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Multiple receptor tyrosine kinases (RTKs), including PDGFR, have been validated as therapeutic targets in glioblastoma multiforme (GBM), yet inhibitors of RTKs have had limited clinical success. As various antiapoptotic mechanisms render GBM cells resistant to chemo- and radiotherapy, we hypothesized that these antiapoptotic mechanisms also confer resistance to RTK inhibition. We found that in vitro inhibition of PDGFR in human GBM cells initiated the intrinsic pathway of apoptosis, as evidenced by mitochondrial outer membrane permeabilization, but downstream caspase activation was blocked by inhibitor of apoptosis proteins (IAPs). Consistent with this, inhibition of PDGFR combined with small molecule inactivation of IAPs induced apoptosis in human GBM cells in vitro and had synergistic antitumor effects in orthotopic mouse models of GBM and in primary human GBM neurospheres. These results demonstrate that concomitant inhibition of IAPs can overcome resistance to RTK inhibitors in human malignant GBM cells, and suggest that blockade of IAPs has the potential to improve treatment outcomes in patients with GBM., Introduction The treatment of malignant gliomas remains one of the greatest challenges facing adult and pediatric oncologists today. At the most severe end of the spectrum is glioblastoma multiforme (GBM), [...]

ABSTRACT Background The presence of tumor-specific mutations in the cancer genome represents a potential opportunity for pharmacologic intervention to therapeutic benefit. Unfortunately, many classes of oncoproteins (e.g., transcription factors) are [...]

The facilitating cell is a rare CD8[sup.+] bone marrow subpopulation that can enhance allogeneic hematopoietic stem cell engraftment across complete major histocompatibility complex barriers without inducing acute graft-versus-host disease. Here we describe a CD3[var epsilon]-associated complex on the facilitating cell surface that consists of the T-cell receptor [beta]-chain disulfide-linked to a previously unknown 33-kilodalton glycoprotein. Provisionally called FCp33, this glycoprotein does not represent any of the known protein chains or surrogates associated with CD3-T-cell receptor [beta]. Expression of this CD3-T-cell receptor [beta]-FCp33 complex directly correlates with the facilitating cell's functional ability to enhance allogeneic stem cell engraftment in vivo., Author(s): Matthew J. Schuchert [1]; Renee D. Wright [2]; Yolonda L. Colson (corresponding author) [2] Facilitating cells (FCs) constitute a unique bone marrow (BM)-derived cell population that promotes allogeneic hematopoietic [...]

The facilitating cell is a rare CD8+ bone marrow subpopulation that can enhance allogeneic hematopoietic stem cell engraftment across complete major histocompatibility complex barriers without inducing acute graft-versus-host disease. Here we describe a CD3?-associated complex on the facilitating cell surface that consists of the T-cell receptor B-chain disulfide-linked to a previously unknown 33-kilodalton glycoprotein. Provisionally called FCp33, this glycoprotein does not represent any of the known protein chains or surrogates associated with CD3-T-cell receptor B. Expression of this CD3-T-cell receptor B-FCp33 complex directly correlates with the facilitating cell's functional ability to enhance allogeneic stem cell engraftment in vivo. [ABSTRACT FROM AUTHOR]

Background: The presence of tumor-specific mutations in the cancer genome represents a potential opportunity for pharmacologic intervention to therapeutic benefit. Unfortunately, many classes of oncoproteins (e.g., transcription factors) are not amenable to conventional small-molecule screening. Despite the identification of tumor-specific somatic mutations, most cancer therapy still utilizes nonspecific, cytotoxic drugs. One illustrative example is the treatment of Ewing sarcoma. Although the EWS/FLI oncoprotein, present in the vast majority of Ewing tumors, was characterized over ten years ago, it has never been exploited as a target of therapy. Previously, this target has been intractable to modulation with traditional small-molecule library screening approaches. Here we describe a gene expression–based approach to identify compounds that induce a signature of EWS/FLI attenuation. We hypothesize that screening small-molecule libraries highly enriched for FDA-approved drugs will provide a more rapid path to clinical application. Methods and Findings: A gene expression signature for the EWS/FLI off state was determined with microarray expression profiling of Ewing sarcoma cell lines with EWS/FLI-directed RNA interference. A small-molecule library enriched for FDA-approved drugs was screened with a high-throughput, ligation-mediated amplification assay with a fluorescent, bead-based detection. Screening identified cytosine arabinoside (ARA-C) as a modulator of EWS/FLI. ARA-C reduced EWS/FLI protein abundance and accordingly diminished cell viability and transformation and abrogated tumor growth in a xenograft model. Given the poor outcomes of many patients with Ewing sarcoma and the well-established ARA-C safety profile, clinical trials testing ARA-C are warranted. Conclusions: We demonstrate that a gene expression–based approach to small-molecule library screening can identify, for rapid clinical testing, candidate drugs that modulate previously intractable targets. Furthermore, this is a generic approach that can, in principle, be applied to the identification of modulators of any tumor-associated oncoprotein in the rare pediatric malignancies, but also in the more common adult cancers.

The incidence of tuberculosis in the United States is on the rise, in part, because of its association with acquired immunodeficiency syndrome. Genitourinary tuberculosis remains one of the most common forms of secondary or extrapulmonary disease. We present an unusual case of tuberculous epididymitis with extensive retroperitoneal and mediastinal spread. The possible routes of dissemination, as well as the efficacy of antimycobacterial therapy in the management of tuberculous epididymitis, are discussed and the relevant literature is reviewed.