Biology subjects

Ioannidis, A.

Publications and source records attributed to Ioannidis, A..

11 recordsLinked to original sources

bioRxiv2025

Repurposing Quetiapine as an Adjuvant Therapeutic Agent for Triple-Negative Breast Cancer

PurposeTriple-negative breast cancer (TNBC) lacks actionable molecular targets, so treatment primarily relies on cytotoxic chemotherapy and radiotherapy, yet relapse, resistance, and metastasis still drives poor long-term survival. Dopamine signaling has recently been linked to tumor aggressiveness, and dopaminel1lreceptor antagonists have shown preclinical benefit in other cancers. We therefore evaluated quetiapine (QTP), an FDAl1lapproved DRD2/DRD3 antagonist, as a therapeutic adjunct in TNBC. MethodsSUM159l1lPT, BTl1l549, and MDAl1lMBl1l231 cells were treated with QTP alone or combined with radiation or standard agents (doxorubicin, paclitaxel, 5l1lfluorouracil). Clonogenic and mammosphere assays measured proliferative and selfl1lrenewal potential. Annexin V/propidiuml1liodide flow cytometry quantified apoptosis, and {gamma}l1lH2AX immunofluorescence tracked DNA doublel1lstrand breaks and repair kinetics. Transwell assays assessed migration of untreated bulk cells and radiationl1lsurviving subclones. ResultsQTP significantly reduced clonogenicity and self-renewal in all TNBC models tested, both alone and in combination with radiation or chemotherapy. In apoptosis assays, QTP treatment induced a marked increase in early and late apoptotic cell populations. QTP also promoted DNA double-strand break formation and delayed repair, as indicated by persistent {gamma}-H2AX foci at 24 hours post-treatment. Additionally, QTP impaired the migratory capacity of both untreated and radiation-surviving cells. Combination treatments with QTP and doxorubicin produced synergistic effects, resulting in complete loss of colony-forming ability and mammosphere formation. ConclusionThe data presented support the repurposing of quetiapine as an adjuvant therapeutic agent alongside radiotherapy and/or chemotherapy in TNBC. By targeting apoptosis, DNA repair, and cancer cell migration, QTP offers a novel, multi-faceted approach to improve outcomes in this high-risk breast cancer subtype.

cancer biology↗

bioRxiv2024

Targeting Innate Immune Signaling in Glioma-Initiating Cells Impairs Self-Renewal and Radiation-Induced Cellular Plasticity

Organisms constantly face environmental stressors that threaten their cellular and genomic integrity. In their response, pathogen-associated molecular patterns (PAMPs) and/or damage-associated molecular patterns (DAMPs) are detected by pattern recognition receptors (PRRs) and trigger the innate immune response. In this study we tested the hypothesis that DAMPs contribute to radiation-induced cellular plasticity in Glioblastoma (GBM). GBM is known to be organized hierarchically with a small number of glioma-initiating cells (GICs) driving treatment resistance and recurrences. Using patient-derived GBM specimens, we employed sphere forming capacity assays and in vitro extreme limiting dilution assays to examine how innate immune receptor signaling impacts the maintenance and self-renewal of GICs. By leveraging an imaging system for putative GICs we determined de novo induction of GICs from non-stem glioma cells. We find that GIC maintenance after irradiation is mediated by cGAS-independent STING signaling, possibly involving signaling through TLR4 and TLR9. Induction of radiation-induced plasticity involves TLR3 signaling, with potential roles for other receptors and processes modulated by MyD88. These findings suggest that targeting innate immune signaling could prevent radiation-induced cellular plasticity for potential therapeutic benefit.

cancer biology↗

bioRxiv2024

Radiation-Induced Cellular Plasticity: A Strategy for Combatting Glioblastoma

Glioblastoma is the deadliest brain cancer in adults and almost all patients succumb to the tumor. While surgery followed by chemo-radiotherapy significantly delays disease progression, these treatments do not lead to long-term tumor control and targeted therapies or biologics have so far failed to further improve survival. Utilizing a transient radiation-induced state of multipotency we used the adenylcyclase activator forskolin to alter the cellular fate of glioma cells in response to radiation. The combined treatment induced the expression of neuronal markers in glioma cells, reduced proliferation and led to a distinct gene expression profile. scRNAseq revealed that the combined treatment forced glioma cells into a microglia- and neuron-like phenotypes. In vivo this treatment led to a loss of glioma stem cells and prolonged median survival in mouse models of glioblastoma. Collectively, our data suggest that revisiting a differentiation therapy with forskolin in combination with radiation could lead to clinical benefit.

cancer biology↗

bioRxiv2023

Activation of the mevalonate pathway in response to anti-cancer treatments drives glioblastoma recurrences through activation of Rac-1

Glioblastoma is the deadliest adult brain cancer. Under the current standard of care almost all patients succumb to the disease and novel treatments are urgently needed. Dopamine receptor antagonists have been shown to target cancer cell plasticity in GBM and repurposing these FDA-approved drugs in combination with radiation improves the efficacy of radiotherapy in glioma models. In cells surviving this combination treatment the mevalonate pathway is upregulated at the transcriptional and functional level. Here we report that glioblastoma treatments that converge in the immediate early response to radiation through activation of the MAPK cascade universally upregulate the mevalonate pathway and increase stemness of GBM cells through activation of the Rho-GTPase Rac-1. Activation of the mevalonate pathway and Rac-1 is inhibited by statins, which leads to improved survival in mouse models of glioblastoma when combined with radiation and drugs that target the glioma stem cell pool and plasticity of glioma cells.

neuroscience↗

bioRxiv2023

Effects of Dopamine Receptor Antagonists and Radiation on Mouse Neural Stem/Progenitor Cells

BackgroundDopamine receptor antagonists are psychotropic drugs that have been originally developed against psychiatric disorders. We recently identified dopamine receptor antagonists as potential anti-cancer agents and some have entered clinical trials against glioblastoma. Radiotherapy is known to cause cognitive impairment in patients receiving cranial irradiation through the elimination of neural stem/progenitor cells and subsequent loss of neurogenesis. MethodsUsing transgenic mice that report the presence of neural stem/progenitor cells through Nestin promoter-driven expression of enhanced green fluorescent protein, the effects of dopamine receptor antagonists alone or in combination with radiation on murine neural stem/progenitor cells were assessed in sphere-formation assays, flow cytometry and immunofluorescence in vitro and in vivo. ResultsWe report that several dopamine receptor antagonists show sex-dependent effects on neural stem/progenitor cells both in vitro and in vivo. Hydroxyzine, trifluoperazine, amisulpride, nemonapride or quetiapine alone or in combination with radiation significantly increased the number of neural stem/progenitor cells in female neurospheres but not in male mice. Dopamine receptor antagonists either protected neural stem/progenitor cells from radiation or expanded the stem cell pool, thus indicating that this combination therapy against glioblastoma will not increase radiation-induced cognitive decline through increasing elimination of neural stem/progenitor cells and subsequent loss of neurogenesis. ConclusionsWe conclude that a therapeutic window for dopamine receptor antagonists in combination with radiation potentially exist, making it a novel combination therapy against glioblastoma. Normal tissue toxicity of this combination potentially differs depending on age and sex and should be taken into consideration when designing clinical trials. Key Points- Neural stem/progenitor cells show sex-dependent sensitivity to dopamine receptor antagonists - Dopamine receptor antagonists active against GBM increase Neural stem/progenitor cells counts Importance of the StudyCombination therapy of dopamine receptor antagonists with radiation have entered clinical trials against glioblastoma but the normal tissue toxicity of this combination has not been fully explored yet. Here we present evidence that some dopamine receptor antagonists show sex-dependent effects on neural stem/progenitor cells either by protecting neural stem/progenitor cells from radiation or inducing an expansion of the stem cell pool, suggesting that this combination therapy against glioblastoma will not increase radiation-induced cognitive decline through increasing elimination of neural stem/progenitor cells and subsequent loss of neurogenesis. Normal tissue toxicity of this combination potentially differs depending on age and sex and should be further explored in clinical trials.

neuroscience↗

bioRxiv2022

Demographic history and genetic structure in pre-Hispanic Central Mexico

Aridoamerica and Mesoamerica are two distinct cultural areas that hosted numerous pre-Hispanic civilizations between 2,500 BCE and 1,521 CE. The division between these regions shifted southward due to severe droughts ca. 1,100 years ago, allegedly driving demographic changes and population replacement in some sites in central Mexico. Here, we present shotgun genome-wide data from 12 individuals and 26 mitochondrial genomes from eight pre-Hispanic archaeological sites across Mexico, including two at the shifting border of Aridoamerica and Mesoamerica. We find population continuity spanning the climate change episode and a broad preservation of the genetic structure across present-day Mexico for the last 2,300 years. Lastly, we identify a contribution to pre-Hispanic populations of northern and central Mexico from an ancient unsampled ghost population.

genomics↗

bioRxiv2020

Synergistic Effects of the DRD2/3 Antagonist ONC201 and Radiation in Glioblastoma

BackgroundGlioblastoma (GBM) is the deadliest of all brain cancers in adults. The current standard-of-care is surgery followed by radiotherapy and temozolomide, leading to a median survival time of only 15 months. GBM are organized hierarchically with a small number of glioma-initiating cells, responsible for therapy resistance and tumor recurrence, suggesting that targeting glioma-initiating cells could improve treatment response. ONC201 is a first-in-class anti-tumor agent with clinical efficacy in some forms of high-grade gliomas. Here we test its efficacy against GBM in combination with radiation. MethodsUsing patient-derived GBM lines and mouse models of GBM we test the effects of radiation and ONC201 on GBM self - renewal in vitro and survival in vivo. A possible resistance mechanism is investigated using RNA-Sequencing. ResultsTreatment of GBM cells with ONC201 reduced self-renewal, clonogenicity and cell viability in vitro. ONC201 exhibited anti-tumor effects on radioresistant GBM cells indicated by reduced self-renewal in secondary and tertiary glioma spheres. Combined treatment with ONC201 and radiation prolonged survival in syngeneic and patient-derived orthotopic xenograft mouse models of GBM. Subsequent transcriptome analyses after combined treatment revealed shifts in gene expression signatures related to quiescent GBM populations, GBM plasticity, and GBM stem cells. ConclusionsOur findings suggest that combined treatment with the DRD2/3 antagonist ONC201 and radiation improves the efficacy of radiation against GBM in vitro and in vivo through suppression of GICs without increasing toxicity in mouse models of GBM. A clinical assessment of this novel combination therapy against GBM is further warranted. Key points- Combined treatment of ONC201 and radiation exhibit anti-tumor effects on cells from primary and recurrent GBM - Combined treatment significantly prolongs survival in vivo - Combined treatment potentially targets the quiescent GBM cell population Importance of the StudyThe survival rates for patients with GBM are unacceptably low and novel treatment approaches are needed. This study provides evidence that a combination of radiation and the dopamine receptor antagonist ONC201 significantly prolongs survival in mouse models of glioma.

neuroscience↗

bioRxiv2020

XGMix: Local-Ancestry Inference With Stacked XGBoost

AO_SCPLOWBSTRACTC_SCPLOWGenomic medicine promises increased resolution for accurate diagnosis, for personalized treatment, and for identification of population-wide health burdens at rapidly decreasing cost (with a genotype now cheaper than an MRI and dropping). The benefits of this emerging form of affordable, data-driven medicine will accrue predominantly to those populations whose genetic associations have been mapped, so it is of increasing concern that over 80% of such genome-wide association studies (GWAS) have been conducted solely within individuals of European ancestry [1]. The severe under-representation of the majority of the worlds populations in genetic association studies stems in part from an addressable algorithmic weakness: lack of simple, accurate, and easily trained methods for identifying and annotating ancestry along the genome (local ancestry). Here we present such a method (XGMix) based on gradient boosted trees, which, while being accurate, is also simple to use, and fast to train, taking minutes on consumer-level laptops.

genomics↗

bioRxiv2020

Tumor Necrosis Factor Receptor Signaling Modulates Carcinogenesis in a Mouse Model of Breast Cancer

Proinflammatory conditions have long been associated with mammary carcinogenesis and breast cancer progression. The underlying mechanisms are incompletely understood but signaling of TNF through its receptors TNFR1 and TNFR2 is a major mediator of inflammation in both, obesity and in the response of tissues to radiation, two known risk factors for the development of breast cancer. Using the MMTV-Wnt1 mouse model for spontaneous breast cancer and knockout mice for TNFR1 and TNFR2 we report that loss of a TNFR2 allele leads to ductal hyperplasia in the mammary gland with increased numbers of mammary epithelial stem cell and terminal endbuds. Furthermore, that loss of one TNFR2 allele increases the incidence of breast cancers in MMTV-Wnt1 mice and results in tumors with a more aggressive phenotype and metastatic potential. The underlying mechanisms include a preferential activation of canonical NF-{kappa}B signaling pathways and autocrine production of TNF. Analysis of the TCGA dataset indicated inferior overall survival for patients with down-regulated TNFR2 expression. We conclude, that imbalances in TNFR signaling promote the development and progression of breast cancer, indicating that selective agonists of TNFR2 could potentially modulate the risk for breast cancer in high-risk populations. Significance StatementOver the past four decades the treatment results for patients suffering from breast cancer have constantly improved, leaving breast cancer prevention as an important frontier against the second leading cause of cancer death in the United States. Obesity has become a national health crisis and is a known proinflammatory risk factor for breast cancer. Our study describes a previously unknown aspect of proinflammatory signaling on breast cancer development and progression, thus suggesting novel potential targets to modulate the incidence of the disease.

cancer biology↗

bioRxiv2020

Combined Treatment with Dopamine Receptor Antagonists and Radiation Creates a Metabolic Vulnerability in Mouse Models of Glioblastoma

BackgroundGlioblastoma is the deadliest brain tumor in adults and the standard-of-care consists of surgery followed by radiation and treatment with temozolomide. Overall survival times for patients suffering from glioblastoma are unacceptably low indicating an unmet need for novel treatment options. MethodsUsing patient-derived glioblastoma lines and mouse models of glioblastoma we test the effect of radiation and the dopamine receptor antagonist on glioblastoma self-renewal in vitro and survival in vivo. A possible resistance mechanism is investigated using RNA-Sequencing. ResultsTreatment of glioma cells with the dopamine receptor antagonist quetiapine reduced glioma cell self-renewal in vitro and combined treatment of mice with quetiapine and radiation prolonged the survival of glioma-bearing animals. The combined treatment induced the expression of genes involved in cholesterol biosynthesis. This rendered the tumors vulnerable to simultaneous treatment with atorvastatin and further significantly prolonged the survival of the animals. ConclusionsOur results indicate high efficacy of a triple combination of quetiapine, atorvastatin and radiation against glioblastoma without increasing the toxicity of radiation. With both drugs readily available for clinical use our study could be rapidly translated into a clinical trial.

neuroscience↗

bioRxiv2020

1--4-phenylpiperazine Treatment After Brain Irradiation Preserves Cognitive Function in Mice

BackgroundNormal tissue toxicity to the CNS is an inevitable consequence of a successful radiotherapy of brain tumors or cancer metastases to the CNS. Cranial irradiation commonly leads to neurocognitive deficits that manifest months or years after treatment. Mechanistically, radiation-induced loss of neural stem/progenitor cells, neuro-inflammation and de-myelinization are contributing factors that lead to progressive cognitive decline. MethodsThe effects of Compound #5 on irradiated murine neurospheres, microglia cells and patients-derived gliomaspheres were assessed in sphere-formation assays, flow cytometry and IL-6 ELISAs, Activation of the Hedgehog pathway was studied by qRT-PCR. The in vivo effects of Compound #5 were analyzed using flow cytometry, sphere-formation assays, immune-histochemistry, behavioral testing and an intracranial mouse model of glioblastoma. ResultsWe report that 1-[(4-Nitrophenyl)sulfonyl]-4-phenylpiperazine (Compound #5) mitigates radiation-induced normal tissue toxicity in the brains of mice. Compound #5 treatment significantly increased the number of neural stem/progenitor cells after brain irradiation in female animals, inhibited radiation-induced microglia activation and expression of the pro-inflammatory cytokine interleukin-6. Behavioral testing revealed that treatment with Compound #5 after radiotherapy successfully mitigates radiation-induced decline in motor, sensory and memory function of the brain. In mouse models of glioblastoma, Compound #5 showed no toxicity and did not interfere with the growth-delaying effects of radiation. ConclusionsWe conclude that Compound #5 has the potential to mitigate cognitive decline in patients undergoing partial or whole brain irradiation without promoting tumor growth and that the use of this compound as a radiation mitigator of radiation late effects on the CNS warrants further investigation. Importance of the StudySuccessful radiotherapy of CNS malignancies inevitably lead to cognitive decline in cancer survivors and treatment options to mitigate this side effect are limited. We present evidence that a piperazine compound can prevent cognitive decline in mice after total brain irradiation without compromising the antitumor effect of radiation, suggesting that this compound could be used to mitigate radiation side effects in brain tumor patients undergoing radiotherapy.

neuroscience↗