To improve prognosis in recurrent glioblastoma we developed a treatment protocol based on a combination of drugs not traditionally thought of as cytotoxic chemotherapy agents but that have a robust history of being well-tolerated and are already marketed and used for other non-cancer indications. Focus was on adding drugs which met these criteria: a) were pharmacologically well characterized, b) had low likelihood of adding to patient side effect burden, c) had evidence for interfering with a recognized, well-characterized growth promoting element of glioblastoma, and d) were coordinated, as an ensemble had reasonable likelihood of concerted activity against key biological features of glioblastoma growth. We found nine drugs meeting these criteria and propose adding them to continuous low dose temozolomide, a currently accepted treatment for relapsed glioblastoma, in patients with recurrent disease after primary treatment with the Stupp Protocol. The nine adjuvant drug regimen, Coordinated Undermining of Survival Paths, CUSP9, then are aprepitant, artesunate, auranofin, captopril, copper gluconate, disulfiram, ketoconazole, nelfinavir, sertraline, to be added to continuous low dose temozolomide. We discuss each drug in turn and the specific rationale for use- how each drug is expected to retard glioblastoma growth and undermine glioblastoma's compensatory mechanisms engaged during temozolomide treatment. The risks of pharmacological interactions and why we believe this drug mix will increase both quality of life and overall survival are reviewed.

The alkylating agent temozolomide (TMZ) together with maximal safe bulk resection and focal radiotherapy comprises the standard treatment for glioblastoma (GB), a particularly aggressive and lethal primary brain tumor. GB affects 3.2 in 100,000 people who have an average survival time of around 14 months after presentation. Several key aspects make GB a difficult to treat disease, primarily including the high resistance of tumor cells to cell death-inducing substances or radiation and the combination of the highly invasive nature of the malignancy, i.e., treatment must affect the whole brain, and the protection from drugs of the tumor bulk—or at least of the invading cells—by the blood brain barrier (BBB). TMZ crosses the BBB, but—unlike classic chemotherapeutics—does not induce DNA damage or misalignment of segregating chromosomes directly. It has been described as a DNA alkylating agent, which leads to base mismatches that initiate futile DNA repair cycles; eventually, DNA strand breaks, which in turn induces cell death. However, while much is assumed about the function of TMZ and its mode of action, primary data are actually scarce and often contradictory. To improve GB treatment further, we need to fully understand what TMZ does to the tumor cells and their microenvironment. This is of particular importance, as novel therapeutic approaches are almost always clinically assessed in the presence of standard treatment, i.e., in the presence of TMZ. Therefore, potential pharmacological interactions between TMZ and novel drugs might occur with unforeseeable consequences.

CUSP9 treatment protocol for recurrent glioblastoma was published one year ago. We now present a slight modification, designated CUSP9*. CUSP9* drugs- aprepitant, artesunate, auranofin, captopril, celecoxib, disulfiram, itraconazole, sertraline, ritonavir, are all widely approved by regulatory authorities, marketed for non-cancer indications. Each drug inhibits one or more important growth-enhancing pathways used by glioblastoma. By blocking survival paths, the aim is to render temozolomide, the current standard cytotoxic drug used in primary glioblastoma treatment, more effective. Although esthetically unpleasing to use so many drugs at once, the closely similar drugs of the original CUSP9 used together have been well-tolerated when given on a compassionate-use basis in the cases that have come to our attention so far. We expect similarly good tolerability for CUSP9*. The combined action of this suite of drugs blocks signaling at, or the activity of, AKT phosphorylation, aldehyde dehydrogenase, angiotensin converting enzyme, carbonic anhydrase -2,- 9, -12, cyclooxygenase-1 and -2, cathepsin B, Hedgehog, interleukin-6, 5-lipoxygenase, matrix metalloproteinase -2 and -9, mammalian target of rapamycin, neurokinin-1, p-gp efflux pump, thioredoxin reductase, tissue factor, 20 kDa translationally controlled tumor protein, and vascular endothelial growth factor. We believe that given the current prognosis after a glioblastoma has recurred, a trial of CUSP9* is warranted.

Purpose Despite significant progress in cancer research many tumor entities still have an unfavorable prognosis. Activating Transcription Factor 5 (ATF5) is up-regulated in various malignancies and promotes apoptotic resistance. We evaluated the efficacy and mechanisms of the first described synthetic cell-penetrating inhibitor of ATF5 function, CP-d/n-ATF5-S1. Experimental Design Preclinical drug testing was performed in various treatment-resistant cancer cells and in vivo xenograft models. Results CP-d/n-ATF5-S1 reduced the transcript levels of several known direct ATF5 targets. It depleted endogenous ATF5 and induced apoptosis across a broad panel of treatment refractory cancer cell lines, sparing non-neoplastic cells. CP-d/n-ATF5-S1 promoted tumor cell apoptotic susceptibility in part by reducing expression of the deubiquitinase Usp9X and lead to diminished levels of anti-apoptotic Bcl-2 family members Mcl-1 and Bcl-2. In line with this, CP-d/n-ATF5-S1 synergistically enhanced tumor cell apoptosis induced by the BH3-mimetic ABT263 and the death ligand TRAIL. In vivo, CP-d/n-ATF5-S1 attenuated tumor growth as a single compound in melanoma, glioblastoma, prostate cancer and triple-receptor-negative breast cancer xenograft models. Finally, the combination treatment of CP-d/n-ATF5-S1 and ABT263 significantly reduced tumor growth in vivo more efficiently than each reagent on its own. Conclusions Our data support the idea that CP-d/n-ATF5-S1, administered as a single reagent or in combination with other drugs, holds promise as an innovative, safe and efficient anti-neoplastic agent against treatment-resistant cancers.

High-grade gliomas account for the majority of intra-axial brain tumors. Despite abundant therapeutic efforts, clinical outcome is still poor. Thus, new therapeutic approaches are intensely being investigated.

Certain gliomas often harbor a mutation in the activity center of IDH1 (R132H), which leads to the production of the oncometabolite 2-R-2-hydroxyglutarate (2-HG). In six model systems, including patient-derived stem cell-like glioblastoma cultures, inhibition of Bcl-xL induces significantly more apoptosis in IDH1-mutated cells than in wild-type IDH1 cells. Anaplastic astrocytoma samples with mutated IDH1 display lower levels of Mcl-1 than IDH1 wild-type tumors and specific knockdown of Mcl-1 broadly sensitizes glioblastoma cells to Bcl-xL inhibition-mediated apoptosis. Addition of 2-HG to glioblastoma cultures recapitulates the effects of the IDH mutation on intrinsic apoptosis, shuts down oxidative phosphorylation and reduces ATP levels in glioblastoma cells. 2-HG-mediated energy depletion activates AMPK (Threonine 172), blunting protein synthesis and mTOR signaling, culminating in a decline of Mcl-1. In an orthotopic glioblastoma xenograft model expressing mutated IDH1, Bcl-xL inhibition leads to long-term survival. These results demonstrate that IDH1-mutated gliomas are particularly vulnerable to Bcl-xL inhibition.

No abstract

The goal of this study is to enhance the efficacy of imipridones, a novel class of AKT/ERK inhibitors that displayed limited therapeutic efficacy against glioblastoma (GBM). Gene set enrichment, LC/MS, and extracellular flux analyses were used to determine the mechanism of action of novel imipridone compounds, ONC206 and ONC212. Orthotopic patient-derived xenografts were utilized to evaluate therapeutic potency. Imipridones reduce the proliferation of patient-derived xenograft and stem-like glioblastoma cell cultures and in multiple xenograft models ONC212 displayed the highest potency. High levels of c-myc predict susceptibility to growth inhibition and apoptosis induction by imipridones and increased host survival in orthotopic patient-derived xenografts. As early as 1 hour, imipridones elicit on-target inhibition, followed by dephosphorylation of GSK3β at serine 9. GSK3β promotes phosphorylation of c-myc at threonine 58 and enhances its proteasomal degradation. Moreover, inhibition of c-myc by BRD4 antagonists sensitizes for imipridone-induced apoptosis in stem-like GBM cells and Imipridones affect energy metabolism by suppressing both glycolysis and oxidative phosphorylation, which is accompanied by a compensatory activation of the serine-one carbon-glycine (SOG) pathway, involving the transcription factor ATF4. Interference with the SOG pathway through novel inhibitors of PHGDH results in synergistic cell death induction and These results suggest that c-myc expression predicts therapeutic responses to imipridones and that imipridones lead to suppression of tumor cell energy metabolism, eliciting unique metabolic vulnerabilities that can be exploited for clinical relevant drug combination therapies..