LPS-induced antitumoral effects on glioblastoma multiforme are mediated, in part, by the Tlr-4 receptor. Further understanding of this process may lead to novel treatment strategies for this uniformly fatal disease.

Intratumoral injections of LPS caused dramatic regression of subcutaneously implanted delayed brain tumor cell mouse gliomas. Investigation of this antitumoral effect may improve treatment responses for patients with malignant gliomas.

The utility of clinical magnetic resonance contrast media (MRCM) in the evaluation of pathologies within the central nervous system (CNS) is well established (1-9). Bloodbrain-barrier (BBB) disruption in tumors and other lesions of the CNS is attributable to abnormal endothelial junctions, and is a key feature of the aggressive neovascular formations within malignant tumors. This characteristic of BBB disruption accounts for the increased enhancement of intracranial tumors on MRI after administration of MRCM, which is helpful in delineating tumor anatomy. For gliomas, increased enhancement is suggestive, although not absolutely indicative, of an increased histological grade of malignancy. Degrees of tumor malignancy previously have been assessed in animal models using covalently Gd-conjugated macromolecule-based MRCM as MRI signal enhancers (3-6). However, these covalently-bound Gd-macromolecules have not been studied in clinical trials in humans. Hence, the available low-molecular-weight extracellular MRCM are now exploited under dynamic protocols for tumor assessment (7-9). These agents extravasate into extracellular space throughout non-CNS tissues, and thus present a limited time window at high concentration for the detection of CNS tumors. Despite successes achieved with the extracellular agents to date, the need for intravascular agents that would extravasate only in the face of BBB disruption continues to be advocated as a next step in improving the diagnostic utility of these and related techniques (10,11).Noncovalent albumin-binding Gd-chelates represent a new class of agents. These agents, unlike the covalently bound Gd-macromolecules, are small chelates with side chains that undergo reversible noncovalent interactions with circulating albumin (12,13). The bound form (the dominant species, with a Ͼ10-fold signal-enhancing potential) assumes the macromolecular attributes of albumin and remains intravascular, while the nonbound minor component (with the low relaxivity typical of small Gdchelates) is free and extravasates. MP-2269 (Mallinckrodt, Inc., St. Louis, MO) is an experimental monomeric Gd-DTPA-derived blood pool agent with a molecular weight of 1179 g/mol. It is the Gd complex of 4-pentylbicyclo-

The purpose of this study was to determine if radiation (RT)-resistant cervical cancers are dependent upon glutamine metabolism driven by activation of the PI3K pathway and test whether PI3K pathway mutation predicts radiosensitization by inhibition of glutamine metabolism. Cervical cancer cell lines with and without PI3K pathway mutations, including SiHa and SiHa PTEN−/− cells engineered by CRISPR/Cas9, were used for mechanistic studies performed in vitro in the presence and absence of glutamine starvation and the glutaminase inhibitor, telaglenastat (CB-839). These studies included cell survival, proliferation, quantification of oxidative stress parameters, metabolic tracing with stable isotope-labeled substrates, metabolic rescue, and combination studies with L-buthionine sulfoximine (BSO), auranofin (AUR), and RT. In vivo studies of telaglenastat ± RT were performed using CaSki and SiHa xenografts grown in immune-compromised mice. PI3K-activated cervical cancer cells were selectively sensitive to glutamine deprivation through a mechanism that included thiol-mediated oxidative stress. Telaglenastat treatment decreased total glutathione pools, increased the percent glutathione disulfide, and caused clonogenic cell killing that was reversed by treatment with the thiol antioxidant, N-acetylcysteine. Telaglenastat also sensitized cells to killing by glutathione depletion with BSO, thioredoxin reductase inhibition with AUR, and RT. Glutamine-dependent PI3K-activated cervical cancer xenografts were sensitive to telaglenastat monotherapy, and telaglenastat selectively radiosensitized cervical cancer cells in vitro and in vivo. These novel preclinical data support the utility of telaglenastat for glutamine-dependent radioresistant cervical cancers and demonstrate that PI3K pathway mutations may be used as a predictive biomarker for telaglenastat sensitivity.