials.gov)

P2, N=65, Recruiting, Vasgene Therapeutics, Inc | Trial completion date: Jun 2022 --> Jun 2025 | Trial primary completion date: Jun 2022 --> Dec 2024

2 years ago

Trial completion date • Trial primary completion date

CD4 (CD4 Molecule)

sEphB4-HSA

2years

A Phase II Study of sEphB4-HSA in Metastatic Castration-Resistant Prostate Cancer. (PubMed, Clin Genitourin Cancer)

In patients with mCRPC who progressed on prior second generation AR-targeted therapy, sEphB4-HSA monotherapy had no discernable anti-tumor activity.

2 years ago

P2 data • Journal

EPHB4 (EPH receptor B4)

sEphB4-HSA

2years

Recombinant Albumin Fusion Protein sEphB4-HSA in Treating Patients With Metastatic or Recurrent Solid Tumors (clinicaltrials.gov)

P2, N=102, Terminated, University of Southern California | Active, not recruiting --> Terminated; Lack of funding

2 years ago

Trial termination

KRAS (KRAS proto-oncogene GTPase)

KRAS mutation

sEphB4-HSA

2years

EphrinB2 Inhibition and Pembrolizumab in Metastatic Urothelial Carcinoma. (PubMed, J Clin Oncol)

The combination of sEphB4-HSA and pembrolizumab appears synergistic with improved OS and ORR compared with historical data for programmed death 1/programmed death ligand 1 monotherapy.

2 years ago

Journal • PD(L)-1 Biomarker

PD-L1 (Programmed death ligand 1) • EPHB4 (EPH receptor B4)

Keytruda (pembrolizumab) • sEphB4-HSA

over2years

sEphB4-HSA in Treating Patients With Kaposi Sarcoma (clinicaltrials.gov)

P2, N=20, Recruiting, AIDS Malignancy Consortium | Trial completion date: Nov 2022 --> Apr 2024 | Trial primary completion date: Nov 2022 --> Mar 2024

over 2 years ago

Trial completion date • Trial primary completion date

EPHB4 (EPH receptor B4)

sEphB4-HSA

almost3years

sEphB4-HSA With RT+Chemo or Cetux in Patients With Intermediate to High Risk LAHNSCC (clinicaltrials.gov)

P1, N=3, Active, not recruiting, University of Colorado, Denver | Trial primary completion date: Dec 2021 --> May 2021

almost 3 years ago

Trial primary completion date • Combination therapy

EGFR (Epidermal growth factor receptor)

EGFR expression • CDKN2A negative

Erbitux (cetuximab) • sEphB4-HSA

almost3years

Combinatorial therapy using RNAi and curcumin nano-architectures regresses tumors in breast and colon cancer models. (PubMed, Nanoscale)

While mammary tumors showed a considerable decrease in size, oral administration of the biodrug conjugate to Apc knockout colon models prolonged the animal survival period by six months. Hence, this study has provided empirical proof that the combinatorial approach involving RNA interference and nanotechnology is a promising alliance for next-generation cancer therapeutics.

almost 3 years ago

Preclinical • Journal

EPHB4 (EPH receptor B4)

EPHB4 expression • EPHB4 overexpression

almost3years

EphB4-HSA Fusion Protein and Cytarabine /or Liposomal Vincristine in Patients With Recurrent or Refractory Acute Leukemia (clinicaltrials.gov)

P1, N=3, Terminated, University of Southern California | N=44 --> 3 | Recruiting --> Terminated; Study drug supply issue

almost 3 years ago

Clinical • Enrollment change • Trial termination • Combination therapy

EPHB4 (EPH receptor B4)

sEphB4-HSA • Marqibo (vincristine liposomal)

almost3years

EFNB1 Acts as a Novel Prognosis Marker in Glioblastoma through Bioinformatics Methods and Experimental Validation. (PubMed, J Oncol)

Finally, EFNB1 inhibition was found to block cell proliferation and migration in GBM cells. The above results indicate that EFNB1 participates in cancer immunity and progression, which is the candidate biomarker for GBM.

almost 3 years ago

Journal

EPHB4 (EPH receptor B4) • STMN2 (Stathmin 2) • THY1 (Thy-1 membrane glycoprotein)

almost3years

P30CA014089: Recombinant EphB4-HSA Fusion Protein and Pembrolizumab, MK-3475 (clinicaltrials.gov)

P2a, N=42, Active, not recruiting, University of Southern California | Recruiting --> Active, not recruiting | Trial completion date: Mar 2022 --> Mar 2024 | Trial primary completion date: Mar 2021 --> Mar 2023

almost 3 years ago

Clinical • Enrollment closed • Trial completion date • Trial primary completion date • Combination therapy • IO biomarker

PD-L1 (Programmed death ligand 1) • BRAF (B-raf proto-oncogene) • ALK (Anaplastic lymphoma kinase) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS)

PD-L1 expression

Keytruda (pembrolizumab) • sEphB4-HSA

almost3years

TAD1822-7 induces ROS-mediated apoptosis of HER2 positive breast cancer by decreasing E-cadherin in an EphB4 dependent manner. (PubMed, Life Sci)

Mechanistic investigation revealed that TAD blockades both EphB4 positive signal transduction and activation of HER2 signal transduction, thereby suppressing E-cadherin/TGF-β/p-Smad2/3 signaling axis to elicit ROS-dependent endogenous mitochondrial apoptosis. Together, these findings not only provide a new approach for HER2-BC therapy but also increase our understanding of the regulating effect of E-cadherin by HER2 and EphB4 in ROS-mediated apoptosis.

almost 3 years ago

Journal

HER-2 (Human epidermal growth factor receptor 2) • CDH1 (Cadherin 1) • TGFB1 (Transforming Growth Factor Beta 1) • EPHB4 (EPH receptor B4)

HER-2 positive • ROS1 positive • CDH1 expression

3years

sEphB4-HSA With RT+Chemo or Cetux in Patients With Intermediate to High Risk LAHNSCC (clinicaltrials.gov)

P1, N=3, Active, not recruiting, University of Colorado, Denver | Recruiting --> Active, not recruiting | N=30 --> 3 | Trial completion date: Sep 2021 --> Dec 2022 | Trial primary completion date: Sep 2021 --> Dec 2021

3 years ago

Clinical • Enrollment closed • Enrollment change • Trial completion date • Trial primary completion date • Combination therapy

EGFR (Epidermal growth factor receptor)

EGFR expression • CDKN2A negative

Erbitux (cetuximab) • sEphB4-HSA

3years

EPHB4 Regulates the Proliferation and Metastasis of Oral Squamous Cell Carcinoma through the HMGB1/NF-κB Signalling Pathway. (PubMed, J Cancer)

Downregulation of HMGB1 inhibited the proliferation and metastasis of OSCC cells and inhibited NF-κB phosphorylation activation but did not affect EPHB4 expression. This study revealed the mechanism by which EPHB4 promotes the proliferation and metastasis of OSCC by activating the HMGB1-mediated NF-κB signalling pathway, which can be exploited as a novel marker or therapeutic target to control metastasis and improve the survival rate of OSCC.

3 years ago

Journal

HMGB1 (High Mobility Group Box 1) • EPHB4 (EPH receptor B4)

EPHB4 expression

3years

EphB4 as a Novel Target for the EGFR-Independent Suppressive Effects of Osimertinib on Cell Cycle Progression in Non-Small Cell Lung Cancer. (PubMed, Int J Mol Sci)

EphB4 is associated with the EGFR-independent suppressive effects of osimertinib on cell cycle and with a poor clinical outcome. Osimertinib can exert significant growth inhibitory effects in EGFR-mutated NSCLC patients with a high EphB4 status.

3 years ago

Journal

EGFR (Epidermal growth factor receptor) • CCND1 (Cyclin D1) • EPHB4 (EPH receptor B4) • CDKN1A (Cyclin-dependent kinase inhibitor 1A)

EGFR mutation • EGFR expression • CCND1 expression

Tagrisso (osimertinib)

3years

Ligand-Dependent and Ligand-Independent Effects of Ephrin-B2-EphB4 Signaling in Melanoma Metastatic Spine Disease. (PubMed, Int J Mol Sci)

For solid metastasis treatment, EphB4 kinase inhibition induced prometastatic effects in the presence of endothelial Ephrin-B2. In the absence of endothelial Ephrin-B2, both therapies showed no effect on the growth of solid metastasis.

3 years ago

Journal

EPHB4 (EPH receptor B4)

over3years

miR-130-3p Promotes MTX-Induced Immune Killing of Hepatocellular Carcinoma Cells by Targeting EPHB4. (PubMed, J Healthc Eng)

Mitoxantrone (MTX) is an antitumor drug that can block type II topoisomerase...Overexpression of this target gene promotes emission of Calreticulin, ATP, and HMGB1 and subsequently promotes DCs maturation and proliferation of CD4+ T cells. In summary, our results demonstrated that miR-130-3p inhibits HCC cell proliferation and migration by targeting EPHB4 and promotes drug-induced immunogenic cell death.

over 3 years ago

Journal

CD4 (CD4 Molecule) • HMGB1 (High Mobility Group Box 1) • CALR (Calreticulin) • EPHB4 (EPH receptor B4)

mitoxantrone

over3years

Low Expression of EphB2, EphB3, and EphB4 in Bladder Cancer: Novel Potential Indicators of Muscular Invasion. (PubMed, Yonsei Med J)

Low expression of EphB receptors (B2, B3, and B4) can be a predictive marker for muscular invasion of bladder cancer.

over 3 years ago

Journal

EPHB2 (EPH Receptor B2) • EPHB4 (EPH receptor B4) • EPHB3 (EPH Receptor B3)

over3years

Tyrosine Phosphoproteomics of Patient-Derived Xenografts Reveals Ephrin Type-B Receptor 4 Tyrosine Kinase as a Therapeutic Target in Pancreatic Cancer. (PubMed, Cancers (Basel))

Immunohistochemistry-based validation using tissue microarrays from 346 patients with PDAC showed significant expression of EphB4 in >70% of patients. In summary, we present a comprehensive landscape of tyrosine phosphoproteome with EphB4 as a promising therapeutic target in pancreatic ductal adenocarcinoma.

over 3 years ago

Clinical • Journal

EPHB4 (EPH receptor B4)

EPHB4 expression

over3years

[VIRTUAL] Phase II trial of soluble EphB4-albumin in combination with PD-1 antibody (pembrolizumab) in relapsed/refractory head neck squamous cell carcinoma. (ASCO 2021)

1 . sEphB4-Alb was well tolerated in combination with PD-1 antibody . 2 .

over 3 years ago

P2 data • Combination therapy • PD(L)-1 Biomarker • IO biomarker

EPHB4 (EPH receptor B4)

Keytruda (pembrolizumab)

over3years

Recombinant Albumin Fusion Protein sEphB4-HSA in Treating Patients With Metastatic or Recurrent Solid Tumors (clinicaltrials.gov)

P2, N=102, Active, not recruiting, University of Southern California | Trial completion date: Sep 2021 --> Sep 2023 | Trial primary completion date: Sep 2020 --> Sep 2022

over 3 years ago

Clinical • Trial completion date • Trial primary completion date

KRAS (KRAS proto-oncogene GTPase)

KRAS mutation

sEphB4-HSA

over3years

Development of non-viral, ligand-dependent, EPHB4-specific chimeric antigen receptor T cells for treatment of rhabdomyosarcoma. (PubMed, Mol Ther Oncolytics)

The PB-EPHB4-CAR-T cells inhibited EPHB4-positive tumor cells without activating cell proliferation downstream of EPHB4, even after multiple tumor re-challenges and suppressed tumor growth in xenograft-bearing mice. Therefore, PB-EPHB4-CAR-T cells possess a memory-rich fraction without early T cell exhaustion and show potential as promising therapeutic agents for treating rhabdomyosarcoma and other EPHB4-positive tumors.

over 3 years ago

Journal • CAR T-Cell Therapy • PD(L)-1 Biomarker • IO biomarker

PD-1 (Programmed cell death 1) • EFNB2 (Ephrin B2) • EPHB4 (EPH receptor B4)

PD-1 expression • PD-1-L • EPHB4 expression • PD-1 underexpression

over3years

In vivo efficacy of tesevatinib in patient-derived xenograft glioblastoma models may be limited by tissue binding and compensatory signaling. (PubMed, Mol Cancer Ther)

Overall, tesevatinib efficacy in EGFR amplified PDX GBM models is robust in vitro but relatively modest in vivo, despite a high brain-to-plasma ratio. This discrepancy may be explained by drug-tissue binding and compensatory signaling.

over 3 years ago

Preclinical • Journal

ABCB1 (ATP Binding Cassette Subfamily B Member 1)

EGFR amplification

tesevatinib (KD019)

over3years

Sanguinarine combats hypoxia-induced activation of EphB4 and HIF-1α pathways in breast cancer. (PubMed, Phytomedicine)

Our results may bring insights to the hypoxia-induced pathways in breast cancers, and suggest sanguinarine as a promising candidate for EphB4 and HIF-1α-targeted inhibition.

over 3 years ago

Journal

HIF1A (Hypoxia inducible factor 1, alpha subunit) • EPHB4 (EPH receptor B4)

HIF1A expression • EPHB4 expression

over3years

The differential expression of EPHB4 and ephrin B2 in cutaneous squamous cell carcinoma according to the grade of tumor differentiation: a clinicopathological study. (PubMed, Int J Dermatol)

These results indicated that EPHB4 and ephrin B2 can be useful markers for poorly differentiated CSCC.

over 3 years ago

Clinical • Journal

EFNB2 (Ephrin B2) • EPHB4 (EPH receptor B4)

EPHB4 expression

almost4years

Inhibition of the erythropoietin-producing receptor EPHB4 antagonizes androgen receptor overexpression and reduces enzalutamide resistance. (PubMed, J Biol Chem)

Mechanistically, we found that EPHB4 stimulates the AR by inducing proto-oncogene c-Myc (c-Myc) expression. Taken together, these results provide critical insight into the mechanism of enzalutamide resistance in PCa, potentially offering a therapeutic avenue for enhancing the efficacy of enzalutamide to better manage this common malignancy.

almost 4 years ago

Journal

MYC (V-myc avian myelocytomatosis viral oncogene homolog) • AR (Androgen receptor) • EPHB4 (EPH receptor B4)

MYC expression • AR overexpression • AR expression • EPHB4 overexpression

Xtandi (enzalutamide capsule)

almost4years

sEphB4-HSA in Treating Patients With Kaposi Sarcoma (clinicaltrials.gov)

P2, N=20, Recruiting, AIDS Malignancy Consortium | Trial completion date: Nov 2020 --> Nov 2022 | Trial primary completion date: Nov 2020 --> Nov 2022

almost 4 years ago

Clinical • Trial completion date • Trial primary completion date

EPHB4 (EPH receptor B4)

sEphB4-HSA

almost4years

Inhibition of the erythropoietin-producing receptor EPHB4 antagonizes androgen receptor overexpression and reduces enzalutamide resistance. (PubMed, J Biol Chem)

almost 4 years ago

Journal

MYC (V-myc avian myelocytomatosis viral oncogene homolog) • AR (Androgen receptor) • EPHB4 (EPH receptor B4)

MYC expression • AR overexpression • AR expression • EPHB4 overexpression

Xtandi (enzalutamide capsule)

almost4years

Targeting the EphB4 receptor tyrosine kinase sensitizes HER2-positive breast cancer cells to Lapatinib. (PubMed, Cancer Lett)

Finally, we demonstrate that, in HER2-positive breast tumors, inhibition of EphB4 combined with Lapatinib is more effective than either alone. These findings provide new insights into the signaling networks dictating therapeutic response to Lapatinib as well as a rationale for co-targeting EphB4 in HER2-positive breast cancer.

almost 4 years ago

Journal

HER-2 (Human epidermal growth factor receptor 2) • MYC (V-myc avian myelocytomatosis viral oncogene homolog) • EPHB4 (EPH receptor B4)

HER-2 positive • HER-2 overexpression • EPHB4 expression • EPHB4 overexpression • HER-2 elevation

lapatinib

almost4years

[VIRTUAL] Comprehensive Genomic Sequencing in Thymic Epithelial Tumors: Identification of Multiple Poor Prognosis Biomarkers in Chinese Patients (IASLC-WCLC 2020)

The most altered genes are focused on signal pathways of cell cycle control, Chromatin remodeling/DNA methylation, PI3K/AKT1/MTOR, MAP kinase signaling and others.In addition, we firstly identified multiple poor prognosis biomarkers in Chinese thymic epithelial tumors patients. These poor prognosis biomarkers are mainly enriched in cell cycle control and PI3K/AKT1/MTOR pathways.

almost 4 years ago

Clinical • Tumor mutational burden

TP53 (Tumor protein P53) • HRAS (Harvey rat sarcoma viral oncogene homolog) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • AKT1 (V-akt murine thymoma viral oncogene homolog 1) • ASXL1 (ASXL Transcriptional Regulator 1) • MTAP (Methylthioadenosine Phosphorylase) • BAP1 (BRCA1 Associated Protein 1) • TET2 (Tet Methylcytosine Dioxygenase 2) • KMT2D (Lysine Methyltransferase 2D) • CDKN2B (Cyclin Dependent Kinase Inhibitor 2B) • TSC2 (TSC complex subunit 2) • STAG2 (Stromal Antigen 2) • MLL2 (Myeloid/lymphoid or mixed-lineage leukemia 2) • EPHB4 (EPH receptor B4)

TP53 mutation • ASXL1 mutation • CDKN2A deletion • KMT2D mutation • BAP1 mutation • HRAS mutation • PAK4 deletion • STAG2 mutation

FoundationOne® CDx

almost4years

Ephrin-B2-EphB4 communication mediates tumor-endothelial cell interactions during hematogenous spread to spinal bone in a melanoma metastasis model. (PubMed, Oncogene)

Timely harvesting of bone tissue after tumor cell injection and intravital bone microscopy revealed less tumor cells attached to ephrin-B2-positive endothelial cells. These results suggest that ephrin-B2-EphB4 communication influences bone metastasis formation by altering melanoma cell repulsion/adhesion to bone endothelial cells, and represents a molecular target for therapeutic intervention.

almost 4 years ago

Journal

EPHB4 (EPH receptor B4)

EPHB4 expression • EPHB4 overexpression

almost4years

[VIRTUAL] Metastatic Basaloid Squamous Cell Carcinoma of the Tongue with Ductal Differentiation Masquerading as Cutaneous Porocarcinoma (ASDP 2020)

Two month interval imaging showed a mild, but widespread decrease in tumor burden. This case of HPV-negative basaloid SCC of the tongue with ductal differentiation metastatic to the skin underscores the importance to clinical decision-making of differentiating porocarcinoma from its mimics.

almost 4 years ago

PD(L)-1 Biomarker • IO biomarker

TP53 (Tumor protein P53) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • PBRM1 (Polybromo 1) • CDKN2B (Cyclin Dependent Kinase Inhibitor 2B) • CDK6 (Cyclin-dependent kinase 6) • EPHB4 (EPH receptor B4)

TP53 mutation • PBRM1 mutation • miR-138 underexpression + miR-497 overexpression