Beta cells are essential drivers of pancreatic ductal adenocarcinoma development.

Pancreatic endocrine-exocrine crosstalk plays a key role in normal physiology and disease. For instance, endocrine islet beta (β) cell secretion of insulin or cholecystokinin (CCK) promotes progression of pancreatic adenocarcinoma (PDAC), an exocrine cell-derived tumor. However, the cellular and molecular mechanisms that govern endocrine-exocrine signaling in tumorigenesis remain incompletely understood.

IRF8 as a Novel Marker to Differentiate Between CD30-Positive Large Cell Lymphomas.

Objectives: Interferon regulatory factor 8 (IRF8) is a new biomarker shown to be positive in monocytic leukemias as well as in B cells. As a transcription factor, it plays a critical role in pre-B-cell differentiation and induction of tolerance pathways, among other functions. Given the frequent diagnostic dilemma in CD30-positive large cell lymphomas that could resemble both Hodgkin lymphoma and anaplastic large cell lymphoma (ALCL), we sought to determine whether IRF8 can be useful in distinguishing between these neoplasms that require different treatment strategies.

Global assessment of IRF8 as a novel cancer biomarker.

Interferon regulatory factor 8 (IRF8) is a member of the IRF family that is specific to the hematopoietic cell and is involved in regulating the development of human monocytic and dendritic-lineage cells, as well as B-cells. Because its utility as a sensitive and specific monoblast marker in the context of acute monocytic leukemias has been recently demonstrated, we hypothesized that it may also be useful as a novel immunohistochemical marker in myeloid sarcomas and blastic plasmacytoid dendritic cell neoplasms (BPDCNs) with respect to their differential diagnoses. In this retrospective study, we analyzed the IHC expression pattern of IRF8 in 385 patient samples across 30 types of cancers, referenced to their mRNA expression data available through The Cancer Genome Atlas.

Small-Molecule Activators of Protein Phosphatase 2A for the Treatment of Castration-Resistant Prostate Cancer.

Primary prostate cancer is generally treatable by androgen deprivation therapy, however, later recurrences of castrate-resistant prostate cancer (CRPC) that are more difficult to treat nearly always occur due to aberrant reactivation of the androgen receptor (AR). In this study, we report that CRPC cells are particularly sensitive to the growth-inhibitory effects of reengineered tricyclic sulfonamides, a class of molecules that activate the protein phosphatase PP2A, which inhibits multiple oncogenic signaling pathways. Treatment of CRPC cells with small-molecule activators of PP2A (SMAP) decreased cellular viability and clonogenicity and induced apoptosis.

The Advantages of Targeted Protein Degradation Over Inhibition: An RTK Case Study.

Proteolysis targeting chimera (PROTAC) technology has emerged over the last two decades as a powerful tool for targeted degradation of endogenous proteins. Herein we describe the development of PROTACs for receptor tyrosine kinases, a protein family yet to be targeted for induced protein degradation. The use of VHL-recruiting PROTACs against this protein family reveals several advantages of degradation over inhibition alone: direct comparisons of fully functional, target-degrading PROTACs with target-inhibiting variants that contain an inactivated E3 ligase-recruiting ligand show that degradation leads to more potent inhibition of cell proliferation and a more durable and sustained downstream signaling response, and thus addresses the kinome rewiring challenge seen with many receptor tyrosine kinase inhibitors.

Activation of tumor suppressor protein PP2A inhibits KRAS-driven tumor growth.

Targeted cancer therapies, which act on specific cancer-associated molecular targets, are predominantly inhibitors of oncogenic kinases. While these drugs have achieved some clinical success, the inactivation of kinase signaling via stimulation of endogenous phosphatases has received minimal attention as an alternative targeted approach. Here, we have demonstrated that activation of the tumor suppressor protein phosphatase 2A (PP2A), a negative regulator of multiple oncogenic signaling proteins, is a promising therapeutic approach for the treatment of cancers.