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Lukas R.V.,University of Chicago | Wainwright D.A.,Northwestern University | Wainwright D.A.,Northwestern Brain Tumor Institute | Laterra J.J.,Johns Hopkins University | Laterra J.J.,Sidney Kimmel Comprehensive Cancer Center
Future Oncology | Year: 2016

The American Neurological Association (ANA) held its annual meeting in Chicago, IL, USA on 27-29 September 2015. The Scientific Programming Advisory Committee was chaired by Dr S Pleasure from the University of California-San Francisco (CA, USA). The Neuro-Oncology session, chaired by Dr A Pruitt from the University of Pennsylvania (PA, USA) and cochaired by Dr J Laterra from Johns Hopkins University (MD, USA), was held on 27 September 2015. Speakers included Dr D Wainwright (Northwestern University, IL, USA), Dr N Kolb (University of Utah, UT, USA), Dr A Nath (NINDS/NIH, MD, USA), Dr D Franz (Cincinnati Children's Hospital, OH, USA) and Dr R Lukas (University of Chicago, IL, USA). A summary of key presentations from the Neuro-Oncology section of the 2015 American Neurological Association annual meeting is reported. Preclinical and clinical advances in the use of immunotherapies for the treatment of primary and metastatic CNS tumors are covered. Particular attention is paid to the enzyme indoleamine dioxygenase and the immune checkpoints CTLA4 and PD1 and their ligands. Specific nervous system toxicities associated with novel immunotherapies are also discussed. The recent success of targeting the mTOR pathway in the neurocutaneous syndrome tuberous sclerosis is detailed. Finally, important early steps in our understanding of the common toxicity of chemotherapy induced neuropathy are reviewed. Source


Li Y.,Institute of Hematology | Feng H.,Shanghai JiaoTong University | Gu H.,Institute of Hematology | Lewis D.W.,University of Pittsburgh | And 11 more authors.
Nature Communications | Year: 2013

Mechanisms underlying the reprogramming process of induced pluripotent stem cells remain poorly defined. Like tumorigenesis, generation of induced pluripotent stem cells was shown to be suppressed by the Trp53 (p53) pathway, at least in part via p21Cdkn1a (p21)-mediated cell cycle arrest. Here we examine the role of PUMA, a pro-apoptotic mediator of p53, during somatic reprogramming in comparison to p21 in the p53 pathway. Using mouse strains deficient in these molecules, we demonstrate that PUMA is an independent mediator of the negative effect of p53 on induced pluripotent stem cell induction. PUMA deficiency leads to a better survival rate associated with reduced DNA damage and fewer chromosomal aberrations in induced pluripotent stem cells, whereas loss of p21 or p53 results in an opposite outcome. Given these new findings, PUMA may serve as a distinct and more desirable target in the p53 pathway for induced pluripotent stem cell generation, thereby having important implications for potential therapeutic applications of induced pluripotent stem cells. © 2013 Macmillan Publishers Limited. All rights reserved. Source


Jane E.P.,Childrens Hospital of Pittsburgh | Premkumar D.R.,Childrens Hospital of Pittsburgh | DiDomenico J.D.,Childrens Hospital of Pittsburgh | Hu B.,Northwestern Brain Tumor Institute | And 7 more authors.
Molecular Cancer Therapeutics | Year: 2013

Antiapoptotic proteins are commonly overexpressed in gliomas, contributing to therapeutic resistance. We recently reported that clinically achievable concentrations of the Bcl-2/Bcl-xL inhibitor ABT-737 failed to induce apoptosis in glioma cells, with persistent expression of survivin and Mcl-1. To address the role of these mediators in glioma apoptosis resistance, we analyzed the effects of YM-155, a survivin suppressant, on survival on a panel of glioma cell lines. YM-155 inhibited cell growth and downregulated survivin and Mcl-1 in a dose- and cell line-dependent manner. While U373, LN18, LNZ428, T98G, LN229, and LNZ308cells exhibited an IC50 of 10 to 75 nmol/L, A172 cells were resistant (IC50 ~ 250 nmol/L). No correlation was found between sensitivity to YM-155 and baseline expression of survivin or cIAP-1/cIAP-2/XIAP. However, strong correlation was observed between EGF receptor (EGFR) activation levels and YM-155 response, which was confirmed using EGFR-transduced versus wild-type cells. Because we postulated that decreasing Mcl-1 expression may enhance glioma sensitivity to ABT-737, we examined whether cotreatment with YM-155 promoted ABT-737 efficacy. YM-155 synergistically enhanced ABT-737-induced cytotoxicity and caspasedependent apoptosis. Downregulation of Mcl-1 using short hairpin RNA also enhanced ABT-737-inducing killing, confirming an important role for Mcl-1 in mediating synergism between ABT-737 and YM-155. As with YM-155 alone, sensitivity to YM-155 and ABT-737 inversely correlated with EGFR activation status. However, sensitivity could be restored in highly resistant U87-EGFRvIII cells by inhibition of EGFR or its downstream pathways, highlighting the impact of EGFR signaling on Mcl-1 expression and the relevance of combined targeted therapies to overcome the multiple resistance mechanisms of these aggressive tumors. © 2012 American Association for Cancer Research. Source


Baldock A.L.,Northwestern University | Baldock A.L.,Northwestern Brain Tumor Institute | Yagle K.,University of Washington | Born D.E.,Stanford University | And 22 more authors.
Neuro-Oncology | Year: 2014

Background Glioblastomas with a specific mutation in the isocitrate dehydrogenase 1 (IDH1) gene have a better prognosis than gliomas with wild-type IDH1. Methods Here we compare the IDH1 mutational status in 172 contrast-enhancing glioma patients with the invasion profile generated by a patient-specific mathematical model we developed based on MR imaging. Results We show that IDH1-mutated contrast-enhancing gliomas were relatively more invasive than wild-type IDH1 for all 172 contrast-enhancing gliomas as well as the subset of 158 histologically confirmed glioblastomas. The appearance of this relatively increased, model-predicted invasive profile appears to be determined more by a lower model-predicted net proliferation rate rather than an increased model-predicted dispersal rate of the glioma cells. Receiver operator curve analysis of the model-predicted MRI-based invasion profile revealed an area under the curve of 0.91, indicative of a predictive relationship. The robustness of this relationship was tested by cross-validation analysis of the invasion profile as a predictive metric for IDH1 status. Conclusions The strong correlation between IDH1 mutation status and the MRI-based invasion profile suggests that use of our tumor growth model may lead to noninvasive clinical detection of IDH1 mutation status and thus lead to better treatment planning, particularly prior to surgical resection, for contrast-enhancing gliomas. © 2014 The Author(s). Source


Kouri F.M.,Northwestern Brain Tumor Institute | Jensen S.A.,Northwestern Brain Tumor Institute | Stegh A.H.,Northwestern Brain Tumor Institute
The Scientific World Journal | Year: 2012

Glioblastoma (GBM) is a highly aggressive and lethal brain cancer with a median survival of less than two years after diagnosis. Hallmarks of GBM tumors include soaring proliferative indices, high levels of angiogenesis, diffuse invasion into normal brain parenchyma, resistance toward therapy-induced apoptosis, and pseudopallisading necrosis. Despite the recent advances in neurosurgery, radiation therapy, and the development of targeted chemotherapeutic regimes, GBM remains one of the deadliest types of cancer. Particularly, the alkylating agent temozolomide (TMZ) in combination with radiation therapy prolonged patient survival only marginally, and clinical studies assessing efficacies of targeted therapies, foremost ATP mimetics inhibiting the activity of receptor tyrosine kinases (RTKs), revealed only few initial responders; tumor recurrence is nearly universal, and salvage therapies to combat such progression remain ineffective. Consequently, myriad preclinical and clinical studies began to define the molecular mechanisms underlying therapy resistance of GBM tumors, and pointed to the Bcl-2 protein family, in particular the atypical member Bcl2-Like 12 (Bcl2L12), as important regulators of therapy-induced cell death. This review will discuss the multi-faceted modi operandi of Bcl-2 family proteins, describe their roles in therapy resistance of malignant glioma, and outline current and future drug development efforts to therapeutically target Bcl-2 proteins. Copyright © 2012 Fotini M. Kouri et al. Source

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