Tumor microenvironments can promote stem cell maintenance, tumor growth, and therapeutic resistance, findings linked by the tumor-initiating cell hypothesis. Standard of care for glioblastoma (GBM) includes temozolomide chemotherapy, which is not curative, due, in part, to residual therapy-resistant brain tumor-initiating cells (BTICs). Temozolomide efficacy may be increased by targeting carbonic anhydrase 9 ( CA9 ), a hypoxia-responsive gene important for maintaining the altered pH gradient of tumor cells. Using patient-derived GBM xenograft cells, we explored whether CA9 and CA12 inhibitor SLC-0111 could decrease GBM growth in combination with temozolomide or influence percentages of BTICs after chemotherapy. In multiple GBMs, SLC-0111 used concurrently with temozolomide reduced cell growth and induced cell cycle arrest via DNA damage in vitro. In addition, this treatment shifted tumor metabolism to a suppressed bioenergetic state in vivo. SLC-0111 also inhibited the enrichment of BTICs after temozolomide treatment determined via CD133 expression and neurosphere formation capacity. GBM xenografts treated with SLC-0111 in combination with temozolomide regressed significantly, and this effect was greater than that of temozolomide or SLC-0111 alone. We determined that SLC-0111 improves the efficacy of temozolomide to extend survival of GBM-bearing mice and should be explored as a treatment strategy in combination with current standard of care.

Significance: Gliomas are central nervous system tumors that primarily occur in the brain and arise from glial cells. Gliomas include the most common malignant brain tumor in adults known as grade IV astrocytoma, or glioblastoma. Glioblastoma is a deadly disease for which the most significant advances in treatment offer an improvement in survival of only approximately two months. Critical Issues: To develop novel treatments and improve patient outcomes, we and others have sought to determine the role of molecular signals in gliomas. Recent Advances: One signaling molecule that mediates important biologies in glioma is the free radical nitric oxide. In glioma cells and the tumor microenvironment, nitric oxide (NO) is produced by three isoforms of nitric oxide synthase (NOS), NOS1, NOS2, and NOS3. NO and NOS effect glioma growth, invasion, angiogenesis, immunosuppression, differentiation state, and therapeutic resistance. Future directions: These multi-faceted effects of NO and NOS on gliomas both in vitro and in vivo suggest the potential of modulating the pathway for anti-glioma patient therapies.

For glioblastoma (GBM) treatments to be effective in vivo, understanding the effects of the tumor microenvironment is imperative. In traditional cell culture conditions, glucose concentrations do not model physiologic levels, nor the diminished concentrations found in tumor niches. We therefore sought to profile the differences in kinase activity in GBM cells cultured in restricted glucose to identify pathways that could be targeted with small molecule inhibitors. Using the PamStation12 platform, we examined the ability of GBM lysates from cells cultured in standard or low glucose conditions to phosphorylate 144 tyrosine and 144 serine/threonine peptides that correspond to known protein phosphorylation sites. Potential kinase targets were identified and validated using small molecule kinase inhibitors in GBM spheroid cultures. Using results from two GBM patient-derived xenografts, we determined common changes to peptides derived from Phospholipase C, Gamma 1 (PLCG1) and Raf-1. Using PLC and Raf inhibitors, we found a significantly stronger growth inhibitory effect of the PLC inhibitor U73122 under restricted glucose conditions. In contrast, Raf inhibitors were significantly growth inhibitory regardless of the nutrient level tested. Together, our data demonstrate that kinase activity is altered in low glucose conditions and that kinomic profiling can assist with the identification of effective strategies to target GBM growth. Our data further suggest the importance of accurately modeling the tumor microenvironment to reproduce cancer cell signaling and develop drug screens for anti-cancer agents.

Background: Major Depressive Disorder is a leading cause of disability worldwide and one of the most common disorders in the United States. Contributors to an individual’s risk for experiencing depressive disorders include individual and social factors. Although the social determinants of health (SDOH) are conditions that contribute to healthy functioning, health outcomes, and quality of life, it is unclear to what extent adverse SDOH experiences are associated with self-reporting depressive disorder (DD). Methods: Data from the 2017 Behavioral Risk Factor Surveillance System (BRFSS), a population-based telephone survey of noninstitutionalized U.S. adults, was employed in this study. Lifetime diagnosis of DD was self-reported among survey participants who also completed the Social Determinants of Health optional module within 17 participating BRFSS states and entities. Rao-Scott chi-square analysis was used to determine the association of individual and SDOH measures with DD. Results: The prevalence of DD among participating states was 19.85%. Among respondents, significant proportional differences were observed for each SDOH indicator regarding DD status. However, significant differences in health insurance coverage were not observed. Conclusion: Survey respondents with a lifetime diagnosis of DD experienced adverse SDOH conditions in greater proportion than individuals not reporting DD. Individual and community-based approaches to address the contextual influences of depressive disorders should be aggressively implemented.