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Glioblastoma (GBM) is the most common and aggressive primary brain tumor with less than 10% of patients surviving beyond 5 years after diagnosis. Even when treated early with the current standard of care, GBM recurs in nearly all patients. Therefore, there is an urgent need to develop novel therapies to overcome treatment resistance in GBM, including those that could be combined with the current standard of care to improve patient outcomes. In previous studies, we identified proteasome subunit alpha type-7 (PSMA7) as a potentially druggable target in GBM. Moreover, we discovered small molecules (SMs), predicted in silico to be blood-brain barrier (BBB)-permeable and target PSMA7, with greater toxicity in GBM cells compared to normal cells. In this study, we further investigated the potential of these SMs to be used as novel therapeutics for the treatment of GBM by examining their ability to inhibit PSMA7 expression, directly bind to PSMA7, block the interaction(s) between PSMA7 with its reported binding partners, and/or disrupt phosphorylation of tyrosine residues on PSMA7. In silico molecular docking screenings were performed using the National Cancer Institute Diversity Set VI SM library and regions of interaction on PSMA7 with its reported binding partners (i.e., HIF-1alpha, Parkin, and PAC4) or regions around two tyrosine residues of PSMA7 (i.e., Y106 and Y153) that are potentially phosphorylated by cABL. Top-scoring SMs were screened using SwissADME to select SMs predicted to be BBB-permeable. Western blots (WB) were performed to examine protein expression. Surface Plasmon Resonance (SPR) was performed using a Biacore S200 to determine real-time quantitative binding affinities and kinetics for interactions between PSMA7 with select SMs. Co-immunoprecipitation (Co-IP) was used to evaluate protein-protein interactions and IP/WB for examining changes to protein phosphorylation. Preliminary in vitro screening of primary human GBM cells with eight SMs predicted to target PSMA7 was performed to identify whether they inhibit PSMA7 protein expression. Western blot analysis revealed that two SMs significantly inhibited PSMA7 in both 08-387 and 3359 cells. SPR data analysis found that three SMs had equilibrium dissociation constant (K D) values < 10-6 M, indicating their direct binding with PSMA7. Co-IP/WB and IP/WB studies were conducted to examine the ability of these three SMs to block interactions with their targeted PSMA7 binding partners and/or inhibit phosphorylation on PSMA7Y106 and PSMA7Y153. Our study identified BBB-permeable SMs that inhibit the biological functions of PSMA7, a potential therapeutic target in GBM. These SMs are potential candidates for in vivo preclinical studies and combining these novel targeted molecules with the standard of care may aid in overcoming treatment resistance in GBM. Our group is actively investigating the binding specificity of these SMs for PSMA7. [ABSTRACT FROM AUTHOR]

Background: Soluble signaling molecules may play an important role in malignant pathogenesis. We hypothesize that perioperative cytokine levels are associated with outcomes in patients with pancreatic adenocarcinoma (PDAC) undergoing surgical resection., Methods: One hundered and eighteen patients with benign or malignant pancreatic disease were enrolled in a prospective study through a protocol for banking biologic samples. Peripheral blood was drawn at time of operation, and a multiplex cytokine assay was performed. Statistical analysis was via χ 2 and Kaplan Meier methods., Results: Of 118 patients enrolled, 85 (72%) had a diagnosis of PDAC, and 60 (70%) ultimately underwent partial pancreatectomy. Cytokine levels were not associated with postoperative complications in this initial cohort. A plasma level of monocyte chemoattractant protein-1 (MCP-1) pg/mL ≤118 was associated with better overall survival (OS) (median survival 21 months vs 12.8 months, P = 0.023), as was non-detectable interleukin-8 (IL-8) (19 months) versus detectable IL-8 (12.8 months, P = 0.05). Patients with both MCP-1 >118 pg/mL and detectable IL-8 had a median survival of 10.6 months (P = 0.028)., Conclusions: MCP-1 and IL-8 cytokine levels are associated with decreased survival following pancreatectomy for PDAC, and may be useful biomarkers. Measurement of these cytokine levels at different time points in future investigations will be important to validate these findings., (© 2017 Wiley Periodicals, Inc.)

Background: Cancer-associated wasting, termed cancer cachexia, has a profound effect on the morbidity and mortality of cancer patients but remains difficult to recognize and diagnose. While increases in circulating levels of a number of inflammatory cytokines have been associated with cancer cachexia, these associations were generally made in patients with advanced disease and thus may be associated with disease progression rather than directly with the cachexia syndrome. Thus, we sought to assess potential biomarkers of cancer-induced cachexia in patients with earlier stages of disease., Methods: A custom multiplex array was used to measure circulating levels of 25 soluble factors from 70 pancreatic cancer patients undergoing attempted tumour resections. A high-sensitivity multiplex was used for increased sensitivity for nine cytokines., Results: Resectable pancreatic cancer patients with cachexia had low levels of canonical pro-inflammatory cytokines including interleukin-6 (IL-6), interleukin-1β (IL-1β), interferon-γ (IFN-γ), and tumour necrosis factor (TNF). Even in our more sensitive analysis, these cytokines were not associated with cancer cachexia. Of the 25 circulating factors tested, only monocyte chemoattractant protein-1 (MCP-1) was increased in treatment-naïve cachectic patients compared with weight stable patients and identified as a potential biomarker for cancer cachexia. Although circulating levels of leptin and granulocyte-macrophage colony-stimulating factor (GM-CSF) were found to be decreased in the same cohort of treatment-naïve cachectic patients, these factors were closely associated with body mass index, limiting their utility as cancer cachexia biomarkers., Conclusions: Unlike in advanced disease, it is possible that cachexia in patients with resectable pancreatic cancer is not associated with high levels of classical markers of systemic inflammation. However, cachectic, treatment-naïve patients have higher levels of MCP-1, suggesting that MCP-1 may be useful as a biomarker of cancer cachexia., (© 2018 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders.)

Involuntary weight loss, a part of the cachexia syndrome, is a debilitating comorbidity of cancer and currently has no treatment options. Results from a recent clinical trial at our institution showed that biliary tract cancer patients treated with a MEK inhibitor exhibited poor tumor responses but surprisingly gained weight and increased their skeletal muscle mass. This implied that MEK inhibition might be anticachectic. To test this potential effect of MEK inhibition, we utilized the established Colon-26 model of cancer cachexia and the MEK1/2 inhibitor MEK162. Results showed that MEK inhibition effectively prevented muscle wasting. Importantly, MEK162 retained its ability to spare muscle loss even in mice bearing a Colon-26 clone resistant to the MEK inhibitor, demonstrating that the effects of blocking MEK are at least in part independent of the tumor. Because single-agent MEK inhibitors have been limited as a first-line targeted therapy due to compensatory activation of other oncogenic signaling pathways, we combined MEK162 with the PI3K/Akt inhibitor buparlisib. Results showed that this combinatorial treatment significantly reduced tumor growth due to a direct activity on Colon-26 tumor cells in vitro and in vivo, while also preserving skeletal muscle mass. Together, our results suggest that as a monotherapy, MEK inhibition preserves muscle mass, but when combined with a PI3K/Akt inhibitor exhibits potent antitumor activity. Thus, combinatorial therapy might serve as a new approach for the treatment of cancer cachexia. Mol Cancer Ther; 16(2); 344-56. ©2016 AACRSee related article by Kobayashi et al., p. 357., (©2016 American Association for Cancer Research.)