a-data-integration-workflow-to-identify-drug-combinations-targeting

A Data Integration Workflow to Identify Drug Combinations Targeting Synthetic Lethal Interactions

A synthetic lethal interaction between two genes is given when knock-out of either one of the two genes does not affect cell viability but knock-out of ...

Medical University of Vienna

Aim of this study was to describe longitudinal assessments of handgrip strength, strength of thigh muscles, and self-reported physical performance in patients with glioblastoma after neurosurgical intervention undergoing chemoradiation.

Strength of skeletal muscle and self-reported physical performance in Austrian glioblastoma-patients.

Prostate cancer is the most prevalent cancer in males in developed countries. Tumor suppressor candidate 3 (TUSC3) has been identified as a putative tumor suppressor gene in prostate cancer, though its function has not been characterized. TUSC3 shares homologies with the yeast oligosaccharyltransferase (OST) complex subunit Ost3p, suggesting a role in protein glycosylation. We provide evidence that TUSC3 is part of the OST complex and affects N-linked glycosylation in mammalian cells. Loss of TUSC3 expression in DU145 and PC3 prostate cancer cell lines leads to increased proliferation, migration and invasion as well as accelerated xenograft growth in a PTEN negative background. TUSC3 downregulation also affects endoplasmic reticulum (ER) structure and stress response, which results in increased Akt signaling. Together, our findings provide first mechanistic insight in TUSC3 function in prostate carcinogenesis in general and N-glycosylation in particular. 

TUSC3 loss alters the ER stress response and accelerates prostate cancer growth in vivo.

Tumor-initiating subpopulations of cancer cells, also known as cancer stem cells (CSC), were recently identified and characterized in prostate cancer. A well-characterized murine model of prostate cancer was used to investigate the regulation of hypoxia-inducible factor 1α (HIF1A/HIF1α) in CSCs and a basal stem cell subpopulation (Lin(-)/Sca-1(+)/CD49f(+)) was identified, in primary prostate tumors of mice, with elevated HIF1α expression. To further analyze the consequences of hypoxic upregulation on stem cell proliferation and HIF1α signaling, CSC subpopulations from murine TRAMP-C1 cells (Sca-1(+)/CD49f(+)) as well as from a human prostate cancer cell line (CD44(+)/CD49f(+)) were isolated and characterized. HIF1α levels and HIF target gene expression were elevated in hypoxic CSC-like cells, and upregulation of AKT occurred through a mechanism involving an mTOR/S6K/IRS-1 feedback loop. Interestingly, resistance of prostate CSCs to selective mTOR inhibitors was observed because of HIF1α upregulation. Thus, prostate CSCs show a hypoxic deactivation of a feedback inhibition of AKT signaling through IRS-1. In light of these results, we propose that deregulation of the PI3K/AKT/mTOR pathway through HIF1α is critical for CSC quiescence and maintenance by attenuating CSC metabolism and growth via mTOR and promoting survival by AKT signaling. We also propose that prostate CSCs can exhibit primary drug resistance to selective mTOR inhibitors.

HIF1α Regulates mTOR Signaling and Viability of Prostate Cancer Stem Cells.

In our study, we investigated the role of ZNF677 in non-small cell lung cancers (NSCLC). By comparing ZNF677 expression in primary tumor (TU) and in the majority of cases also of corresponding non-malignant lung tissue (NL) samples from > 1,000 NSCLC patients, we found tumor-specific downregulation of ZNF677 expression (adjusted p-values < 0.001). We identified methylation as main mechanism for ZNF677 downregulation in NSCLC cells and we observed tumor-specific ZNF677 methylation in NSCLC patients (p < 0.0001). In the majority of TUs, ZNF677 methylation was associated with loss of ZNF677 expression. Moreover, ZNF677 overexpression in NSCLC cells was associated with reduced cell proliferation and cell migration. ZNF677 was identified to regulate expression of many genes mainly involved in growth hormone regulation and interferon signalling. Finally, patients with ZNF677 methylated TUs had a shorter overall survival compared to patients with ZNF677 not methylated TUs (p = 0.013). Overall, our results demonstrate that ZNF677 is trancriptionally regulated by methylation in NSCLCs, suggest that ZNF677 has tumor cell growth suppressing properties in NSCLCs and that ZNF677 methylation might serve as prognostic parameter in these patients.

DNA methylation transcriptionally regulates the putative tumor cell growth suppressor ZNF677 in non-small cell lung cancers.

[Not Available].

An innovative form of whole body vibration therapy on a treatment bed (Evocell®) to fight against the disabling and isolating symptom of postoperative incontinence in a prostate cancer patient is presented. A supervised program with outpatient active pelvic floor training and a novel form of synchronous high-intensity whole body vibration therapy using the Evocell® device was performed in a patient with postprostatectomy stress urinary incontinence. The patient had previously failed regular pelvic floor exercise. During the intervention, namely a whole body vibration treatment in a lying position on a treatment bed, the patient performed active and passive pelvic floor exercises under professional guidance. Over a period of 6 weeks after starting treatment, the patient regained continence (usage of 1 safety pad). Furthermore, his ability to work increased (return to work) and his ability to attend social activities improved.

Whole body vibration therapy on a treatment bed as additional means to treat postprostatectomy urinary incontinence.

The aim of this systematic review was to update scientific knowledge concerning the safety of neuromuscular electrical stimulation (NMES) to increase exercise capacity and prevent cardiac cachexia in patients with implantable cardioverter defibrillators (ICDs).

Neuromuscular electrical stimulation of the thighs in cardiac patients with implantable cardioverter defibrillators.

DNA methylation regulates together with other epigenetic mechanisms the transcriptional activity of genes and is involved in the pathogenesis of malignant diseases including lung cancer. In non-small cell lung cancer (NSCLC) various tumor suppressor genes are already known to be tumor-specifically methylated. However, from the vast majority of a large number of genes which were identified to be tumor-specifically methylated, tumor-specific methylation was unknown so far. Thus, the major aim of this study was to investigate in detail the mechanism(s) responsible for transcriptional regulation of the genes SPAG6 and L1TD1 in NSCLCs.

SPAG6 and L1TD1 are transcriptionally regulated by DNA methylation in non-small cell lung cancers.

In recent years, the concept of synthetic lethality, describing a cellular state where loss of two genes leads to a non-viable phenotype while loss of one gene can be compensated, has emerged as a novel strategy for cancer therapy. Various compounds targeting synthetic lethal pathways are either under clinical investigation or are already routinely used in multiple cancer entities such as breast cancer. Most of them target the well-described synthetic lethal interplay between PARP1 and BRCA1/2. In our study, we investigated, using an  methodological approach, clinically utilized drug combinations for breast cancer treatment, by correlating their known molecular targets with known homologous interaction partners that cause synthetic lethality in yeast. Further, by creating a machine-learning algorithm, we were able to suggest novel synthetic lethal drug combinations of low-toxicity drugs in breast cancer and showed their negative effects on cancer cell viability . Our findings foster the understanding of evolutionarily conserved synthetic lethality in breast cancer cells and might lead to new drug combinations with favorable toxicity profile in this entity.

Synthetic lethal combinations of low-toxicity drugs for breast cancer identified  by genetic screens in yeast.

Synthetic lethality describes a relationship between two genes where single loss of either gene does not trigger significant impact on cell viability, but simultaneous loss of both gene functions results in lethality. Targeting synthetic lethal interactions with drug combinations promises increased efficacy in tumor therapy.

Synthetic lethality guiding selection of drug combinations in ovarian cancer.

To assess the prevalence of sarcopenia and whether body composition parameters are associated with disease progression and overall survival (OS) in castration-resistant prostate cancer (CRPC) patients.

Assessment of body composition in the advanced stage of castration-resistant prostate cancer: special focus on sarcopenia.

Hormonal control of cancer: an outdated topic?

Novel treatment modalities like targeted therapy and immunotherapy are currently changing treatment strategies and protocols in the field of medical oncology.

Thirteen-year analyses of medical oncology outpatient day clinic data: a changing field.

Loss of hepatocellular carcinoma-related protein 1 (HCRP1) (alias VPS37A) plays a role in endocytosis of receptor tyrosine kinases as a member of the ESCRT complex and has been linked to poor patient outcome in various types of epithelial cancer. To this date, the molecular and biological mechanisms explaining how its absence would contribute to tumor progression remain unknown. Using genomic editing with CRISPR-Cas9, we generated ovarian and breast cancer cell lines with loss-of-function mutations of HCRP1. We hypothesized that pathways downstream of receptor tyrosine kinases such as epidermal growth factor receptor are affected by HCRP1 loss and looked for deregulated signaling using immunoblotting and classical cancer biology assays. In our study, we show that endogenous deletion of HCRP1 leads to elevated phosphorylation of the transcription factor Signal transducer and activator of transcription 3 (STAT3) and induces upregulation of PD-L1, an important regulator of immune checkpoint inhibition. HCRP1 loss further leads to a mesenchymal phenotype switch in cancer cells, leading to increased proliferation and migration. Concludingly, our data emphasize the role of the tumor microenvironment in tumors with low or absent HCRP1 expression and suggest HCRP1 loss as a potential marker for metastatic potential and immunogenicity of epidermal growth factor receptor-driven cancer.

Loss of HCRP1 leads to upregulation of PD-L1 via STAT3 activation and is of prognostic significance in EGFR-dependent cancer.

Breast cancer (BC) is the most common malignancy and the second cause of cancer-specific death in women from high-income countries. Recently, gut microbiota dysbiosis emerged as a key player that may directly and/or indirectly influence development, treatment, and prognosis of BC through diverse biological processes: host cell proliferation and death, immune system function, chronic inflammation, oncogenic signalling, hormonal and detoxification pathways. Gut colonisation occurs during the prenatal period and is later diversified over distinct phases throughout life. In newly diagnosed postmenopausal BC patients, an altered faecal microbiota composition has been observed compared with healthy controls. Particularly, β-glucuronidase bacteria seem to modulate the enterohepatic circulation of oestrogens and their resorption, increasing the risk of hormone-dependent BC. Moreover, active phytoestrogens, short-chain fatty acids, lithocholic acid, and cadaverine have been identified as bacterial metabolites influencing the risk and prognosis of BC. As in gut, links are also being made with local microbiota of tumoural and healthy breast tissues. In breast microbiota, different microbial signatures have been reported, with distinct patterns per stage and biological subtype. Total bacterial DNA load was lower in tumour tissue and advanced-stage BC when compared with healthy tissue and early stage BC, respectively. Hypothetically, these findings reflect local dysbiosis, potentially creating an environment that favours breast tumour carcinogenesis (oncogenic trigger), or the natural selection of microorganisms adapted to a specific microenvironment. In this review, we discuss the origin, composition, and dynamic evolution of human microbiota, the links between gut/breast microbiota and BC, and explore the potential implications of metabolomics and pharmacomicrobiomics that might impact BC development and treatment choices toward a more personalised medicine. Finally, we put in perspective the potential limitations and biases regarding the current microbiota research and provide new horizons for stronger accurate translational and clinical studies that are needed to better elucidate the complex network of interactions between host, microorganisms, and drugs in the field of BC.

Article	Year
Strength of skeletal muscle and self-reported physical performance in Austrian glioblastoma-patients. Wiener klinische Wochenschrift\| PubMed ID: 22688136	2012
TUSC3 loss alters the ER stress response and accelerates prostate cancer growth in vivo. Scientific reports\| PubMed ID: 24435307	2014
HIF1α Regulates mTOR Signaling and Viability of Prostate Cancer Stem Cells. Molecular cancer research : MCR\| PubMed ID: 25349289	2015
DNA methylation transcriptionally regulates the putative tumor cell growth suppressor ZNF677 in non-small cell lung cancers. Oncotarget\| PubMed ID: 25504438	2015
[Not Available]. Wiener klinische Wochenschrift\| PubMed ID: 26905876	2016
Whole body vibration therapy on a treatment bed as additional means to treat postprostatectomy urinary incontinence. Wiener medizinische Wochenschrift (1946)\| PubMed ID: 27342596	2017
Neuromuscular electrical stimulation of the thighs in cardiac patients with implantable cardioverter defibrillators. Wiener klinische Wochenschrift\| PubMed ID: 27457876	2016
SPAG6 and L1TD1 are transcriptionally regulated by DNA methylation in non-small cell lung cancers. Molecular cancer\| PubMed ID: 28093071	2017
Synthetic lethal combinations of low-toxicity drugs for breast cancer identified by genetic screens in yeast. Oncotarget\| PubMed ID: 30555636	2018
Synthetic lethality guiding selection of drug combinations in ovarian cancer. PloS one\| PubMed ID: 30682083	2019
Assessment of body composition in the advanced stage of castration-resistant prostate cancer: special focus on sarcopenia. Prostate cancer and prostatic diseases\| PubMed ID: 31745255	2020
Hormonal control of cancer: an outdated topic? ESMO open\| PubMed ID: 32763958	2020
Thirteen-year analyses of medical oncology outpatient day clinic data: a changing field. ESMO open\| PubMed ID: 33051192	2020
Loss of HCRP1 leads to upregulation of PD-L1 via STAT3 activation and is of prognostic significance in EGFR-dependent cancer. Translational research : the journal of laboratory and clinical medicine\| PubMed ID: 33197651	2021
Human Microbiota and Breast Cancer-Is There Any Relevant Link?-A Literature Review and New Horizons Toward Personalised Medicine. Frontiers in microbiology\| PubMed ID: 33716996	2021

Maximilian Marhold

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