Targeting PP2A for cancer therapeutic modulation

Protein phosphatases play essential roles as negative regulators of kinases and signaling cascades involved in cytoskeletal organization.Protein phosphatase 2A(PP2A)is highly conserved and is the predominant serine/threonine phosphatase in the nervous system,constituting more than 70%of all neuronal phosphatases.PP2A is involved in diverse regulatory functions,including cell cycle progression,apoptosis,and DNA repair.Although PP2A has historically been identified as a tumor suppressor,inhibition of PP2A has paradoxically demonstrated potential as a therapeutic target for various cancers.LB100,a water-soluble,small-molecule competitive inhibitor of PP2A,has shown particular promise as a chemo-and radio-sensitizing agent.Preclinical success has led to a profusion of clinical trials on LB100 adjuvant therapies,including a phase I trial in extensive-stage small-cell lung cancer,a phase I/II trial in myelodysplastic syndrome,a phase II trial in recurrent glioblastoma,and a completed phase I trial assessing the safety of LB100 and docetaxel in various relapsed solid tumors.Herein,we review the development of LB100,the role of PP2A in cancer biology,and recent advances in targeting PP2A inhibition in immunotherapy.

Breast Cancer Therapies Present and Future

Significant advances in breast cancer treatment have been made where it is now possible to treat localized disease to a curable state. However, for approximately 30% of women with primary disease, metastatic breast cancer (MBC) or recurrent disease, treatment has remained challenging. Major obstacles in the effective treatment of breast cancer in these populations include: 1) the molecular heterogeneity of the disease;2) treatment of MBC and more specifically brain metastasis;and 3) defining combination therapies that address the evolution of resistance with disease relapse. The acknowledgement of these difficulties has led to an effort to further understand the roadblocks to therapy with the anticipation that more appropriate treatments will result. Here we describe the current state of breast cancer treatment, and the potential for improved therapy.

Understanding the transcriptional control of gene expression using ChIP-chip technology

Gene expression profiling using cDNA or high-density oligonucleotide microarray contributes signifi cantly to our understanding on the transcriptome of a given biological condition. Using this technology, huge number of differentially-expressed genes of interest have been identified in a broad range of circumstances. Making sense biologically on these genes using the recently-improved functional annotation and data integration has leveraged our understanding in diseases and their biological mechanisms. However, understanding the codes encrypt- ed in the cis-aeting regulatory regions and gaining insights into the circuitry of functional regulatory networks on the genomic scale will require additional empirical data sets that are capable of revealing the cohorts or regulons of the transcription and the dynamic progression of molecular events responsible for certain biological function.

Carrimycin,a first in-class anti-cancer agent,targets selenoprotein H to induce nucleolar oxidative stress and inhibit ribosome biogenesis

Carrimycin is a synthetic macrolide antibiotic that has been shown to have anti-cancer activity;however,its exact mechanism of action and molecular target were previously unknown.It was recently elucidated that Isovalerylspiramycin I(ISP I),the active component of carrimycin,targets selenoprotein H(SelH),a nucleolar reactive oxygen species-scavenging enzyme in the selenoprotein family.ISP I treatment accelerates SelH degradation,resulting in oxidative stress,disrupted ribosomal biogenesis,and apoptosis in tumor cells.Specifically,ISP I disrupts the association between RNA polymerase I and ribosomal DNA in the nucleolus.This inhibits ribosomal RNA transcription and subsequent ribosomal assembly,which prevents cancer cells from sustaining elevated rates of protein synthesis and cellular proliferation that are necessary for tumor growth and malignancy.In this review,we(1)describe the historical categorization and evolution of anti-cancer agents,including macrolide antibiotics,(2)outline the discovery of SelH as a target of ISP I,and(3)summarize the ways in which carrimycin has been used both clinically and at the bench to date and propose additional potential therapeutic uses.