Targeted therapeutics made significant advances in the treatment of patients with advanced clear cell renal cell carcinoma (ccRCC). Resistance and serious adverse events associated with standard therapy of patients with advanced ccRCC highlight the need to identify alternative ‘druggable’ targets to those currently under clinical development. Although the Von Hippel-Lindau (VHL) and Polybromo1 (PBRM1) tumor-suppressor genes are the two most frequently mutated genes and represent the hallmark of the ccRCC phenotype, stable expression of hypoxia-inducible factor-1α/2α (HIFs), microRNAs-210 and -155 (miR_S), transforming growth factor-beta (TGF-ß), nuclear factor erythroid 2-related factor 2 (Nrf2), and thymidine phosphorylase (TP) are targets overexpressed in the majority of ccRCC tumors. Collectively, these altered biomarkers are highly interactive and are considered master regulators of processes implicated in increased tumor angiogenesis, metastasis, drug resistance, and immune evasion. In recognition of the therapeutic potential of the indicated biomarkers, considerable efforts are underway to develop therapeutically effective and selective inhibitors of individual targets. It was demonstrated that HIF_S, miR_S, Nrf2, and TGF-ß are targeted by a defined dose and schedule of a specific type of selenium-containing molecules, seleno-L-methionine (SLM) and methylselenocystein (MSC). Collectively, the demonstrated pleiotropic effects of selenium were associated with the normalization of tumor vasculature, and enhanced drug delivery and distribution to tumor tissue, resulting in enhanced efficacy of multiple chemotherapeutic drugs and biologically targeted molecules. Higher selenium doses than those used in clinical prevention trials inhibit multiple targets altered in ccRCC tumors, which could offer the potential for the development of a new and novel therapeutic modality for cancer patients with similar selenium target expression. Better understanding of the underlying mechanisms of selenium modulation of specific targets altered in ccRCC could potentially have a significant impact on the development of a more efficacious and selective mechanism-based combination for the treatment of patients with cancer.

Breast cancer, melanoma and glioblastoma cells undergo cell-mediated aggregation and aggregate coalescence in a transparent 3D Matrigel environment. Cells from normal tissue and non-tumorigenic cell lines do not exhibit these behaviors. Here, 266 monoclonal antibodies (mAbs) demonstrated to interact with a wide variety of membrane, secreted and matrix proteins, have been screened for their capacity to block these tumorigenic cell-specific behaviors in a 3D environment. Remarkably, only six of the 266 tested mAbs exhibited blocking activity, four targeting integrin ß-1, one targeting integrin α-3 and one targeting CD44. Colocalization of integrins ß-1 and α-3 in fixed cells and in live aggregates suggests that the integrin α-3 ß-1 dimer plays a central role in cancer cell aggregation in the 3D environment provided by Matrigel. Our results suggest that blocking by anti-integrin and anti-CD44 mAbs involves interference in cell-cell interactions.

Purpose: Data on clear-cell renal cell carcinoma (ccRCC) xenografts defined the seleno-L-methionine (SLM) dose and the plasma selenium concentrations associated with the enhancement of hypoxia-inducible factor-1α/2α degradation, stabilization of tumor vasculature, enhanced drug delivery, and efficacy of axitinib. The data provided the rationale for the development of this phase I clinical trial of SLM and axitinib in advanced or metastatic relapsed ccRCC. Patients and Methods: Patients were ≥18 years with histologically and radiologically confirmed advanced or metastatic ccRCC who had received at least one prior systemic therapy, which could include axitinib (last dose ≥6 months prior to enrollment). Escalating dose levels of SLM (2,500, 3,000, and 4,000 μg) were administered orally twice daily for 14 days and then once daily concurrently with axitinib 5 mg twice daily using a 3 + 3 design in phase I. Patients were treated at the 4,000 μg dose level in the expansion cohort to obtain preliminary estimates of efficacy. Results: No dose-limiting toxicities occurred at the 4,000 μg SLM dose level. Among the 27 patients treated with 4,000 μg of SLM, the overall response rate was 55.6%, median duration of response was 18.4 months, median progression-free survival was 14.8 months, and median overall survival was 19.6 months. Preliminary results have shown that plasma selenium concentrations, inhibition of TGF-β1, and stabilization of tumor vasculature by SLM are time dependent. Conclusions: SLM (4,000 μg) in sequential combination with axitinib is well tolerated with encouraging efficacy.

Alopecia areata (AA) is an autoimmune disease defined by hair loss and peribulbar infiltrate of CD8 and CD4 T cells. Prior studies have focused on the role of CD8 T cells in the development of AA. Multiple roles for CD4 T cell help have been demonstrated for support of CD8 T cell responses; however, the role of CD4 T cells in AA remains unclear. Here, we demonstrate that CD4 T cells from the skin-draining lymph nodes (SDLNs) of AA mice transferred disease to recipient mice. These cells exhibited a T helper type 1 (T _H 1) effector transcriptional and phenotypic profile, and their pathogenic activity required endogenous CD8 T cells and host IFN-γ responsiveness. Targeted deletion of CD4 T cell–mediated production of IFN-γ abrogated the ability of this cell population to transfer disease. Together, these data provide mechanistic insights into pathways driving AA development, strengthening our understanding of the disease and inviting studies into exploring alternative therapeutic strategies for human patients.

Representativeness of Study Participants.

Cutaneous T cell lymphoma (CTCL) comprises a clinically and molecularly heterogeneous group of skin-homing non-Hodgkin lymphomas for which robust biomarkers remain limited. Prior single-cell RNA sequencing (scRNA-seq) studies have provided important insights into CTCL biology, but many of these prior studies have been limited by small sample sizes and focused on niche questions of interest. Additionally, many studies have suffered from pseudoreplication, resulting in inflated test statistics and reduced external validity. Here, we assembled and integrated scRNA-seq data spanning 244 unique samples and 132 patients across CTCL, healthy control (HC), and benign inflammatory dermatoses (BID) conditions, generating the most diverse atlas of CTCL to date. Following identification of malignant cell populations and heterogeneous, within-sample gene expression alterations, we applied pseudobulk aggregation and robust linear mixed-effects modeling to nominate recurrent changes across this highly heterogeneous patient cohort. Interrogation of the skin microenvironment identified significant compositional and cell type-specific expression changes in CTCL lesions as compared to control lesions and across clinical stages of disease. Finally, we used unbiased clustering to identify stable, molecularly defined subtypes of disease that were predictive of outcome in an independent dataset. Together, this study provides a rigorous analysis of the most diverse scRNA-seq dataset of CTCL ever compiled, nominating specific alterations in cell type composition and gene expression across malignant cell and microenvironmental populations with significant clinical implications.