Molecular targeting of cancer stem cells has therapeutic potential for efficient treatment of cancer although relatively few specific targets have so far been identified. Hypoxia-inducible factor was recently shown to regulate tumorigenic capacity of glioma stem cells under hypoxic condition. Surprisingly, we found that, under normoxia, HIF1α signaling was selectively activated in the stem cells of mouse lymphoma and human acute myeloid leukemia (AML). HIF1a ShRNA and HIF inhibitors abrogated the colony forming unit activity of mouse lymphoma and human AML CSCs. Importantly, the HIF inhibitor echinomycin efficiently eradicated mouse lymphoma and serially transplantable human AML in xenogeneic model by preferential elimination of CSCs. HIF1α maintains mouse lymphoma CSCs by repressing a negative feedback loop in the Notch pathway. Taken together, our results demonstrate an essential function of HIF1α-Notch interaction in maintaining CSCs and provide an effective approach to target CSCs for therapy of hematological malignancies.

Peptide–drug conjugates (PDCs) represent an important class of therapeutic agents that combine one or more drug molecules with a short peptide through a biodegradable linker. This prodrug strategy uniquely and specifically exploits the biological activities and self-assembling potential of small molecule peptides to improve the treatment efficacy of medicinal compounds. We review here the recent progress in the design and synthesis of peptide–drug conjugates in the context of targeted drug delivery and cancer chemotherapy. We analyze carefully the key design features in choosing the peptide sequence and linker chemistry for the drug of interest, as well as the strategies to optimize the conjugate design. We highlight the recent progress in the design and synthesis of self-assembling peptide-drug amphiphiles to construct supramolecular nanomedicine and nanofiber hydrogels for both systemic and topical delivery of active pharmaceutical ingredients.

SUMMARY We recently reported that atypical teratoid rhabdoid tumors (ATRTs) comprise at least two transcriptional subtypes with different clinical outcomes; however, the mechanisms underlying therapeutic heterogeneity remained unclear. In this study, we analyzed 191 primary ATRTs and 10 ATRT cell lines to define the genomic and epigenomic landscape of ATRTs and identify subgroup-specific therapeutic targets. We found ATRTs segregated into three epigenetic subgroups with distinct genomic profiles, SMARCB1 genotypes, and chromatin landscape that correlated with differential cellular responses to a panel of signaling and epigenetic inhibitors. Significantly, we discovered that differential methylation of a PDGFRB-associated enhancer confers specific sensitivity of group 2 ATRT cells to dasatinib and nilotinib, and suggest that these are promising therapies for this highly lethal ATRT subtype.

Although several recent publications have suggested that microRNAs contribute to the pathogenesis of diabetic nephropathy, the role of miRNAs in vivo still remains poorly understood. Using an integrated in vitro and in vivo comparative miRNA expression array, we identified miR-29c as a signature miRNA in the diabetic environment. We validated our profiling array data by examining miR-29c expression in the kidney glomeruli obtained from db/db mice in vivo and in kidney microvascular endothelial cells and podocytes treated with high glucose in vitro. Functionally, we found that miR-29c induces cell apoptosis and increases extracellular matrix protein accumulation. Indeed, forced expression of miR-29c strongly induced podocyte apoptosis. Conversely, knockdown of miR-29c prevented high glucose-induced cell apoptosis. We also identified Sprouty homolog 1 (Spry1) as a direct target of miR-29c with a nearly perfect complementarity between miR-29c and the 3-untranslated region (UTR) of mouse Spry1. Expression of miR-29c decreased the luciferase activity of Spry1 when co-transfected with the mouse Spry1 3-UTR reporter construct. Overexpression of miR-29c decreased the levels of Spry1 protein and promoted activation of Rho kinase. Importantly, knockdown of miR-29c by a specific antisense oligonucleotide significantly reduced albuminuria and kidney mesangial matrix accumulation in the db/db mice model in vivo. These findings identify miR-29c as a novel target in diabetic nephropathy and provide new insights into the role of miR-29c in a previously unrecognized signaling cascade involving Spry1 and Rho kinase activation. MicroRNAs (miRNAs)2 comprise a broad class of small noncoding RNAs that negatively regulate gene expression by basepairing to partially complementary sites in the 3Ј-untranslated regions (UTR) of specific target mRNAs (1, 2). An emerging body of evidence suggests that miRNAs serve as important therapeutic targets in a wide range of complex human diseases, including cancer and cardiovascular diseases, by targeting multiple transcripts (3-6). Recent studies have also revealed the involvement of miRNAs in diabetic nephropathy (DN) (7-9). However, despite the growing evidence for the regulatory effects of miRNAs in DN, limited information is available on the consequences of modulating miRNAs expression in vivo.We hypothesized that an unbiased global miRNA expression profiling might reveal novel miRNAs, which may play critical regulatory roles in the pathogenesis of DN. Accordingly, by using an integrated in vitro and in vivo comparative miRNA expression profiling, we identified up-regulated miR-29c as a signature miRNA in the diabetic environment.Previously published work suggested that down-regulation of miR-29c resulted in cardiac fibrosis (10, 11). In contrast, herein we identified miR-29c as a signature miRNA in the diabetic milieu whose expression was increased in hyperglycemic conditions both in vitro and in vivo. Thus, our objective was to explore the role of increased miR-29c expression in DN.We found t...

Myeloid-derived suppressor cells (MDSC) contribute to immune suppression in cancer, but the mechanisms through which they drive metastatic progression are not fully understood. In this study, we show how MDSC convey stem-like qualities to breast cancer cells that coordinately help enable immune suppression and escape. We found that MDSC promoted tumor formation by enhancing breast cancer cell stem-like properties as well as by suppressing T cell activation. Mechanistic investigations indicated that these effects relied upon crosstalk between the STAT3 and NOTCH pathways in cancer cells, with MDSC inducing IL-6-dependent phosphorylation of STAT3 and activating NOTCH through nitric oxide (NO), leading to prolonged STAT3 activation. In clinical specimens of breast cancer, the presence of MDSC correlated with the presence of cancer stem-like cells (CSC) and independently predicted poor survival outcomes. Collectively, our work revealed an immune-associated mechanism that extrinsically confers cancer cell stemness properties and affects patient outcome. We suggest that targeting STAT3-NOTCH crosstalk between MDSC and CSC could offer a unique locus to improve cancer treatment, by coordinately targeting a coupled mechanism that enables cancer stemness and immune escape.