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bioRxiv2022

Effects of the investigational drug sodium phenylbutyrate-TUDCA (AMX0035) on the transcriptional and metabolic landscape of sporadic ALS fibroblasts

ALS is a rapidly progressive, fatal disorder caused by motor neuron degeneration, for which there is a great unmet therapeutic need. AMX0035, a combination of sodium phenylbutyrate (PB) and taurursodiol (TUDCA, Turso), has shown promising results in early ALS clinical trials, but its mechanisms of action remain to be elucidated. To obtain an unbiased landscape of AMX0035 effects we investigated the transcriptomic and metabolomic profiles of primary skin fibroblasts from sporadic ALS patients and healthy controls treated with PB, TUDCA, or PB-TUDCA combination (Combo). Combo changed many more genes and metabolites than either PB or TUDCA individually. Most changes were unique to Combo and affected the expression of genes involved in ALS-relevant pathways, such as nucleocytoplasmic transport, unfolded protein response, mitochondrial function, RNA metabolism, and innate immunity. Weighted gene coexpression network analysis showed that significant correlations between ALS gene expression modules and clinical parameters were abolished by Combo. This study is the first to explore the molecular effects of Combo in ALS patient-derived cells. It shows that Combo has a greater and distinct impact compared to the individual compounds and provides clues to drug targets and mechanisms of actions, which may underlie the benefits of this investigational drug combination.

neuroscience↗

bioRxiv2019

Differential genomic and transcriptomic events associated with high-grade transformation of Chronic Lymphocytic Leukemia

The transformation of chronic lymphocytic leukemia (CLL) to high-grade diffuse large B-cell lymphoma (DLBCL), also called Richters Syndrome (RS), is a rare cancer with dismal prognosis. Drug discovery for RS is hampered by the lack of suitable experimental models, and effective therapies remain elusive rendering RS an area of high unmet clinical need. We performed whole genome sequencing (WGS) to interrogate paired CLL and RS samples from 17 patients enrolled in a prospective multicenter Phase 2 clinical trial (CHOP-OR) and we found that subclones affected by mutations in MAPK and PI3K pathways show a high expansion probability during transformation. We also demonstrate for the first time that non-coding mutation clusters in a PAX5 enhancer, situated 330kb upstream from the transcription initiation site, correlate with transformation. Finally, we confirm our findings by employing targeted DNA sequencing (TGS) and RNA expression profiling on an extended cohort of 38 patients.\n\nStatement of significanceThrough integrated analysis of WGS, TGS and RNA expression data, we identified drivers of transformation not previously implicated in RS, which can be targeted therapeutically and tested in the clinic. Our results have informed the design of a new clinical platform study, which is now open to recruitment in the UK.

genomics↗

bioRxiv2021

Antimicrobial Effects of Ibuprofen Combined with Standard of Care Antimicrobials against Cystic Fibrosis Pathogens

Cystic Fibrosis (CF) is a common fatal genetic disease caused by mutations happened to cystic fibrosis transmembrane conductance regulator (CFTR) gene. Lungs of CF patients are often colonized or infected with microorganisms. Drug resistant bacterial infection has been problematic in cystic fibrosis patient. The chronic bacterial infections and concomitant airway inflammation could damage the lung and lead to respiratory failure. Several clinical trials have demonstrated that high-dose ibuprofen reduces the rate of pulmonary function decline in CF patients. This beneficial effect has been attributed to the anti-inflammatory properties of ibuprofen. Previously, we have confirmed that high-dose ibuprofen demonstrated antimicrobial activity against P. aeruginosa in in vitro and in vivo. However, no study has examined the antimicrobial effect of combining ibuprofen with standard-of-care (SoC) antimicrobials. Here, we evaluated possible synergistic activity of combinations of common nonsteroidal anti-inflammatory drugs (NSAIDs), namely, aspirin, naproxen, and ibuprofen, with commonly used antibiotics for CF patients. The drug combinations were screened against different CF clinical isolates. Drugs that demonstrated efficacy in the presence of ibuprofen were further verified synergistic effects between these antimicrobials and NSAIDs. Finally, the survival analysis of an P. aeruginosa murine infection model was used to demonstrate the efficacy of synergistic combination. Our results suggest that combinations of ibuprofen with commonly used antibiotics demonstrate synergistic antimicrobial activity against drug resistant, clinical bacterial strains in in vitro. The efficacy of combination ceftazidime and ibuprofen was demonstrated in in vivo.

microbiology↗

bioRxiv2024

Focused ultrasound increases gene delivery to deep brain structure following the administration of a recombinant adeno-associated virus in the cerebrospinal fluid

Gene delivery via adeno-associated viral vectors can provide lasting clinical benefits following a one-time treatment. Delivery throughout the brain is needed for the treatment of neurological disorders with widespread pathology, including Alzheimer and Parkinson diseases, and amyotrophic lateral sclerosis. Most gene vectors have poor diffusion in the brain tissue. Furthermore, it is only at high intravenous doses that gene vectors can overcome the blood-brain barrier. In contrast, relatively lower doses of gene vectors injected in the cerebrospinal fluid enable significant transduction of superficial brain regions. The remaining challenge and unmet need of gene therapy is to deliver gene vectors to deep brain structures using a minimally invasive strategy. Here, we demonstrate that non-invasive focused ultrasound blood-brain barrier modulation can increase the delivery of recombinant adeno-associated virus by 5-fold to deep brain structures following injection in the cisterna magna. Delivery of adeno-associated viral vectors to the central nervous system, via administration in the cerebrospinal fluid, is being evaluated in several clinical trials for treating beta-galactosidase-1 deficiency, Batten disease, Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, and spinal muscular atrophy. Our findings suggest that the efficacy of gene therapies delivered in the cerebrospinal fluid can be enhanced by targeting brain areas of interest with focused ultrasound. Significance statementAdministration of viral vectors in the cerebrospinal fluid through the cisterna magna is being evaluated in patients with neurological disorders. Focused ultrasound combined with intravenous microbubbles safely increases the permeability of the blood-brain barrier in humans and enables delivery of intravenous adeno-associated virus in non-human primates. Here, we demonstrate that combining these two clinically relevant gene delivery methods, intracisterna magna administration and focused ultrasound with microbubbles, can facilitate gene delivery to superficial and deep brain structures. Our findings have the potential to increase the efficacy of gene therapies, particularly for disorders with brain regions that have remained difficult to reach.

neuroscience↗

bioRxiv2019

Efficacy of PCV vaccine is primarily mediated by controlling pneumococcal colonisation density

Widespread use of Pneumococcal Conjugate Vaccines (PCV) has resulted in a reduction in nasopharyngeal colonisation and invasive pneumococcal disease caused by vaccine-types. In a double-blind, randomised controlled trial using the Experimental Human Pneumococcal Challenge (EHPC) model, PCV-13 (Prevenar-13) conferred 78% protection against colonisation acquisition and a reduction in bacterial intensity (AUC) in experimentally colonised volunteers as measured by classical culture. In this study, we used a multiplex quantitative PCR assay targeting lytA and pneumococcal serotype 6A/B cpsA genes to re-assess the experimental colonisation status of the same trial volunteers. Increase in detection of low-density colonised volunteers by this molecular method led to a decrease of PCV efficacy against colonisation acquisition (29%), as compared to classical culture (83%). For subjects who were colonised following pneumococcal challenge, PCV had a pronounced effect on decreasing colonisation density. These results have implications for vaccine efficacy and surveillance studies as they indicate that the success of PCV vaccination could primarily be mediated by the control of vaccine-type colonisation density which results in decreased transmission and the reported herd effect of PCVs. Studies assessing the impact of PCV should account for density measurements in their design. Clinical trial registration with ISRCTN: 45340436

microbiology↗

bioRxiv2020

AlzGPS: A Genome-wide Positioning Systems Platform to Catalyze Multi-omics for Alzheimer's Therapeutic Discovery

BackgroundOver15 million family members and caregivers have expended $220 billion for care of patients with AD and other dementias, and the attrition rate for AD clinical trials (2002-2012) is estimated at 99.6%. While recent DNA/RNA sequencing and other multi-omics technologies have advanced the understanding of the biology and pathophysiology of AD, no effective disease-modifying or preventive therapies, for AD have emerged in the past two decades. A new approach to integration of the genome, transcriptome, proteome, and human interactome in the drug discovery and development process is essential for this endeavor. MethodsIn this study, we developed AlzGPS (Genome-wide Positioning Systems platform for Alzheimers Therapeutic Discovery, https://alzgps.lerner.ccf.org), a comprehensive systems biology tool to enable searching, visualizing, and analyzing multi-omics, various types of heterogeneous biological networks, and clinical databases for target identification and effective prevention and treatment of AD. ResultsVia AlzGPS: (1) we curated more than 100 AD multi-omics data sets capturing DNA, RNA, protein, and small molecules profiles underlying AD pathogenesis (e.g., early vs. late stage and tau vs. amyloid endophenotype); (2) we constructed endophenotype disease modules by incorporating multi-omics findings and human protein-protein interactome networks; (3) we identified repurposable drugs from [~]3,000 FDA approved/investigational drugs for AD using state-of-the-art network proximity analyses; (4) we curated 300 literature references for highly repurposable drugs; (5) we included information from over 200 ongoing AD clinicals noting drug mechanisms and primary drug targets, and linking them to our integrated multi-omics view for targets and network analyses results for the drugs; (6) we implemented a highly interactive web-interface for database browsing and network visualization. ConclusionsNetwork visualization enabled by the AlzGPS includes brain-specific neighborhood networks for genes-of-interest, endophenotype disease module networks for data sets-of-interest, and mechanism-of-action networks for drugs targeting disease modules. By virtue of combining systems pharmacology and network-based integrative analysis of multi-omics data, the AlzGPS offers actionable systems biology tools for accelerating therapeutic development in AD.

systems biology↗

bioRxiv2026

Subchronic Toxicity Study of Nitric Oxide Nano Bubbles Injection in Sprague-Dawley Rats

Following the success of hydrogen nanobubble technology, development has expanded to include similar products with other gases, such as nitric oxide (NO). In previous studies, NO donors have been frequently used for both therapeutic and diagnostic purposes. However, the use of NO in nanoformulations has received little attention thus far. Thus, 90 days of subchronic toxicity testing in Sprague-Dawley rats were used in this study to assess potential adverse effects of intravenous administration of NO nanobubbles (NONB). Hematological factors, serum biochemistry, and histology of the liver, kidney, heart, lung, and spleen were investigated. The findings of the intravenous NONB injection trial in rats, using graded doses of 0.01 mL, 0.04 mL, and 0.06 mL, demonstrated no deaths during the 90-day treatment period. Biochemical parameters for liver function, lipid profile, kidney function, and serum electrolyte levels remain within acceptable limits, with slight variations in sodium and potassium levels. This condition was also supported by histological findings in the liver, kidney, and spleen, indicating mild to moderate damage, while the heart and lungs were normal. Thus, the intravenous administration of NONB at a dose of up to 0.06 mL in this subchronic toxicity test remains safe. Further studies with adjustments to the test formulation are highly encouraged until the clinical trial stage in humans.

pharmacology and toxicology↗

bioRxiv2021

Evaluating denoising strategies in resting-state fMRI in traumatic brain injury (EpiBioS4Rx)

ObjectiveResting-state functional MRI is increasingly used in the clinical setting and is now included in some diagnostic guidelines for severe brain injury patients. However, to ensure high-quality data, one should mitigate fMRI-related noise typical of this population. Therefore, we aimed to evaluate the ability of different preprocessing strategies to mitigate noise-related signal (i.e., in-scanner movement and physiological noise) in functional connectivity of traumatic brain injury patients. MethodsWe applied nine commonly used denoising strategies, combined into 17 pipelines, to 88 traumatic brain injury patients from the Epilepsy Bioinformatics Study for Anti-epileptogenic Therapy clinical trial (EpiBioS4Rx). Pipelines were evaluated by three quality control metrics across three exclusion regimes based on the participants head movement profile. ResultsWhile no pipeline eliminated noise effects on functional connectivity, some pipelines exhibited relatively high effectiveness depending on the exclusion regime. Once high-motion participants were excluded, the choice of denoising pipeline becomes secondary - although this strategy leads to substantial data loss. Pipelines combining spike regression with physiological regressors were the best performers, whereas pipelines that used automated data driven methods performed comparatively worse. ConclusionIn this study, we report the first large-scale evaluation of denoising pipelines aimed at reducing noise-related functional connectivity in a clinical population known to be highly susceptible to in-scanner motion and significant anatomical abnormalities. If resting-state functional magnetic resonance is to be a successful clinical technique, it is crucial that procedures mitigating the effect of noise be systematically evaluated in the most challenging populations, such as traumatic brain injury datasets.

neuroscience↗

bioRxiv2024

Seclidemstat blocks the transcriptional function of multiple FET-fusion oncoproteins

Genes encoding the RNA-binding proteins FUS, EWSR1, and TAF15 (FET proteins) are involved in chromosomal translocations in rare sarcomas. FET-rearranged sarcomas are often aggressive malignancies affecting patients of all ages. New therapies are needed. These translocations fuse the 5 portion of the FET gene with a 3 partner gene encoding a transcription factor (TF). The resulting fusion proteins are oncogenic TFs with a FET protein low complexity domain (LCD) and a DNA binding domain. FET fusion proteins have proven stubbornly difficult to target directly and promising strategies target critical co-regulators. One candidate is lysine specific demethylase 1 (LSD1). LSD1 is recruited by multiple FET fusions, including EWSR1::FLI1. LSD1 promotes EWSR1::FLI1 activity and treatment with the noncompetitive inhibitor SP-2509 blocks EWSR1::FLI1 transcriptional function. A similar molecule, seclidemstat (SP-2577), is currently in clinical trials for FET-rearranged sarcomas (NCT03600649). However, whether seclidemstat has pharmacological activity against FET fusions has not been demonstrated. Here, we evaluate the in vitro potency of seclidemstat against multiple FET-rearranged sarcoma cell lines, including Ewing sarcoma, desmoplastic small round cell tumor, clear cell sarcoma, and myxoid liposarcoma. We also define the transcriptomic effects of seclidemstat treatment and evaluated the activity of seclidemstat against FET fusion transcriptional regulation. Seclidemstat showed potent activity in cell viability assays across FET-rearranged sarcomas and disrupted the transcriptional function of all tested fusions. Though epigenetic and targeted inhibitors are unlikely to be effective as a single agents in the clinic, these data suggest seclidemstat remains a promising new treatment strategy for patients with FET-rearranged sarcomas. SIGNIFICANCEHere, we show the noncompetitive inhibitor, seclidemstat, has in vitro activity against multiple FET fusion proteins that cause a number of rare and aggressive sarcomas. These data represent one of the largest analyses of FET fusion activity across multiple malignancies and are a valuable resource for those studying FET-rearranged sarcomas.

cancer biology↗

bioRxiv2026

Loss of UBP1 drives oxaliplatin resistance through a targetable dependency on translation initiation

Oxaliplatin is a common component of various chemotherapeutic regimens for the treatment of gastrointestinal cancers. However, the majority of patients exhibit resistance to oxaliplatin-based therapy. Here, we integrated knockout and transcription-activation CRISPR screens in patient-derived gastric cancer organoids (GC PDOs) to comprehensively profile major genetic and transcriptomic changes observed over the course of resistance acquisition. Our screens identified UBP1, a transcription factor frequently lost in GC, as a critical determinant of oxaliplatin resistance development. Leveraging a large GC organoid biobank from a co-clinical trial and primary tumor omics data, we reveal that downregulation of specifically MYC-driven ribosome biogenesis drives oxaliplatin resistance, highlighting the drugs role as a ribosome biogenesis stressor. Mechanistically, UBP1 loss reduced expression of its direct target, MAX, a MYC cofactor, leading to downregulation of ribosome biogenesis and protection against nucleolar stress. Crucially, we discover that such downregulation is inevitably followed by a compensatory reliance on translation initiation, making it a therapeutic vulnerability in oxaliplatin-resistant tumors. Consequently, the resistance could be overcome by a synergistic action of the translation initiation repressor 4EGI, and the effect was also maintained in PDO that acquired resistance in vivo under clinically relevant conditions. Our data uncover a common marker of oxaliplatin resistance and identify a novel therapeutic strategy to reverse resistance to one of the most frequently used anticancer drugs.

cancer biology↗

bioRxiv2023

Rapid assessment of changes in phage bioactivity using dynamic light scattering

Extensive efforts are underway to develop bacteriophages as therapies against antibiotic-resistant bacteria. However, these efforts are confounded by the instability of phage preparations and a lack of suitable tools to assess active phage concentrations over time. Here, we use Dynamic Light Scattering (DLS) to measure changes in phage physical state in response to environmental factors and time, finding that phages tend to decay and form aggregates and that the degree of aggregation can be used to predict phage bioactivity. We then use DLS to optimize phage storage conditions for phages from human clinical trials, predict bioactivity in 50-year-old archival stocks, and evaluate phage samples for use in a phage therapy/wound infection model. We also provide a web-application (Phage-ELF) to facilitate DLS studies of phages. We conclude that DLS provides a rapid, convenient, and non-destructive tool for quality control of phage preparations in academic and commercial settings. Significance StatementPhages are promising for use in treating antibiotic-resistant infections, but their decay over time in refrigerated storage and higher temperatures has been a difficult barrier to overcome. This is in part because there are no suitable methods to monitor phage activity over time, especially in clinical settings. Here, we show that Dynamic Light Scattering (DLS) can be used to measure the physical state of phage preparations, which provides accurate and precise information on their lytic function - the key parameter underlying clinical efficacy. This study reveals a "structure-function" relationship for lytic phages and establishes DLS as a method to optimize the storage, handling, and clinical use of phages.

biophysics↗

bioRxiv2020

An effective, safe and cost-effective cell-based chimeric vaccine against SARS-CoV2

More than one hundred vaccines against SARS-CoV-2 have been developed and some of them have entered clinical trials, but the latest results revealed that these vaccines still face great challenges. Here, we developed a novel cell-based gp96-Ig-secreting chimeric vaccine which is composed of two viral antigens, the RBD of spike protein, and a truncated nucleocapsid protein that could induce epitope-specific cytotoxic T lymphocytes but low antibody response. Syrian hamsters immunized with the cell-based vaccine produced high level of SARS-CoV-2 specific NAbs and specific T cell immunity which could eliminate RBD-truncated N-expressing cells, without the induction of antibody against N protein and other observed toxicity. This study provides a proof of concept for clinical testing of this safe, effective and cost-effective vaccine against SARS-CoV2 infection.

immunology↗

bioRxiv2021

Enhancing cancer targeting of γ9δ2TCR through modified NKG2D co-stimulation

Despite the ability of {gamma}{delta}T cells to mediate tumor killing independently of MHC recognition, all the clinical trials that have been carried out using these cells showed low response rate in patients, in part due to its poor proliferation ability. Recently, a new generation of CAR-T cells called {beta}T cells engineered to express a defined {gamma}{delta}TCR (TEG) has been developed. TEGs are {beta}T cells engineered to express a defined {gamma}{delta}TCR. These cells are able to mediate effective antitumor reactivity without showing any reactivity towards healthy tissue, and combine the best qualities of both {beta}T and {gamma}{delta}T cells. In fact, the high affinity {gamma}9{delta}2TCR clone 5 has recently been selected within the TEG format as a clinical candidate (TEG001). Here we present a strategy to improve the antitumor activity of TEG001 by co-expressing an activating chimeric co-receptor together with {gamma}{delta}TCR-Cl5.Therefore, we developed three different co-receptors by fusing the extracellular domain of the activating cell surface receptor NKG2D, that is able to bind stress induced ligands typically expressed on tumor cells, to the cytoplasmic signaling domains of the T cell costimulatory proteins ICOS, CD28 and 4-1BB. We determined that introduction of the chimeric co-receptors NKG2D-CD28wt and NKG2D-4-1BBCD28TM improved the activity of TEG001 against tumors that were recognized by {gamma}{delta}TCR-Cl5 and expressed NKG2D ligands, but did not affect tumors that either were not recognized by {gamma}{delta}TCR-Cl5 or did not express NKG2D ligands. This chimeric co-receptors approach open a wide range of opportunities that lead to a next generation of TEGs.

immunology↗

bioRxiv2023

PI3K/mTOR is a therapeutically targetable genetic dependency in diffuse intrinsic pontine glioma

Diffuse midline glioma (DMG), including tumors diagnosed in the brainstem (diffuse intrinsic pontine glioma - DIPG), are uniformly fatal brain tumors that lack effective pharmacological treatment. Analysis of pooled CRISPR-Cas9 loss-of-function gene deletion screen datasets, identified PIK3CA and MTOR as targetable molecular dependencies across DIPG patient derived models, highlighting the therapeutic potential of the blood-brain barrier penetrant PI3K/Akt/mTOR inhibitor paxalisib. At the human equivalent maximum tolerated dose, mice treated with paxalisib experienced systemic feedback resulting in increased blood glucose and insulin levels, commensurate with DIPG patients in Phase 1b clinical trials who experienced hyperglycemia/hyperinsulinemia. To exploit genetic dependences, but maintain compliance and benefit, we optimized a paxalisib treatment regimen that employed reduced dosing more frequently, in combination with the anti-hyperglycemic drug, metformin. Combining optimized dosing with metformin restored glucose homeostasis and decreased phosphorylation of the insulin receptor in vivo, a common mechanism of PI3K-inhibitor resistance, extending the survival of DIPG xenograft models. RNA sequencing and phosphoproteomic profiling of DIPG models treated with paxalisib identified increased calcium-activated PKC signaling. Using the brain penetrant PKC inhibitor, enzastaurin in combination with paxalisib, we synergistically extended the survival of orthotopic xenograft models, benefits further promoted by metformin; thus, identifying a clinically relevant DIPG combinatorial approach. Brief SummaryDiffuse intrinsic pontine glioma is a lethal childhood brain tumor. Here we identify PIK3CA as a genetic dependency targeted by the brain penetrant pan-PI3K-inhibitor paxalisib.

cancer biology↗

bioRxiv2024

Preclinical Pediatric Molecular Analysis for Therapy Choice (MATCH)

Pediatric solid tumors arise from diverse tissues during development and exhibit a wide range of molecular, cellular and genetic features. This diversity, combined with the low incidence of pediatric cancer makes it increasingly difficult to personalize therapy for individual patients based on the unique features of their tumors. Therefore, well-credentialed preclinical models that capture the diversity and heterogeneity of pediatric solid tumors are essential for identifying molecular targeted therapeutics for precision medicine. Here, we report 281 orthotopic patient derived xenografts (O-PDXs) from 224 patients representing 24 different types of pediatric solid tumors. We have performed genomic characterization of the O-PDXs and compared them to their corresponding patient tumors. To demonstrate the feasibility and utility of using such a diverse collection of O-PDXs in preclinical studies, we performed a preclinical pediatric precision medicine trial based on the NCI-COG Pediatric MATCH trial enrollment criteria. We also tested molecular targeted therapy for a novel oncogenic fusion recently reported in pediatric melanoma and precision drug delivery using nano-liposomal irinotecan. Our studies demonstrate the value of large, well-credentialed preclinical models for future precision medicine in pediatric oncology using single agents, drug combinations and novel drug formulations. Translational RelevanceThis study demonstrates the value of utilizing fully characterized preclinical models of pediatric solid tumors to evaluate the response to precision medicine approaches. Our results demonstrate the importance of performing comprehensive preclinical testing using multiple orthotopic patient derived xenografts to validate and prioritize vulnerabilities identified through genomic or integrated analyses which can be translated into clinical trials. Importantly, this study identified combinations using nano-liposomal irinotecan in a precision drug delivery approach that may benefit pediatric solid tumor patients. In addition, all models and their associated data are made freely available to the scientific community through the Childhood Solid Tumor Network.

cancer biology↗

bioRxiv2024

Development of a pipeline to evaluate YAP-TEAD inhibitor potential - direct TEAD inhibition represses cancerous growth in a NF2-mutant model of mesothelioma

As the core, tumorigenic downstream effectors of the Hippo signalling pathway, YAP/TAZ and the TEAD family of transcription factors represent attractive targets for drug discovery efforts within cancer research. This is particularly true within the context of pleural mesothelioma, in which there are many recent preclinical developments and clinical trials evaluating the efficacy of TEAD inhibitors. The range of inhibitors have shown great promise, but comparisons of their performances are so far limited. Here we develop a high content pipeline that enables a comparative analysis of currently developed YAP/TAZ-TEAD inhibitors. We take advantage of isogenic cellular models that enable us to examine inhibitor specificity. We identify genetic compensation of the Hippo pathway transcriptional module, with implications for therapeutic targeting, and implement Cell Painting to develop a detailed morphological profiling pipeline that enables further characterisation, quantification, and analysis of off-target effects. Our pipeline is scalable and allows us to establish specificity and comparative potency within cancer relevant assays in a clinically relevant cellular model.

cancer biology↗

bioRxiv2017

The impact of tumor receptor heterogeneity on the response to anti-angiogenic cancer treatment

Multiple promoters and inhibitors mediate angiogenesis, the formation of new blood vessels, and these factors represent potential targets for impeding vessel growth in tumors. Vascular endothelial growth factor (VEGF) is a potent angiogenic factor targeted in anti-angiogenic cancer therapies. In addition, thrombospondin-1 (TSP1) is a major endogenous inhibitor of angiogenesis, and TSP1 mimetics are being developed as an alternative type of anti-angiogenic agent. The combination of bevacizumab, an anti-VEGF agent, and ABT-510, a TSP1 mimetic, has been tested in clinical trials to treat advanced solid tumors. However, the patients responses are highly variable and show disappointing outcomes. To obtain mechanistic insight into the effects of this combination anti-angiogenic therapy, we have constructed a novel whole-body systems biology model including the VEGF and TSP1 reaction networks. Using this molecular-detailed model, we investigated how the combination anti-angiogenic therapy changes the amounts of pro-angiogenic and anti-angiogenic complexes in cancer patients. We particularly focus on answering the question of how the effect of the combination therapy is influenced by tumor receptor expression, one aspect of patient-to-patient variability. Overall, this model complements the clinical administration of combination anti-angiogenic therapy, highlights the role of tumor receptor variability in the heterogeneous responses to anti-angiogenic therapy, and identifies the tumor receptor profiles that correlate with a high likelihood of a positive response to the combination therapy. Our model provides novel understanding of the VEGF-TSP1 balance in cancer patients at the systems-level and could be further used to optimize combination anti-angiogenic therapy.

systems biology↗

bioRxiv2023

Data Driven Taxonomy for Antipsychotic Medication: A New Classification System

BackgroundThere are over 25 licensed antipsychotic medications with diverse pharmacological and clinical profiles. Antipsychotics are commonly described as either typical or atypical, but this does not accurately reflect pharmacological profiles. There is thus a need for a data driven antipsychotic classification scheme suitable for clinicians and researchers which maps onto both pharmacological and clinical effects. MethodWe analysed affinities of 27 antipsychotics for 42 receptors from 3,325 receptor binding studies. We used a clustering algorithm to group antipsychotics based on their pattern of receptor affinity. Using a machine learning model, we examined the ability of this grouping to predict antipsychotic-induced side effects quantified according to an umbrella review of clinical trial and treatment guideline data. ResultsClustering resulted in four groups of antipsychotics. The predominant receptor affinity and effect/side effect fingerprints of these four groups were defined, as follows: Group 1 - Muscarinic (M3-M5) receptor antagonism; Cholinergic and metabolic side effects. Group 2 - Dopamine (D2) partial agonism and adrenergic antagonism; Globally low side effect burden. Group 3 - Serotonergic and dopaminergic antagonism; Globally moderate side effect burden. Group 4 - Dopaminergic antagonism; Extrapyramidal and motor side effects. Groups 1 and 4 were more efficacious than clusters 2 and 3. The novel classification was superior to existing approaches when predicting side effects. ConclusionsA receptor affinity-based grouping not only reflects compound pharmacology but also detects meaningful clinical differences to a greater extent than existing approaches. The approach has the potential to benefit both patients and researchers by guiding treatment and informing drug development.

pharmacology and toxicology↗