Summary Heterozygous mutation of IDH1 in cancers modifies IDH1 enzymatic activity, reprogramming metabolite flux and markedly elevating 2-hydroxyglutarate (2-HG). Here, we found that 2-HG depletion did not inhibit growth of several IDH1 mutant solid cancer types. To identify other metabolic therapeutic targets, we systematically profiled metabolites in endogenous IDH1 mutant cancer cells after mutant IDH1 inhibition and discovered a profound vulnerability to depletion of the coenzyme NAD+. Mutant IDH1 lowered NAD+ levels by downregulating the NAD+ salvage pathway enzyme nicotinate phosphoribosyltransferase (Naprt1), sensitizing to NAD+ depletion via concomitant nicotinamide phosphoribosyltransferase (NAMPT) inhibition. NAD+ depletion activated the intracellular energy sensor AMPK, triggered autophagy and resulted in cytotoxicity. Thus, we identify NAD+ depletion as a metabolic susceptibility of IDH1 mutant cancers.

AS1411 binds nucleolin (NCL) and is the first oligodeoxynucleotide aptamer to reach phase I and II clinical trials for the treatment of several cancers. However, the mechanisms by which AS1411 targets and kills glioma cells and tissues remain unclear. Here we report that AS1411 induces cell apoptosis and cycle arrest, and inhibits cell viability by up-regulation of p53 and down-regulation of Bcl-2 and Akt1 in human glioma cells. NCL was overexpressed in both nucleus and cytoplasm in human glioma U87, U251 and SHG44 cells compared to normal human astrocytes (NHA). AS1411 bound NCL and inhibited the proliferation of glioma cells but not NHA, which was accompanied with up-regulation of p53 and down-regulation of Bcl-2 and Akt1. Moreover, AS1411 treatment resulted in the G2/M cell cycle arrest in glioma cells, which was however abolished by overexpression of NCL. Further, AS1411 induced cell apoptosis, which was prevented by silencing of p53 and overexpression of Bcl-2. In addition, AS1411 inhibited the migration and invasion of glioma cells in an Akt1-dependent manner. Importantly, AS1411 inhibited the growth of glioma xenograft and prolonged the survival time of glioma tumor-bearing mice. These results revealed a promising treatment of glioma by oligodeoxynucleotide aptamer.

Meningiomas are the most common type of primary central nervous system tumors. Approximately, 80% of meningiomas are classified by the World Health Organization (WHO) as grade I, and 20% of these tumors are grade II and III, considered high-grade meningiomas (HGMs). Clinical control of HGMs, as well as meningiomas that relapse after surgery, and radiation therapy is difficult, and novel therapeutic approaches are necessary. However, traditional chemotherapies, interferons, hormonal therapies, and other targeted therapies have so far failed to provide clinical benefit. During the last several years, next generation sequencing has dissected the genetic heterogeneity of meningioma and enriched our knowledge about distinct oncogenic pathways driving different subtypes of meningiomas, opening up a door to new personalized targeted therapies. Molecular classification of meningioma allows a new design of clinical trials that assign patients to corresponding targeted agents based on the tumor genetic subtypes. In this review, we will shed light on emerging medical treatments of meningiomas with a particular focus on the new targets identified with genomic sequencing that have led to clinical trials testing novel compounds. Moreover, we present recent development of patient-derived preclinical models that provide platforms for assessing targeted therapies as well as strategies with novel mechanism of action such as oncolytic viruses.