Cancer specific inhibitors reflective of unique metabolic needs, are rare. We describe a novel small molecule, Gboxin, that specifically inhibits primary mouse and human glioblastoma (GBM) cell growth but not mouse embryo fibroblasts or neonatal astrocytes. Gboxin rapidly and irreversibly compromises GBM oxygen consumption. Reliant on its positive charge, Gboxin associates with mitochondrial oxidative phosphorylation complexes in a proton gradient dependent manner and inhibits F0F1 ATP synthase activity. Gboxin resistant cells require a functional mitochondrial permeability transition pore that regulates pH impeding matrix accumulation. Administration of a pharmacologically stable Gboxin analog inhibits GBM allografts and patient derived xenografts. Gboxin toxicity extends to established human cancer cell lines of diverse organ origin and exposes the elevated proton gradient pH in cancer cell mitochondria as a new mode of action for antitumor reagent development.

Purpose Glioblastoma multiforme (GBM) is the most lethal form of brain cancer with a median survival of only 12–15 months. Current standard treatment consists of surgery followed by chemoradiation. The poor survival of GBM patients is due to aggressive tumor invasiveness, an inability to remove all tumor tissue, and an innate tumor chemo- and radioresistance. ATM, ataxia telangiectasia (A-T) mutated, is an excellent target for radiosensitizing GBM because of its critical role in regulating the DNA damage response and p53, among other cellular processes. As a first step toward this goal, we recently showed that the novel ATM kinase inhibitor KU-60019 reduced migration, invasion, growth, and potently radiosensitized human glioma cells in vitro. Experimental Design Using orthotopic xenograft models of GBM, we now show that KU-60019 is also an effective radiosensitizer in vivo. Human glioma cells expressing reporter genes for monitoring tumor growth and dispersal were grown intra-cranially, and KU-60019 was administered intra-tumorally by convection-enhanced delivery or osmotic pump. Results Our results demonstrate that the combined effect of KU-60019 and radiation significantly increased survival of mice 2–3 fold over controls. Importantly, we show that glioma with mutant p53 is much more sensitive to KU-60019 radiosensitization than genetically matched wild-type glioma. Conclusions Taken together, our results suggest that an ATM kinase inhibitor may be an effective radiosensitizer and adjuvant therapy for patients with mutant p53 brain cancers.

Highlights d Persister BRAF-mutant melanoma cells emerge during RAF and MEK inhibition d Persister cells escape cell-cycle arrest via sporadic receptordriven ERK pulses d ERK pulses arise spontaneously in neighboring cells via autocrine/paracrine signaling d Oncogenic vs. receptor-driven MAPK signaling are differentially sensitive to inhibitors

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Neurofibromatosis Type 1 (NF1) is an autosomal disorder that affects neural crest-derived tissues, leading to a wide spectrum of clinical presentations. Patients commonly present with plexiform neurofibromas, benign but debilitating growths that can transform into malignant peripheral nerve sheath tumors (MPNSTs), a main cause of mortality. Currently, surgery is the primary course of treatment for MPNST, but with the limitation that these tumors are highly invasive. Radiation therapy is another treatment option, but is undesirable because it can induce additional mutations. MPNST patients may also receive doxorubicin as therapy, but this DNA-intercalating agent has relatively low tumor specificity and limited efficacy. In this study, we exploited a robust genetically-engineered mouse model of MPNST that recapitulates human NF1 associated MPNST to identify a novel small chemical compound that inhibits tumor cell growth. Compound 21 (Cpd21) inhibits growth of all available in vitro models of MPNST and human MPNST cell lines, while remaining non-toxic to normally-dividing Schwann cells or mouse embryonic fibroblasts. We show that this compound delays the cell cycle and leads to cellular apoptosis. Moreover, Cpd21 can reduce MPNST burden in a mouse allograft model, underscoring the compound’s potential as a novel chemotherapeutic agent.

Gliomas are the most frequently occurring primary malignancies in the central nervous system, and glioblastoma multiforme (GBM) is the most common and most aggressive of these tumors. Despite vigorous basic and clinical studies over past decades, the median survival of patients with this disease remains at about one year. Recent studies have suggested that GBMs contain a subpopulation of tumor cells that displays stem cell characteristics and could therefore be responsible for in vivo tumor growth. We will summarize the major oncogenic pathways abnormally regulated in gliomas, and review the recent findings from mouse models that our laboratory as well as others have developed for the study of GBM. The concept of cancer stem cells in GBM and their potential therapeutic importance will also be discussed.

Detecting relative rather than absolute changes in extracellular signals enables cells to make decisions in constantly fluctuating environments. It is currently not well understood how mammalian signaling networks store the memories of past stimuli and subsequently use them to compute relative signals, that is perform fold change detection. Using the growth factor-activated PI3K-Akt signaling pathway, we develop here computational and analytical models, and experimentally validate a novel non-transcriptional mechanism of relative sensing in mammalian cells. This mechanism relies on a new form of cellular memory, where cells effectively encode past stimulation levels in the abundance of cognate receptors on the cell surface. The surface receptor abundance is regulated by background signal-dependent receptor endocytosis and down-regulation. We show the robustness and specificity of relative sensing for two physiologically important ligands, epidermal growth factor (EGF) and hepatocyte growth factor (HGF), and across wide ranges of background stimuli. Our results suggest that similar mechanisms of cell memory and fold change detection may be important in diverse signaling cascades and multiple biological contexts.