Therapeutic Potential of 5'-Methylschweinfurthin G in Merkel Cell Polyomavirus-Positive Merkel Cell Carcinoma.

Merkel cell carcinoma (MCC) is a rare but aggressive form of skin cancer predominantly caused by the human Merkel cell polyomavirus (MCPyV). Treatment for MCC includes excision and radiotherapy of local disease, and chemotherapy or immunotherapy for metastatic disease. The schweinfurthin family of natural compounds previously displayed potent and selective growth inhibitory activity against the NCI-60 panel of human-derived cancer cell lines.

Cytotoxic Effects of the Schweinfurthin Analog 5'-Methylschweinfurthin G in Malignant Plasma Cells.

Introduction: Multiple myeloma (MM) is a B plasma cell malignancy currently incurable, and novel therapeutics are needed. Evidences regarding the effect of natural compound schweinfurthins suggest that hematological cancers showed growth inhibitory effects to this family of compounds at single nanomolar concentrations. In this study, we evaluated the cytotoxicity of the schweinfurthin synthetic analog 5'-methylschweinfurthin G (MeSG) in MM cell lines, to better understand the validity of this compound as a therapeutic candidate for further studies in MM.

RNAseq reveals extensive metabolic disruptions in the sensitive SF-295 cell line treated with schweinfurthins.

The schweinfurthin family of natural compounds exhibit a unique and potent differential cytotoxicity against a number of cancer cell lines and may reduce tumor growth in vivo. In some cell lines, such as SF-295 glioma cells, schweinfurthins elicit cytotoxicity at nanomolar concentrations. However, other cell lines, like A549 lung cancer cells, are resistant to schweinfurthin treatment up to micromolar concentrations.

Antipsychotic drugs elicit cytotoxicity in glioblastoma multiforme in a calcium-dependent, non-D receptor-dependent, manner.

Dopamine D -like receptor antagonists have been suggested as being potential anticancer therapeutics with specific utility for central nervous system cancers due to their ability to cross the blood-brain barrier. Despite a plethora of data reporting anticancer effects for D R antagonists in cell or animal studies, the ligand concentrations or doses required to achieve such effects greatly exceed the levels known to cause high degrees of occupancy of the D receptor. To resolve this conundrum, we interrogated a panel of glioblastoma multiforme (GBM) cell lines using D antagonists of varying chemotype.

Prostate Cancer Incidence and Aggressiveness in Appalachia versus Non-Appalachia Populations in Pennsylvania by Urban-Rural Regions, 2004-2014.

Background: Few studies have examined prostate cancer incidence and aggressiveness in urban-rural Appalachian populations. We examined these rates in urban-rural Appalachia and non-Appalachia Pennsylvania (PA), and the association between these areas and more aggressive prostate cancer at diagnosis.

Methods: Men, ages ≥ 40 years with a primary prostate cancer diagnosis, were identified from the 2004-2014 Pennsylvania Cancer Registry.

Prostate cancer in Pennsylvania: The role of older age at diagnosis, aggressiveness, and environmental risk factors on treatment and mortality using data from the Pennsylvania Cancer Registry.

Background: To assess: (a) cancer treatment in prostate cancer survivors (PCS) by age at diagnosis (ADx) and prostate cancer (PC) aggressiveness; (b) potential impact on PC mortality; and (c) these results in the context of environmental/behavioral risk factors on PCS in Pennsylvania.

Methods: Prostate cancer survivors ages ≥40 years were identified from the 2004-2014 Pennsylvania Cancer Registry (PCR). Demographic/clinical descriptors and PC treatment were extracted from PCR.

The Dopamine D2 Receptor Contributes to the Spheroid Formation Behavior of U87 Glioblastoma Cells.

Background: Glioblastoma multiforme (GBM) is a common and lethal cancer of the central nervous system. This cancer is difficult to treat because most anticancer therapeutics do not readily penetrate into the brain due to the tight control at the cerebrovascular barrier. Numerous studies have suggested that dopamine D2 receptor (D2R) antagonists, such as first generation antipsychotics, may have anticancer efficacy in vivo and in vitro.

Multi-dimensional analysis identifies an immune signature predicting response to decitabine treatment in elderly patients with AML.

Decitabine is a DNA-hypomethylating agent that has been widely applied for the treatment of acute myeloid leukaemia (AML) patients who are elderly or unfit for intensive therapy. Although effective, the complete response rate to decitabine is only around 30% and the overall survival remains poor. Emerging data support that regulation of DNA methylation is critical to control immune cell development, differentiation and activation.

Cancer and the Dopamine D Receptor: A Pharmacological Perspective.

The dopamine D receptor (DR) family is upregulated in many cancers and tied to stemness. Reduced cancer risk has been correlated with disorders such as schizophrenia and Parkinson's disease, in which dopaminergic drugs are used. DR antagonists are reported to have anticancer efficacy in cell culture and animal models where they have reduced tumor growth, induced autophagy, affected lipid metabolism, and caused apoptosis, among other effects.

Schweinfurthin natural products induce regression of murine melanoma and pair with anti-PD-1 therapy to facilitate durable tumor immunity.

Metastatic melanoma is a significant clinical problem with a 5-year survival rate of only 15-20%. Recent approval of new immunotherapies and targeted inhibitors have provided much needed options for these patients, in some cases promoting dramatic disease regressions. In particular, antibody-based therapies that block the PD-1/PD-L1 checkpoint inhibitory pathway have achieved an increased overall response rate in metastatic melanoma, yet durable response rates are reported only around 15%.

EomesT-bet CD8 T Cells Are Functionally Impaired and Are Associated with Poor Clinical Outcome in Patients with Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is a devastating blood cancer with poor prognosis. Immunotherapy targeting inhibitory pathways to unleash the antileukemia T-cell response is a promising strategy for the treatment of leukemia, but we must first understand the underlying molecular mechanisms. Eomesodermin (Eomes) and T-bet are both T-box transcription factors that regulate CD8 T-cell responses in a context-specific manner.

Brain cholesterol metabolism and Parkinson's disease.

Background: Circulating cholesterol levels have been linked to PD, but not directly to brain physiology.

Objective: To assess whether brain cholesterol metabolism is related to PD.

Methods: Sixty PD patients and 64 controls were recruited from an academic movement disorder clinic (2009-2012).

VISTA is highly expressed on MDSCs and mediates an inhibition of T cell response in patients with AML.

Treatment of acute myeloid leukemia (AML) remains challenging. Enhancement of anti-tumor responses by blocking negative immune regulators is a promising strategy for novel effective leukemia therapeutics. V-domain Ig suppressor of T-cell activation (VISTA) is a recently defined negative regulator mediating immune evasion in cancer.

Inhibiting geranylgeranyl diphosphate synthesis reduces nuclear androgen receptor signaling and neuroendocrine differentiation in prostate cancer cell models.

Background: Following androgen deprivation for the treatment of advanced adenocarcinoma of the prostate, tumors can progress to neuroendocrine prostate cancer (NEPC). This transdifferentiation process is poorly understood, but trafficking of transcriptional factors and/or cytoskeletal rearrangements may be involved. We observed the role of geranylgeranylation in this process by treatment with digeranyl bisphosphonate (DGBP), a selective inhibitor of geranylgeranyl pyrophosphate synthase which blocks the prenylation of small GTPases such as Rho and Rab family proteins, including Cdc42 and Rac1.

Blimp-1 impairs T cell function via upregulation of TIGIT and PD-1 in patients with acute myeloid leukemia.

Background: T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT) and programmed cell death protein 1 (PD-1) are important inhibitory receptors that associate with T cell exhaustion in acute myeloid leukemia (AML). In this study, we aimed to determine the underlying transcriptional mechanisms regulating these inhibitory pathways. Specifically, we investigated the role of transcription factor B lymphocyte-induced maturation protein 1 (Blimp-1) in T cell response and transcriptional regulation of TIGIT and PD-1 in AML.

PIGN gene expression aberration is associated with genomic instability and leukemic progression in acute myeloid leukemia with myelodysplastic features.

Previous studies have linked increased frequency of glycosylphosphatidylinositol-anchor protein (GPI-AP) deficiency with genomic instability and the risk of carcinogenesis. However, the underlying mechanism is still not clear. A randomForest analysis of the gene expression array data from 55 MDS patients (GSE4619) demonstrated a significant (p = 0.

Targeting protein geranylgeranylation slows tumor development in a murine model of prostate cancer metastasis.

The isoprenoid biosynthetic pathway (IBP) plays a critical role in providing substrates and enzymes necessary for the post-translational modification and thus activation of a number of proteins involved in prostate cancer metastasis. Previous work by our lab found novel compound disodium [(6Z,11E,15E)-9-[bis(sodiooxy)phosphoryl]-17-hydroxy-2,6,12,16-tetramethyheptadeca-2,6,11,15-tetraen-9-yl]phosphonate (GGOHBP), which inhibits the IBP enzyme geranylgeranyl diphosphate synthase (GGDPS), reduced protein geranylgeranylation without altering protein farnesylation. This activity significantly reduced adrenal gland tumor burden in a murine model of human prostate cancer metastasis which relied on treatment of established disease.

GBM-associated mutations and altered protein expression are more common in young patients.

Background: Geriatric glioblastoma (GBM) patients have a poorer prognosis than younger patients, but IDH1/2 mutations (more common in younger patients) confer a favorable prognosis. We compared key GBM molecular alterations between an elderly (age ≥ 70) and younger (18 < = age < = 45) cohort to explore potential therapeutic opportunities.

Results: Alterations more prevalent in the young GBM cohort compared to the older cohort (P < 0.

Phase 1 Study of Tabalumab, a Human Anti-B-Cell Activating Factor Antibody, and Bortezomib in Patients with Relapsed/Refractory Multiple Myeloma.

Purpose: Tabalumab, a human mAb that neutralizes B-cell-activating factor (BAFF), demonstrated antitumor activity in xenograft models of multiple myeloma. Here we report on a phase I study of relapsed/refractory multiple myeloma patients in which the primary objective was to identify a tolerable and potentially efficacious dose of tabalumab when combined with bortezomib.

Experimental Design: Forty-eight patients were enrolled; 20 to the dose-escalation cohort, and 28 to cohort expansion in which a dose of 100 mg of tabalumab was evaluated.

3-Deoxyschweinfurthin B Lowers Cholesterol Levels by Decreasing Synthesis and Increasing Export in Cultured Cancer Cell Lines.

The schweinfurthins have potent antiproliferative activity in multiple glioblastoma multiforme (GBM) cell lines; however, the mechanism by which growth is impeded is not fully understood. Previously, we demonstrated that the schweinfurthins reduce the level of key isoprenoid intermediates in the cholesterol biosynthetic pathway. Herein, we describe the effects of the schweinfurthins on cholesterol homeostasis.