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Development of PROTACS degrading KRAS and SOS1

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Oncology Research 2024年第8期32卷 1257-1264页

作者： gerhard hamilton MARIE-THERESE EGGERSTORFER SANDRA STICKLER Institute of Pharmacology Medical University of ViennaVienna1090Austria

The Kirsten rat sarcoma virus—son of sevenless 1(KRAS-SOS1)axis drives tumor growth preferentially in pancreatic,colon,and lung ***,KRAS G12C mutated tumors can be successfully treated with inhibitors that covalently block the cysteine of the switch II binding pocket of ***,the range of other KRAS mutations is not amenable to treatment and the G12C-directed agents Sotorasib and Adragrasib show a response rate of only approximately 40%,lasting for a mean period of 8 *** approach to increase the efficacy of inhibitors is their inclusion into proteolysis-targeting chimeras(PROTACs),which degrade the proteins of interest and exhibit much higher antitumor activity through multiple cycles of ***,PROTACs have been developed based on KRAS-or SOS1-directed inhibitors coupled to either von Hippel-Lindau(VHL)or Cereblon(CRBN)ligands that invoke the proteasomal *** of these PROTACs show increased activity in vitro and in vivo compared to their cognate inhibitors but their toxicity in normal tissues is not *** CRBN PROTACs containing thalidomide derivatives cannot be tested in experimental *** to such PROTACS arises through downregulation or inactivation of CRBN or factors of the functional VHL E3 ubiquitin *** highly active KRAS and SOS1 PROTACs have been formulated their clinical application remains difficult.

关键词： Proteolysis-targeting chimeras(PROTACs) Kirsten rat sarcoma virus(KRAS) Son of sevenless 1(SOS1) Von Hippel-Lindau Cereblon

Changes of protein expression during tumorosphere formation of small cell lung cancer circulating tumor cells

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Oncology Research 2023年第1期31卷 13-22页

作者： SANDRA STICKLER BARBARA RATH MAXIMILIAN HOCHMAIR CLEMENS LANG LUKAS WEIGL gerhard hamilton Institute of Pharmacology Medical University of ViennaViennaAustria Karl Landsteiner Institute of Lung Research and Pulmonary Oncology Klinik FloridsdorfViennaAustria Department of Trauma Surgery Sozialmedizinisches Zentrum OstDonauspitalViennaAustria Division of Special Anesthesia and Pain Medicine Medical University of ViennaViennaAustria

Small cell lung cancer(SCLC)is frequently disseminated and has a dismal prognosis with survival times of approximately two *** cancer responds well to initial chemotherapy but recurs within a short time as a globally chemoresistant *** tumor cells(CTCs)are held responsible for metastasis,the extremely high numbers of these cells in advanced SCLC allowed us to establish several permanent CTC cell *** CTCs are distinguished by the spontaneous formation of large spheroids,termed tumorospheres,in regular tissue *** contain quiescent and hypoxic cells in their interior and are associated with high chemoresistance compared to single cell *** CTC lines were compared for their expression of 84 proteins associated with cancer either as single cells or in the form of tumorospheres in Western blot *** the exception of the UHGc5 line,all other CTC lines express EpCAM and lack a complete EpCAM-negative,vimentin-positive epithelial-mesenchymal transition(EMT)*** formation of tumorospheres the expression of EpCAM,that mediates cell-cell adhesion is markedly *** such as E-Cadherin,p27 KIP1,Progranulin,BXclx,Galectin-3,and Survivin showed variable changes for the distinct CTC cell *** conclusion,EpCAM presents the most critical marker for individual SCLC CTCs and the assembly of highly chemoresistant tumorospheres.

关键词： SCLC Spheroid Chemoresistance EpCAM Topotecan Epirubicin

Role of circulating tumor cell spheroids in drug resistance

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Cancer Drug Resistance 2019年第3期2卷 762-772页

作者： gerhard hamilton Barbara Rath Department of Surgery Medical University of ViennaVienna A-1090Austria

Cancer cell spheroids are used for drug screening as these three-dimensional(3D)assemblies recapitulate tumors more realistic than the widely employed 2D in vitro *** drug diffusion and gradients of oxygen and nutrients in spheroids represent avascular tumor regions containing quiescent and hypoxic tumor cells with high drug *** tumor cells(CTCs)effect metastatic spread and are present in high numbers in malignant diseases such as small-cell lung cancer(SCLC)and in other cancer patients with high tumor *** are heterogeneous and only a small fraction of these cells survive in the circulation and cause distal *** may circulate as single cells but small CTC clusters or CTC spheroids have been detected in cancer patients and demonstrated to possess increased metastatic *** our lab we have obtained 9 permanent SCLC CTC cell lines(BHGc7,BHGc10,BHGc16,BHGc26,BHGc27,BHGc50,BHGc59,BHGc71,and UHGc5)of distinct patients exhibiting similar characteristics and spontaneous formation of large spheroids,termed *** aggregates were shown to exhibit high drug resistance compared to the corresponding single cell *** increased metastatic capability of small circulating tumor clusters/spheroids may be explained by their role as putative precursors of tumorospheres eventually trapped in *** drug penetration and the presence of hypoxic/quiescent cells can readily account for the global drug resistance of advanced SCLC which has resulted in clinical failure of a wide range of chemotherapeutics and low ***,we have detected such tumorospheres in non-small-cell lung cancer(NSCLC)patients progressing under EGFR-directed tyrosine kinase inhibitor therapy which had undergone NSCLC-SCLC transformation.

关键词： Cancer spheroid circulating tumor cells small cell lung cancer non-small-cell lung cancer transformation dormancy

Non-small cell lung cancer-small cell lung cancer transformation as mechanism of resistance to tyrosine kinase inhibitors in lung cancer

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Cancer Drug Resistance 2020年第2期3卷 171-178页

作者： Barbara Rath Adelina Plangger gerhard hamilton Department of Vascular Surgery Medical University of ViennaVienna A-1090Austria

Mutated or rearranged driver kinases in non-small cell lung cancer(NSCLC)cells are clinically amenable to treatment with tyrosine kinase inhibitors(TKIs)resulting in prolonged survival and significant benefit compared to cytotoxic *** most frequent genomic alterations are observed for epidermal growth factor receptor and anaplastic lymphoma kinase,which can be blocked by a range of specific TKIs in *** clinics,resistance to TKIs emerges after approximately one year and comprises secondary mutations of the kinases(on-target)or alternative pathways circumventing the original kinase(off-target)alterations.A special feature of NSCLC is the occurrence of histological transformation to small cell lung cancer(SCLC)in up to 14%of cases,which,in general,is accompanied by resistance to the original *** transformed tumors may be treated with the classical platinum/etoposide regimen but thus far there are no definitive *** transformed pleural SCLC lines in our lab indicate the presence of a gradual NSCLC-SCLC shift with overlapping drug *** conclusion,the treatment of NSCLC-SCLC transformed cancer cells would need a better chemosensitivity assessment using functional genomics to guide further therapy.

关键词： Lung cancer non-small cell lung cancer small cell lung cancer transformation epidermal growth factor receptor tyrosine kinase inhibitor chemotherapy drug resistance

Protection of small-cell lung cancer circulating tumor cells by cellular fragmentation

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Journal of Cancer Metastasis and Treatment 2020年第1期6卷 345-354页

作者： Barbara Rath Adelina Plangger Doris Moser Maximilian Hochmair Ernst Ulsperger gerhard hamilton Department of Vascular Surgery Medical University of ViennaVienna A-1190Austria Department of Cranio-Maxillofacial and Oral Surgery Medical University of ViennaVienna A-1090Austria Hospital Floridsdorf Vienna A-1210Austria Hospital Horn Horn A-3580Austria

Aim:Small-cell lung cancer(SCLC)disseminates aggressively and may exhibit high chemoresistance and poor survival *** this study,we aimed to investigate a new mechanism of drug resistance for SCLC circulating tumor cells(CTCs).Methods:SCLC CTC cell lines(n=4)which shed cellular fragments(MAT),as demonstrated by light and scanning electron microscopy,are compared to permanent SCLC *** proteins are detected by proteome arrays and the functional impact of MAT is studied using cytotoxicity tests involving cisplatin and ***:The SCLC CTC lines revealed layers of attached cellular fragments with a range of decreasing sizes from intact cells(approximately 12μm)down to small debris(approximately 2μm)which are not detectable in permanent SCLC *** SCLC CTC clusters represent cores of these fragment-coated *** profiling of MAT revealed a protein pattern similar to intact *** tests employing SCLC and SCLC CTC lines with chemotherapeutics used in therapy of SCLC demonstrated an inhibitory activity of MAT on the resulting ***:Generation of cell-associated debris by SCLC CTCs offers protective effects against cytotoxic drugs,representing a novel mechanism allowing survival of SCLC CTCs in patients.

关键词： Small cell lung cancer circulating tumor cells shedding topotecan

Insights into mechanisms of tumor dissemination from circulating tumor cell lines of small cell lung cancer

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Journal of Cancer Metastasis and Treatment 2016年第1期2卷 446-452页

作者： gerhard hamilton Barbara Rath Society for Research on Biology and Treatment of Cancer A-1160 ViennaAustria

Despite the fact that the majority of cancer patients succumb to metastatic disease,most aspects of tumor metastasis are not understood in detail at *** biologic steps of dissemination are difficult to characterize in human tumors and research is in large part confined to cell line and experimental animal ***-mesenchymal transition(EMT),intravasation of malignant cells,dissemination as circulating tumor cells(CTCs)and eventually mesenchymal-epithelial transition(MET)at distal sites are steps believed to be involved in *** cell lung cancer(SCLC)is distinguished by early dissemination and excessive numbers of CTCs,which allowed for the ex vivo expansion of six permanent CTC lines taken from relapsed *** exhibit an epithelial phenotype with partial EMT traits and are chemoresistant due to formation of large *** cells may have invaded without undergoing EMT,the role of MET is *** SCLC CTC cell lines seem to represent the metastasis-inducing cancer cells;these are the minute subpopulation of CTCs capable of surviving in the circulation and transitioning to metastases,leading in turn to resistance and failure of *** characterization of these lines is expected to provide the markers to find the relevant CTCs among the highly heterogeneous population observable in the context of tumor recurrence.

关键词： Cancer metastasis small cell lung cancer circulating tumor cells epithelial-mesenchymal transition tumorosphere chemotherapy drug resistance

Therapy-Induced Changes of Gene Expression in a Matched Pair of Small Cell Lung Cancer (SCLC) Cell Lines

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Journal of Cancer Therapy 2012年第4期3卷 442-451页

作者： gerhard hamilton Ernst Ulsperger Klaus Geissler Ulrike Olszewski Ludwig Boltzmann Cluster of Translational Oncology Vienna Austria

Extended stage small cell lung cancer (SCLC) responds to platinum/vepeside-based first-line chemotherapy but relapses early as drug-resistant tumor associated with a dismal prognosis. A pair of SCLC cell lines obtained from a single patient at different time points during treatment allows for the investigation of the changes in gene expression prior to (GLC14) and following cycles of chemotherapy and irradiation (GLC19). GLC19 cells were reported to reveal an increased doubling time and exhibit increased chemoresistance to doxorubicin, etoposide, melphalan and vinblastine. Upregulated transcripts in GLC19, as assessed by microarray analysis, comprised proteins involved in regulation of cellular growth (NGFRAP1/BEX3), adhesion, glutathione metabolism and, in particular, WNT/Notch pathways and the putative cancer stem cell phenotype (CD44, ALDH1A1, and AKR1C1/13). Metallothioneins, tubulins TUBA3/4 and tumor protein p53 inducible protein 11 (TP53IP11) were downregulated in this cell line compared to GLC14. Except increased expression of glutathione transferases no classical markers of chemoresistance were found, pointing to a role of altered growth control/differentiation and reduced accessibility of this SCLC tumor cells growing as multicellular spheroids. In conclusion, treatment of this single SCLC with cyclophosphamide, doxorubicin and etoposide (CDE) followed by radiotherapy ultimately resulted in an enrichment of tumor cells displaying the typical signature of tumor-initiating or cancer stem cells (CIC/CSC).

关键词： Small Cell Lung Cancer GLC14 GLC19 Chemotherapy Chemoresistance Gene Expression Cancer-Initiating Cells

Synergistic Anticancer Activity of Topotecan— Cyclin-Dependent Kinase Inhibitor Combinations against Drug-Resistant Small Cell Lung Cancer (SCLC) Cell Lines

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Journal of Cancer Therapy 2013年第8期4卷 47-53页

作者： gerhard hamilton Ulrike Olszewski, Lukas Klameth Ernst Ulsperger Klaus Geissler Ludwig Boltzmann Cluster of Translational Oncology Vienna Austria Ludwig Boltzmann Cluster of Translational Oncology Vienna Austria.

Extended-stage small cell lung cancer (SCLC) responds to platinum/vepeside-based first-line chemotherapy but relapses rapidly as drug-resistant tumor. Topotecan (TPT) is the single chemotherapeutic agent approved for second-line treatment of SCLC. However, the response to TPT is short-lived and novel treatment modalities need to be developed. Sequential treatment of cytotoxic drugs and inhibitors of cyclin-dependent kinases (CDKs) showed promising preclinical anticancer activity and, in the present work, combinations of TPT with CDK inhibitors olomoucine, roscovitine and CDK4I are shown to exhibit synergistic cytotoxic activity against SCLC cell lines. Highest activity was found against TPT-resistant NCI-H417 and DMS153 cell lines and moderate chemosensitizing effects against a primary SCLC cell line and sensitive GLC19 cells at levels of CDK inhibitors which exerted low toxicity. A combination of 0.6 μM TPT with 0.6 μM roscovitine, exhibiting no significant cytotoxicity as single agents, reduced viability of the TPT-resistant NCI-H417 line (IC50 > 10 μM) by 50%. In the TPT resistant cell lines olomoucine and roscovitine, targeting CDK1,2,5,7, were highly effective, whereas in the more sensitive cell lines CDK4I, inhibiting mainly CDK4/6, showed activity. In NCI-417 cells, preincubation with roscovitine for one day proved synergistic with TPT. Thus, in good accordance with previous findings, CDK inhibitors are able to convert SCLC cancer cells which are cell-cycle arrested by a blockade of topoisomerase I by TPT to apoptotic cells. Since nowadays several CDK inhibitors are at various phases of clinical testing their combination with TPT seems to constitute a promising approach to improve second-line chemotherapy in SCLC.

关键词： Small Cell Lung Cancer Chemoresistance Topotecan CDK Inhibitor Olomoucine Roscovitine

The future of computer-aided sperm analysis

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Asian Journal of Andrology 2015年第4期17卷 545-553页

作者： Sharon T Mortimer gerhard van der Horst David Mortimer Oozoa Biomedical West Vancouver BC Canada Department of Medical Biosciences University ofthe Western Cape Bellville South Africa 0ozoaBiomedical West Vancouver BC Canada.

Computer-aided sperm analysis （CASA） technology was developed in the late 1980s for analyzing sperm movement characteristics or kinematics and has been highly successful in enabling this field of research. CASA has also been used with great success for measuring semen characteristics such as sperm concentration and proportions of progressive motility in many animal species, including wide application in domesticated animal production laboratories and reproductive toxicology. However, attempts to use CASA for human clinical semen analysis have largely met with poor success due to the inherent difficulties presented by many human semen samples caused by sperm clumping and heavy background debris that, until now, have precluded accurate digital image analysis. The authors review the improved capabilities of two modern CASA platforms （hamilton Thorne CASA-II and Microptic SCA6） and consider their current and future applications with particular reference to directing our focus towards using this technology to assess functional rather than simple descriptive characteristics of spermatozoa. Specific requirements for validating CASA technology as a semi-automated system for human semen analysis are also provided, with particular reference to the accuracy and uncertainty of measurement expected of a robust medical laboratory test for implementation in clinical laboratories operating according to modern accreditation standards.

关键词： HISTORICAL INTRODUCTION