Identification and Characterization of a Small Molecule Bcl-2 Functional Converter.

Unlabelled: Cancer cells exploit the expression of anti-apoptotic protein Bcl-2 to evade apoptosis and develop resistance to therapeutics. High levels of Bcl-2 leads to sequestration of pro-apoptotic proteins causing the apoptotic machinery to halt. In this study, we report discovery of a small molecule, BFC1108 (5-chloro-N-(2-ethoxyphenyl)-2-[(4-methoxybenzyol)amino]benzamide), which targets Bcl-2 and converts it into a pro-apoptotic protein.

Head and Neck Cutaneous Soft-Tissue Sarcoma Demonstrate Sex and Racial/Ethnic Disparities in Incidence and Socioeconomic Disparities in Survival.

Background: Cutaneous soft-tissue sarcoma (CSTS) of the head and neck are rare and are known to have aggressive clinical course. The current study utilizes a population-based registry in the U.S.

Socioeconomic and insurance-related disparities in disease-specific survival among patients with metastatic bone disease.

Background: Approximately 5% of cancer patients in the United States presented with metastatic bone disease (MBD) at diagnosis. Current study explores the disparities in survival for patients with MBD.

Methods: Patients with the diagnosis of MBD at presentation for the five most common primary anatomical sites were extracted from Surveillance, Epidemiology, and End Results Census tract-level dataset (2010-2016).

Impact of local treatment modality on overall- and disease-specific survival for nonmetastatic pelvic and sacral Ewing sarcoma.

Purpose: The ideal local treatment modality for pelvic and sacral Ewing sarcoma (EWS) is controversial.

Methods: We present the data from the American College of Surgeon's National Cancer Database (NCDB) and the National Cancer Institute's Surveillance, Epidemiology and End Result (SEER) database to investigate the impact of local treatment modalities on survival for nonmetastatic pelvic and sacral Ewing sarcoma. Local treatment includes "surgery," "radiation," and a combination of "surgery and radiation.

Sex, racial/ethnic and socioeconomic disparities in patients with metastatic bone disease.

Background: We have analyzed sex, race/ethnicity or socioeconomic disparities in the incidence of metastatic bone disease (MBD).

Methods: Patients with the diagnosis of MBD at presentation for five most common primary anatomical sites was extracted from Surveillance, Epidemiology, and End Results Census tract-level dataset. Mean incidence of MBD for different sex, racial/ethnic and socioeconomic groups were compared.

Discovery and Mechanistic Characterization of a Select Modulator of AhR-regulated Transcription (SMAhRT) with Anti-cancer Effects.

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor and a member of the bHLH/PAS (basic Helix-Loop-Helix/Per-Arnt-Sim) family of proteins. The AhR was cloned and characterized for its role in mediating the toxicity of dioxins. Subsequent research has identified the role of AhR in suppression of cancer cell growth.

Analysis of tumor-infiltrating NK and T cells highlights IL-15 stimulation and TIGIT blockade as a combination immunotherapy strategy for soft tissue sarcomas.

Purpose: Given the unmet need for novel immunotherapy in soft tissue sarcoma (STS), we sought to characterize the phenotype and function of intratumoral natural killer (NK) and T cells to identify novel strategies to augment tumor-infiltrating lymphocyte (TIL) function.

Experimental Design: Using prospectively collected specimens from dogs and humans with sarcomas, archived specimens, and The Cancer Genome Atlas (TCGA) data, we evaluated blood and tumor NK and T cell phenotype and function and correlated those with outcome. We then assessed the effects of interleukin 15 (IL-15) stimulation on both NK and T cell activation and TIGIT upregulation.

Down-regulation of Skp2 expression inhibits invasion and lung metastasis in osteosarcoma.

Osteosarcoma (OS), the most common primary cancer of bone, exhibits a high propensity for local invasion and distant metastasis. This study sought to elucidate the role of S phase kinase-associated protein (Skp2) in osteosarcoma invasion and metastasis and to explore flavokawain A (FKA), a natural chalcone from kava extract, as a potential Skp2 targeting agent for preventing osteosarcoma progression. Skp2 was found to be overexpressed in multiple osteosarcoma cell lines, including 5 standard and 8 primary patient-derived cell lines.

Induction of apoptosis and suppression of tumor growth by Nur77-derived Bcl-2 converting peptide in chemoresistant lung cancer cells.

Resistance to chemotherapy is a major cause of treatment failure and poor overall survival in patients with lung cancer. Identification of molecular targets present in resistant cancer cells is essential for addressing therapeutic resistance and prolonging lung cancer patient survival. Members of the B-cell lymphoma 2 (Bcl-2) family of proteins are associated with chemotherapeutic resistance.

Identification of a Raloxifene Analog That Promotes AhR-Mediated Apoptosis in Cancer Cells.

We previously reported that raloxifene, an estrogen receptor modulator, is also a ligand for the aryl hydrocarbon receptor (AhR). Raloxifene induces apoptosis in estrogen receptor-negative human cancer cells through the AhR. We performed structure-activity studies with seven raloxifene analogs to better understand the structural requirements of raloxifene for induction of AhR-mediated transcriptional activity and apoptosis.

The aryl hydrocarbon receptor is required for induction of p21cip1/waf1 expression and growth inhibition by SU5416 in hepatoma cells.

The aryl hydrocarbon receptor (AhR) is a potential clinical target for cancer and autoimmune dysfunction. Identifying selective AhR modulators that produce desirable clinical outcomes represents an opportunity for developing new anti-cancer agents. Repurposing clinically-used drugs with established safety profiles that activate the AhR represents a good starting place to pursue this goal.

The aryl hydrocarbon receptor mediates leflunomide-induced growth inhibition of melanoma cells.

A novel role of the dihydroorotatedehydrogenase (DHODH) inhibitor leflunomide as a potential anti-melanoma therapy was recently reported (Nature 471:518-22, 2011). We previously reported that leflunomide strongly activates the transcriptional activity of the Aryl Hydrocarbon Receptor (AhR). We therefore tested whether the AhR regulates the anti-proliferative effects of leflunomide in melanoma.

The anti-inflammatory drug leflunomide is an agonist of the aryl hydrocarbon receptor.

Background: The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that mediates the toxicity and biological activity of dioxins and related chemicals. The AhR influences a variety of processes involved in cellular growth and differentiation, and recent studies have suggested that the AhR is a potential target for immune-mediated diseases.

Methodology/principal Findings: During a screen for molecules that activate the AhR, leflunomide, an immunomodulatory drug presently used in the clinic for the treatment of rheumatoid arthritis, was identified as an AhR agonist.

Modeling of the aryl hydrocarbon receptor (AhR) ligand binding domain and its utility in virtual ligand screening to predict new AhR ligands.

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor; the AhR Per-AhR/Arnt-Sim (PAS) domain binds ligands. We developed homology models of the AhR PAS domain to characterize previously observed intra- and interspecies differences in ligand binding using molecular docking. In silico structure-based virtual ligand screening using our model resulted in the identification of pinocembrin and 5-hydroxy-7-methoxyflavone, which promoted nuclear translocation and transcriptional activation of AhR and AhR-dependent induction of endogenous target genes.