A retrospective survival analysis of Glioblastoma patients treated with selective serotonin reuptake inhibitors

Otto-Meyer, Sebastian; DeFaccio, Rian; Dussold, Corey; Ladomersky, Erik; Zhai, Lijie; Lauing, Kristen L.; Bollu, Lakshmi Reddy; Amidei, Christina; Lukas, Rimas V.; Scholtens, Denise M.; Wainwright, Derek A.

doi:10.1016/j.bbih.2019.100025

Cited by 23 publications

(22 citation statements)

References 36 publications

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“…Depression and psychological distress are associated with worse outcomes with respect to glioblastoma progression. Otto-Meyer et al showed that the treatment of glioblastoma patients with SSRI, which is often prescribed to treat psychological illness in these patients, does not significantly affect the overall survival rate of those patients 123 .…”

Section: Glioblastomamentioning

confidence: 99%

Role of serotonin receptor signaling in cancer cells and anti-tumor immunity

Karmakar

Lal

2021

Theranostics

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Serotonin or 5-hydroxytryptamine (5-HT) is a neurotransmitter known to affect emotion, behavior, and cognition, and its effects are mostly studied in neurological diseases. The crosstalk between the immune cells and the nervous system through serotonin and its receptors (5-HTRs) in the tumor microenvironment and the secondary lymphoid organs are known to affect cancer pathogenesis. However, the molecular mechanism of - alteration in the phenotype and function of - innate and adaptive immune cells by serotonin is not well explored. In this review, we discuss how serotonin and serotonin receptors modulate the phenotype and function of various immune cells, and how the 5-HT-5-HTR axis modulates antitumor immunity. Understanding how 5-HT and immune signaling are involved in tumor immunity could help improve therapeutic strategies to control cancer progression and metastasis.

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Section: Glioblastomamentioning

confidence: 99%

Role of serotonin receptor signaling in cancer cells and anti-tumor immunity

Karmakar

Lal

2021

Theranostics

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“…First, as we have shown here, fluoxetine differs from other SSRI's with vastly differing effects on patient survival and on inhibiting oncogenic EGFR signaling. Therefore, it is not surprising that the two major studies that have looked at the effect of anti-depressants on the outcome for GBM patients did not find a significant signal; they did not distinguish amongst SSRIs (Caudill et al, 2011;Otto-Meyer et al, 2020). In fact, they would not likely have been able to do so while being sufficiently statistically powered.…”

Section: Discussionmentioning

confidence: 99%

Targeting Glioblastoma Signaling and Metabolism with A Re-Purposed Brain-Penetrant Drug

Khan

Tang

et al. 2021

Preprint

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The highly lethal brain cancer glioblastoma (GBM) poses a daunting challenge because the blood-brain barrier renders potentially druggable amplified or mutated oncoproteins relatively inaccessible. Here, we identify SMPD1, an enzyme that regulates the conversion of sphingomyelin to ceramide and a critical regulator of plasma membrane structure and organization, as an actionable drug target in glioblastoma. We show that the safe and highly brain-penetrant antidepressant fluoxetine, potently inhibits SMPD1 activity, killing GBMs, in vitro and in patient-derived xenografts, through inhibition of EGFR signaling and via activation of lysosomal stress. Combining fluoxetine with the chemotherapeutic agent temozolomide, a standard of care for GBM patients, causes massive increases in GBM cell death, and complete and long-lived tumor regression in mice. Incorporation of real-world evidence from electronic medical records from insurance databases, reveals significantly increased survival in glioblastoma patients treated with fluoxetine, which was not seen in patients treated with other SSRI anti-depressants. These results nominate the repurposing of fluoxetine as a potentially safe and promising therapy for GBM patients and suggest prospective randomized clinical trials.

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“…Furthermore, because antidepressants seem to inactivate Klf8, it is possible that antidepressants may help treat brain cancers. This does appear to be the case for some gliomas treated with antidepressants alone or in combination with other treatments ( Liu et al, 2015 ; Shchors et al, 2015 ; Kushal et al, 2016 ), although a firm consensus has not been reached ( Otto-Meyer et al, 2020 ). Further investigation into the role of Klf8 in the efficacy of antidepressants may help introduce a new class of treatment for brain cancers— an attractive option for drugs that are already on the market and can cross the blood brain barrier.…”

Section: Discussionmentioning

confidence: 99%

Systems Toxicology Approach for Assessing Developmental Neurotoxicity in Larval Zebrafish

Talikka

Gubian

et al. 2021

Front. Genet.

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Adverse outcomes that result from chemical toxicity are rarely caused by dysregulation of individual proteins; rather, they are often caused by system-level perturbations in networks of molecular events. To fully understand the mechanisms of toxicity, it is necessary to recognize the interactions of molecules, pathways, and biological processes within these networks. The developing brain is a prime example of an extremely complex network, which makes developmental neurotoxicity one of the most challenging areas in toxicology. We have developed a systems toxicology method that uses a computable biological network to represent molecular interactions in the developing brain of zebrafish larvae. The network is curated from scientific literature and describes interactions between biological processes, signaling pathways, and adverse outcomes associated with neurotoxicity. This allows us to identify important signaling hubs, pathway interactions, and emergent adverse outcomes, providing a more complete understanding of neurotoxicity. Here, we describe the construction of a zebrafish developmental neurotoxicity network and its validation by integration with publicly available neurotoxicity-related transcriptomic datasets. Our network analysis identified consistent regulation of tumor suppressors p53 and retinoblastoma 1 (Rb1) as well as the oncogene Krüppel-like factor (Klf8) in response to chemically induced developmental neurotoxicity. The developed network can be used to interpret transcriptomic data in a neurotoxicological context.

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A retrospective survival analysis of Glioblastoma patients treated with selective serotonin reuptake inhibitors

Cited by 23 publications

References 36 publications

Role of serotonin receptor signaling in cancer cells and anti-tumor immunity

Role of serotonin receptor signaling in cancer cells and anti-tumor immunity

Targeting Glioblastoma Signaling and Metabolism with A Re-Purposed Brain-Penetrant Drug

Systems Toxicology Approach for Assessing Developmental Neurotoxicity in Larval Zebrafish

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