GDF15 reprograms the microenvironment to drive the development of uveal melanoma liver metastases.

Uveal melanoma (UM) results in fatal liver metastasis, yet little is known about the interactions between UM and host cells in the tumor microenvironment that promote this distinctive proclivity. Here, we used single cell (sc)-RNA-Seq analysis of UM-hepatic stellate cell (HSC) co-cultures to demonstrate that HSCs enriched for UM cell states that expressed genes implicated in cell survival, metabolic reprogramming and angiogenesis. A lead candidate driver of HSC reprogramming was the TGF-β family member GDF15, which was associated with a metastatic UM phenotype.

A multi-step immune-competent genetic mouse model reveals phenotypic plasticity in uveal melanoma.

Uveal melanoma (UM) is a highly aggressive intraocular malignancy with limited therapeutic options for metastatic disease. Existing transgenic UM mouse models inadequately recapitulate human disease progression, while transplant models lack immune competence for studying the tumor immune microenvironment and therapeutic interventions. To address these limitations, we developed a genetically engineered mouse model incorporating stepwise genetic alterations implicated in human UM progression.

Selective inhibition of DNA ligase IV provides additional efficacy to the treatment of anaplastic thyroid cancer.

Background: Although the incidence of anaplastic thyroid carcinoma (ATC) is low (2.5% of thyroid cancer cases), this cancer has a very poor prognosis (survival rates < 5 months) and accounts for 14-39% of deaths. Conventional therapies based on surgery in combination with radiotherapy or chemotherapy showed limited effectiveness primarily due to the robust and protective DNA damage response in thyroid cancer cells.

HDAC11 activity contributes to MEK inhibitor escape in uveal melanoma.

We previously demonstrated that pan-HDAC inhibitors could limit escape from MEK inhibitor (MEKi) therapy in uveal melanoma (UM) through suppression of AKT and YAP/TAZ signaling. Here, we focused on the role of specific HDACs in therapy adaptation. Class 2 UM displayed higher expression of HDACs 1, 2, and 3 than Class 1, whereas HDACs 6, 8, and 11 were uniformly expressed.

MEK-ing the Most of It: Strategies to Co-target Gαq and MAPK in Uveal Melanoma.

Most uveal melanomas harbor mutations in Gαq and show constitutive MAPK activation. Although MEK inhibition has some efficacy against uveal melanoma, clinical responses are typically poor. The Gαq inhibitor-MEK inhibitor combination showed prolonged suppression of MAPK signaling in preclinical uveal melanoma models and led to improved therapeutic responses.

TGFα Promotes Chemoresistance of Malignant Pleural Mesothelioma.

: There is no standard chemotherapy for refractory or relapsing malignant pleural mesothelioma (MPM). Our previous reports nevertheless indicated that a combination of an anthracycline (doxorubicin) and a lysine deacetylase inhibitor (valproic acid, VPA) synergize to induce the apoptosis of MPM cells and reduce tumor growth in mouse models. A Phase I/II clinical trial indicated that this regimen is a promising therapeutic option for a proportion of MPM patients.

The role of epigenetics in malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is an almost invariably fatal cancer of the pleura due to asbestos exposure. Increasing evidence indicates that unresponsiveness to chemotherapy is due to epigenetic errors leading to inadequate gene expression in tumor cells. The availability of compounds that modulate epigenetic modifications, such as histone acetylation or DNA methylation, offers new prospects for treatment of MPM.

Curcumin ameliorates oxaliplatin-induced chemoresistance in HCT116 colorectal cancer cells in vitro and in vivo.

The aims of this study were to determine potency of oxaliplatin in combination with curcumin in oxaliplatin-resistant cell lines in vitro and to evaluate the efficacy of a novel curcumin formulation (Meriva®) alone and in combination with oxaliplatin in colorectal tumor-bearing mice, exploring relevant pharmacodynamic markers in vivo. Oxaliplatin-resistant HCT116 p53wt and p53(-/-) cell lines were generated, and the effects of oxaliplatin in combination with curcumin on resistance- and proliferation-associated proteins investigated. Eighty nude mice were implanted with HCT116 p53wt colorectal cancer cells before randomization into the following treatment groups: control; Meriva only; oxaliplatin only; Meriva + oxaliplatin.