Efficacy of adenovirally expressed soluble TRAIL in human glioma organotypic slice culture and glioma xenografts

Liu, Y.; Lang, Frederick F.; Xie, Xiaoming; Prabhu, Sujit S.; Xu, Jing; Sampath, Deepa; Aldape, Kenneth; Fuller, Gregory N.; Puduvalli, Vinay K.

doi:10.1038/cddis.2010.95

Cited by 27 publications

(18 citation statements)

References 26 publications

(34 reference statements)

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“…Nude mouse intracranial glioma xenografts were generated by implanting U251HF-Luc cells (10 6 cells/5 μl) into the forebrain as described (26), after which luciferin solution (100mg/kg) was injected and tumor growth was determined by measuring the bioluminescence emitted using a ZFOV-24 zoom lens-installed IVIS Lumina Series III Pre-clinical In Vivo Imaging System (Perkin Elmer, American Fork, UT).…”

Section: Methodsmentioning

confidence: 99%

Efficacy of Onalespib, a Long-Acting Second-Generation HSP90 Inhibitor, as a Single Agent and in Combination with Temozolomide against Malignant Gliomas

Canella

Welker

Yoo

et al. 2017

Clinical Cancer Research

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Purpose HSP90, a highly conserved molecular chaperone that regulates the function of several oncogenic client proteins is altered in glioblastoma. However, HSP90 inhibitors currently in clinical trials are short-acting, have unacceptable toxicities or are unable to cross the blood brain barrier (BBB). We examined the efficacy of onalespib, a potent, long-acting novel HSP90 inhibitor as a single agent and in combination with temozolomide (TMZ) against gliomas in vitro and in vivo. Experimental Design The effect of onalespib on HSP90, its client proteins, and on the biology of glioma cell lines and patient-derived glioma-initiating cells (GSC) was determined. Brain and plasma pharmacokinetics of onalespib and its ability to inhibit HSP90 in vivo was assessed in non-tumor bearing mice. Its efficacy as a single agent or in combination with TMZ was assessed in vitro and in vivo using zebrafish and patient derived GSC xenograft mouse glioma models. Results Onalespib mediated HSP90 inhibition depleted several survival-promoting client proteins such as EGFR, EGFRvIII and AKT, disrupted their downstream signaling and decreased the proliferation, migration, angiogenesis and survival of glioma cell lines and GSCs. Onalespib effectively crossed the BBB to inhibit HSP90 in vivo and extended survival as a single agent in zebrafish xenografts and in combination with TMZ in both zebrafish and GSC mouse xenografts. Conclusions Our results demonstrate the long-acting effects of onalespib against gliomas in vitro and in vivo which combined with its ability to cross the BBB support its development as a potential therapeutic agent in combination with TMZ against gliomas.

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Section: Methodsmentioning

confidence: 99%

Efficacy of Onalespib, a Long-Acting Second-Generation HSP90 Inhibitor, as a Single Agent and in Combination with Temozolomide against Malignant Gliomas

Canella

Welker

Yoo

et al. 2017

Clinical Cancer Research

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“…Consequently, tissue slices became an attractive alternative to immortalized cell lines since at the time it was widely recognized that there is a need for more complex model systems. In the last decades, precision‐cut slices from various patient tumors such as carcinomas from breast [134–139], lung [138, 140–142], brain [143, 144], ovary [145, 146], cervix [147], kidney [148], and prostate [149] were introduced and used in various fields of cancer research.…”

Section: Tumor Tissue Slices: Culture System Preserving the Individmentioning

confidence: 99%

Three‐dimensional models of cancer for pharmacology and cancer cell biology: Capturing tumor complexity in vitro/ex vivo

Hickman¹,

Graeser²,

Hoogt³

et al. 2014

Biotechnology Journal

340

276

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Cancers are complex and heterogeneous pathological "organs" in a dynamic interplay with their host. Models of human cancer in vitro, used in cancer biology and drug discovery, are generally highly reductionist. These cancer models do not incorporate complexity or heterogeneity. This raises the question as to whether the cancer models' biochemical circuitry (not their genome) represents, with sufficient fidelity, a tumor in situ. Around 95% of new anticancer drugs eventually fail in clinical trial, despite robust indications of activity in existing in vitro pre-clinical models. Innovative models are required that better capture tumor biology. An important feature of all tissues, and tumors, is that cells grow in three dimensions. Advances in generating and characterizing simple and complex (with added stromal components) three-dimensional in vitro models (3D models) are reviewed in this article. The application of stirred bioreactors to permit both scale-up/scale-down of these cancer models and, importantly, methods to permit controlled changes in environment (pH, nutrients, and oxygen) are also described. The challenges of generating thin tumor slices, their utility, and potential advantages and disadvantages are discussed. These in vitro/ex vivo models represent a distinct move to capture the realities of tumor biology in situ, but significant characterization work still remains to be done in order to show that their biochemical circuitry accurately reflects that of a tumor.

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“…The finding that recombinant Trail preferentially induced apoptosis in cancer cells while sparing normal cells supported by its low or absent toxicity in vivo [40, 41] have attracted growing interest on the possibility to exploit this pathway for cancer therapy. Despite a large investigative effort however the reason for this selective activity is poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Role of Apoptosis in disease

Favaloro

Allocati²,

Graziano³

et al. 2012

Aging

475

344

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Since the initial description of apoptosis, a number of different forms of cell death have been described. In this review we will focus on classic caspase-dependent apoptosis and its variations that contribute to diseases. Over fifty years of research have clarified molecular mechanisms involved in apoptotic signaling as well and shown that alterations of these pathways lead to human diseases. Indeed both reduced and increased apoptosis can result in pathology. More recently these findings have led to the development of therapeutic approaches based on regulation of apoptosis, some of which are in clinical trials or have entered medical practice.

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Efficacy of adenovirally expressed soluble TRAIL in human glioma organotypic slice culture and glioma xenografts

Cited by 27 publications

References 26 publications

Efficacy of Onalespib, a Long-Acting Second-Generation HSP90 Inhibitor, as a Single Agent and in Combination with Temozolomide against Malignant Gliomas

Efficacy of Onalespib, a Long-Acting Second-Generation HSP90 Inhibitor, as a Single Agent and in Combination with Temozolomide against Malignant Gliomas

Three‐dimensional models of cancer for pharmacology and cancer cell biology: Capturing tumor complexity in vitro/ex vivo

Role of Apoptosis in disease

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