Spherical Nucleic Acids as Precision Therapeutics for the Treatment of Cancer-From Bench to Bedside.

Spherical Nucleic Acids (SNAs) emerged as a new class of nanotherapeutics consisting of a nanoparticle core densely functionalized with a shell of radially oriented synthetic oligonucleotides. The unique three-dimensional architecture of SNAs protects the oligonucleotides from nuclease-mediated degradation, increases oligonucleotide bioavailability, and in the absence of auxiliary transfection agents, enables robust uptake into tumor and immune cells through polyvalent association with cell surface pattern recognition receptors. When composed of gene-regulatory small interfering (si)RNA or immunostimulatory DNA or RNA oligonucleotides, SNAs silence gene expression and induce immune responses superior to those raised by the oligonucleotides in their "free" form. Early phase clinical trials of gene-regulatory siRNA-based SNAs in glioblastoma (NCT03020017) and immunostimulatory Toll-like receptor 9 (TLR9)-agonistic SNAs carrying unmethylated CpG-rich oligonucleotides in solid tumors (NCT03086278) have shown that SNAs represent a safe, brain-penetrant therapy for inhibiting oncogene expression and stimulating immune responses against tumors. This review focuses on the application of SNAs as precision cancer therapeutics, summarizes the findings from first-in-human clinical trials of SNAs in solid tumors, describes the most recent preclinical efforts to rationally design next-generation multimodal SNA architectures, and provides an outlook on future efforts to maximize the anti-neoplastic activity of the SNA platform.

Cancer-associated mutation and beyond: The emerging biology of isocitrate dehydrogenases in human disease.

Isocitrate dehydrogenases (IDHs) are critical metabolic enzymes that catalyze the oxidative decarboxylation of isocitrate to α-ketoglutarate (αKG), NAD(P)H, and CO2. IDHs epigenetically control gene expression through effects on αKG-dependent dioxygenases, maintain redox balance and promote anaplerosis by providing cells with NADPH and precursor substrates for macromolecular synthesis, and regulate respiration and energy production through generation of NADH. Cancer-associated mutations in IDH1 and IDH2 represent one of the most comprehensively studied mechanisms of IDH pathogenic effect. Mutant enzymes produce (R)-2-hydroxyglutarate, which in turn inhibits αKG-dependent dioxygenase function, resulting in a global hypermethylation phenotype, increased tumor cell multipotency, and malignancy. Recent studies identified wild-type IDHs as critical regulators of normal organ physiology and, when transcriptionally induced or down-regulated, as contributing to cancer and neurodegeneration, respectively. We describe how mutant and wild-type enzymes contribute on molecular levels to disease pathogenesis, and discuss efforts to pharmacologically target IDH-controlled metabolic rewiring.

Genomic comparison of early-passage conditionally reprogrammed breast cancer cells to their corresponding primary tumors.

Conditionally reprogrammed cells (CRCs) are epithelial cells that are directly isolated from patients' specimens and propagated in vitro with feeder cells and a Rho kinase inhibitor. A number of these cells have been generated from biopsies of breast cancer patients, including ductal carcinoma in situ and invasive carcinomas. The characterization of their genomic signatures is essential to determine their ability to reflect the natural biology of their tumors of origin. In this study, we performed the genomic characterization of six newly established invasive breast cancer CRC cultures in comparison to the original patients' primary breast tumors (PBT) from which they derived. The CRCs and corresponding PBTs were simultaneously profiled by genome-wide array-CGH, targeted next generation sequencing and global miRNA expression to determine their molecular similarities in the patterns of copy number alterations (CNAs), gene mutations and miRNA expression levels, respectively. The CRCs' epithelial cells content and ploidy levels were also evaluated by flow cytometry. A similar level of CNAs was observed in the pairs of CRCs/PBTs analyzed by array-CGH, with >95% of overlap for the most frequently affected cytobands. Consistently, targeted next generation sequencing analysis showed the retention of specific somatic variants in the CRCs as present in their original PBTs. Global miRNA profiling closely clustered the CRCs with their PBTs (Pearson Correlation, ANOVA paired test, P<0.05), indicating also similarity at the miRNA expression level; the retention of tumor-specific alterations in a subset of miRNAs in the CRCs was further confirmed by qRT-PCR. These data demonstrated that the human breast cancer CRCs of this study maintained at early passages the overall copy number, gene mutations and miRNA expression patterns of their original tumors. The further characterization of these cells by other molecular and cellular phenotypes at late cell passages, are required to further expand their use as a unique and representative ex-vivo tumor model for basic science and translational breast cancer studies.