scholarly journals Synthetic Lethality Screening Identifies FDA-Approved Drugs that Overcome ATP7B-Mediated Tolerance of Tumor Cells to Cisplatin

Cancers ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 608 ◽  
Author(s):  
Marta Mariniello ◽  
Raffaella Petruzzelli ◽  
Luca G. Wanderlingh ◽  
Raffaele La Montagna ◽  
Annamaria Carissimo ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Therapeutic Potential ◽  
Synthetic Lethality ◽  
Resistance Mechanisms ◽  
Ovarian Cancer Cells ◽  
Tumor Resistance ◽  
Development Of Resistance ◽  
Wide Range ◽  
Important Challenge ◽  
Approved Drugs

Tumor resistance to chemotherapy represents an important challenge in modern oncology. Although platinum (Pt)-based drugs have demonstrated excellent therapeutic potential, their effectiveness in a wide range of tumors is limited by the development of resistance mechanisms. One of these mechanisms includes increased cisplatin sequestration/efflux by the copper-transporting ATPase, ATP7B. However, targeting ATP7B to reduce Pt tolerance in tumors could represent a serious risk because suppression of ATP7B might compromise copper homeostasis, as happens in Wilson disease. To circumvent ATP7B-mediated Pt tolerance we employed a high-throughput screen (HTS) of an FDA/EMA-approved drug library to detect safe therapeutic molecules that promote cisplatin toxicity in the IGROV-CP20 ovarian carcinoma cells, whose resistance significantly relies on ATP7B. Using a synthetic lethality approach, we identified and validated three hits (Tranilast, Telmisartan, and Amphotericin B) that reduced cisplatin resistance. All three drugs induced Pt-mediated DNA damage and inhibited either expression or trafficking of ATP7B in a tumor-specific manner. Global transcriptome analyses showed that Tranilast and Amphotericin B affect expression of genes operating in several pathways that confer tolerance to cisplatin. In the case of Tranilast, these comprised key Pt-transporting proteins, including ATOX1, whose suppression affected ability of ATP7B to traffic in response to cisplatin. In summary, our findings reveal Tranilast, Telmisartan, and Amphotericin B as effective drugs that selectively promote cisplatin toxicity in Pt-resistant ovarian cancer cells and underscore the efficiency of HTS strategy for identification of biosafe compounds, which might be rapidly repurposed to overcome resistance of tumors to Pt-based chemotherapy.

scholarly journals Synthetic lethality screening identifies FDA-approved drugs that overcome ATP7B-mediated tolerance of tumor cells to cisplatin

2019 ◽  
Author(s):  
Marta Mariniello ◽  
Raffaella Petruzzelli ◽  
Luca G. Wanderlingh ◽  
Raffaele La Montagna ◽  
Annamaria Carissimo ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Therapeutic Potential ◽  
Synthetic Lethality ◽  
Rapid Development ◽  
Resistance Mechanisms ◽  
Tumor Resistance ◽  
Ovarian Carcinoma Cell Line ◽  
Development Of Resistance ◽  
Wide Range ◽  
Approved Drugs

ABSTRACTTumor resistance to chemotherapy represents an important challenge in modern oncology. Although platinum (Pt)-based drugs have demonstrated excellent therapeutic potential, their effectiveness in a wide range of tumors is limited by the development of resistance mechanisms. One of these mechanisms includes increased cisplatin sequestration/efflux by the copper-transporting ATPase, ATP7B. However, targeting ATP7B to reduce Pt tolerance in tumors could represent a serious risk because suppression of ATP7B might compromise copper homeostasis, as happens in Wilson disease.To circumvent ATP7B-mediated Pt tolerance we employed a high-throughput screen (HTS) of an FDA/EMA-approved drug library to detect safe therapeutic molecules that promote cisplatin toxicity in the resistant ovarian carcinoma cell line IGROV-CP20. Using a synthetic lethality approach we identified and validated three hits (Tranilast, Telmisartan and Amphotericin B) that could reduce cisplatin resistance. All three drugs induced Pt-mediated DNA damage and inhibited either expression or trafficking of ATP7B in a tumor-specific manner. Global transcriptome analyses showed that Tranilast and Amphotericin B affect expression of genes operating in several pathways that confer tolerance to cisplatin. In the case of Tranilast, these included key molecular players operating in the distribution of platinum to different intracellular compartments. In particular, Tranilast was found to suppress ATOX1 and, as a consequence, ATOX1-mediated trafficking of ATP7B in response to cisplatin.Considering the well-known safety profiles of Tranilast, Telmisartan and Amphotericin B, these drugs emerge as potential candidates that might be used for the rapid development of new therapeutic strategies to overcome resistance of tumors to Pt-based chemotherapy.

scholarly journals Tumor Resistance against ALK Targeted Therapy-Where It Comes From and Where It Goes

Cancers ◽  
2018 ◽  
Vol 10 (3) ◽  
pp. 62 ◽  
Author(s):  
Geeta Sharma ◽  
Ines Mota ◽  
Luca Mologni ◽  
Enrico Patrucco ◽  
Carlo Gambacorti-Passerini ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Resistance Mechanisms ◽  
Therapeutic Strategies ◽  
Tumor Resistance ◽  
Alk Inhibitors ◽  
Anaplastic Lymphoma ◽  
Development Of Resistance ◽  
Fda Approval ◽  
Novel Therapeutic Strategies

Anaplastic lymphoma kinase (ALK) is a validated molecular target in several ALK-rearranged malignancies, particularly in non-small-cell lung cancer (NSCLC), which has generated considerable interest and effort in developing ALK tyrosine kinase inhibitors (TKI). Crizotinib was the first ALK inhibitor to receive FDA approval for ALK-positive NSCLC patients treatment. However, the clinical benefit observed in targeting ALK in NSCLC is almost universally limited by the emergence of drug resistance with a median of occurrence of approximately 10 months after the initiation of therapy. Thus, to overcome crizotinib resistance, second/third-generation ALK inhibitors have been developed and received, or are close to receiving, FDA approval. However, even when treated with these new inhibitors tumors became resistant, both in vitro and in clinical settings. The elucidation of the diverse mechanisms through which resistance to ALK TKI emerges, has informed the design of novel therapeutic strategies to improve patients disease outcome. This review summarizes the currently available knowledge regarding ALK physiologic function/structure and neoplastic transforming role, as well as an update on ALK inhibitors and resistance mechanisms along with possible therapeutic strategies that may overcome the development of resistance.

Isoform-Selective PI3K Inhibitors for Various Diseases

2020 ◽  
Vol 20 (12) ◽  
pp. 1074-1092 ◽  
Author(s):  
Rammohan R.Y. Bheemanaboina
Keyword(s):  
Intracellular Signaling ◽  
Kinase Inhibitors ◽  
Therapeutic Potential ◽  
Type I ◽  
Selective Inhibitors ◽  
Pi3k Inhibitors ◽  
Wide Range ◽  
Lipid Kinases ◽  
Isoform Selectivity

Phosphoinositide 3-kinases (PI3Ks) are a family of ubiquitously distributed lipid kinases that control a wide variety of intracellular signaling pathways. Over the years, PI3K has emerged as an attractive target for the development of novel pharmaceuticals to treat cancer and various other diseases. In the last five years, four of the PI3K inhibitors viz. Idelalisib, Copanlisib, Duvelisib, and Alpelisib were approved by the FDA for the treatment of different types of cancer and several other PI3K inhibitors are currently under active clinical development. So far clinical candidates are non-selective kinase inhibitors with various off-target liabilities due to cross-reactivities. Hence, there is a need for the discovery of isoform-selective inhibitors with improved efficacy and fewer side-effects. The development of isoform-selective inhibitors is essential to reveal the unique functions of each isoform and its corresponding therapeutic potential. Although the clinical effect and relative benefit of pan and isoformselective inhibition will ultimately be determined, with the development of drug resistance and the demand for next-generation inhibitors, it will continue to be of great significance to understand the potential mechanism of isoform-selectivity. Because of the important role of type I PI3K family members in various pathophysiological processes, isoform-selective PI3K inhibitors may ultimately have considerable efficacy in a wide range of human diseases. This review summarizes the progress of isoformselective PI3K inhibitors in preclinical and early clinical studies for anticancer and other various diseases.

scholarly journals Molecular disruption of DNA polymerase β for platinum sensitisation and synthetic lethality in epithelial ovarian cancers

Oncogene ◽  
2021 ◽  
Author(s):  
Reem Ali ◽  
Adel Alblihy ◽  
Islam M. Miligy ◽  
Muslim L. Alabdullah ◽  
Mansour Alsaleem ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Dna Polymerase ◽  
Synthetic Lethality ◽  
Ovarian Cancer Cells ◽  
Dna Polymerase Β ◽  
Mesenchymal Transition ◽  
Platinum Sensitivity ◽  
Cycle Arrest ◽  
Ovarian Cancers

AbstractTargeting PARP1 [Poly(ADP-Ribose) Polymerase 1] for synthetic lethality is a new strategy for BRCA germ-line mutated or platinum sensitive ovarian cancers. However, not all patients respond due to intrinsic or acquired resistance to PARP1 inhibitor. Development of alternative synthetic lethality approaches is a high priority. DNA polymerase β (Polβ), a critical player in base excision repair (BER), interacts with PARP1 during DNA repair. Here we show that polβ deficiency is a predictor of platinum sensitivity in human ovarian tumours. Polβ depletion not only increased platinum sensitivity but also reduced invasion, migration and impaired EMT (epithelial to mesenchymal transition) of ovarian cancer cells. Polβ small molecular inhibitors (Pamoic acid and NSC666719) were selectively toxic to BRCA2 deficient cells and associated with double-strand breaks (DSB) accumulation, cell cycle arrest and increased apoptosis. Interestingly, PARG [Poly(ADP-Ribose) Glycohydrolase] inhibitor (PDD00017273) [but not PARP1 inhibitor (Olaparib)] was synthetically lethal in polβ deficient cells. Selective toxicity to PDD00017273 was associated with poly (ADP-ribose) accumulation, reduced nicotinamide adenine dinucleotide (NAD+) level, DSB accumulation, cell cycle arrest and increased apoptosis. In human tumours, polβ-PARG co-expression adversely impacted survival in patients. Our data provide evidence that polβ targeting is a novel strategy and warrants further pharmaceutical development in epithelial ovarian cancers.

scholarly journals The PARP Enzyme Family and the Hallmarks of Cancer Part 1. Cell Intrinsic Hallmarks

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2042 ◽  
Author(s):  
Máté A. Demény ◽  
László Virág
Keyword(s):  
Cancer Biology ◽  
Cancer Metabolism ◽  
Replicative Senescence ◽  
Synthetic Lethality ◽  
Family Members ◽  
Hallmarks Of Cancer ◽  
Novel Therapy ◽  
Cancer Hallmarks ◽  
Enzyme Family ◽  
Wide Range

The 17-member poly (ADP-ribose) polymerase enzyme family, also known as the ADP-ribosyl transferase diphtheria toxin-like (ARTD) enzyme family, contains DNA damage-responsive and nonresponsive members. Only PARP1, 2, 5a, and 5b are capable of modifying their targets with poly ADP-ribose (PAR) polymers; the other PARP family members function as mono-ADP-ribosyl transferases. In the last decade, PARP1 has taken center stage in oncology treatments. New PARP inhibitors (PARPi) have been introduced for the targeted treatment of breast cancer 1 or 2 (BRCA1/2)-deficient ovarian and breast cancers, and this novel therapy represents the prototype of the synthetic lethality paradigm. Much less attention has been paid to other PARPs and their potential roles in cancer biology. In this review, we summarize the roles played by all PARP enzyme family members in six intrinsic hallmarks of cancer: uncontrolled proliferation, evasion of growth suppressors, cell death resistance, genome instability, reprogrammed energy metabolism, and escape from replicative senescence. In a companion paper, we will discuss the roles of PARP enzymes in cancer hallmarks related to cancer-host interactions, including angiogenesis, invasion and metastasis, evasion of the anticancer immune response, and tumor-promoting inflammation. While PARP1 is clearly involved in all ten cancer hallmarks, an increasing body of evidence supports the role of other PARPs in modifying these cancer hallmarks (e.g., PARP5a and 5b in replicative immortality and PARP2 in cancer metabolism). We also highlight controversies, open questions, and discuss prospects of recent developments related to the wide range of roles played by PARPs in cancer biology. Some of the summarized findings may explain resistance to PARPi therapy or highlight novel biological roles of PARPs that can be therapeutically exploited in novel anticancer treatment paradigms.

scholarly journals Bioactive potential of natural biomaterials: identification, retention and assessment of biological properties

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Kieran Joyce ◽  
Georgina Targa Fabra ◽  
Yagmur Bozkurt ◽  
Abhay Pandit
Keyword(s):  
Tissue Engineering ◽  
Therapeutic Potential ◽  
Biological Properties ◽  
Biological Assessment ◽  
Cross Linking ◽  
Natural Polymers ◽  
Drug Delivery Device ◽  
Biomedical Device ◽  
Wide Range ◽  
Bioactive Potential

AbstractBiomaterials have had an increasingly important role in recent decades, in biomedical device design and the development of tissue engineering solutions for cell delivery, drug delivery, device integration, tissue replacement, and more. There is an increasing trend in tissue engineering to use natural substrates, such as macromolecules native to plants and animals to improve the biocompatibility and biodegradability of delivered materials. At the same time, these materials have favourable mechanical properties and often considered to be biologically inert. More importantly, these macromolecules possess innate functions and properties due to their unique chemical composition and structure, which increase their bioactivity and therapeutic potential in a wide range of applications. While much focus has been on integrating these materials into these devices via a spectrum of cross-linking mechanisms, little attention is drawn to residual bioactivity that is often hampered during isolation, purification, and production processes. Herein, we discuss methods of initial material characterisation to determine innate bioactivity, means of material processing including cross-linking, decellularisation, and purification techniques and finally, a biological assessment of retained bioactivity of a final product. This review aims to address considerations for biomaterials design from natural polymers, through the optimisation and preservation of bioactive components that maximise the inherent bioactive potency of the substrate to promote tissue regeneration.

scholarly journals FEN1 Blockade for Platinum Chemo-Sensitization and Synthetic Lethality in Epithelial Ovarian Cancers

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1866
Author(s):  
Katia A. Mesquita ◽  
Reem Ali ◽  
Rachel Doherty ◽  
Michael S. Toss ◽  
Islam Miligy ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
High Throughput Screening ◽  
Nuclear Translocation ◽  
Synthetic Lethality ◽  
Excision Repair ◽  
Progression Free Survival ◽  
Ovarian Cancer Cells ◽  
Physical Interaction ◽  
Base Excision

FEN1 plays critical roles in long patch base excision repair (LP-BER), Okazaki fragment maturation, and rescue of stalled replication forks. In a clinical cohort, FEN1 overexpression is associated with aggressive phenotype and poor progression-free survival after platinum chemotherapy. Pre-clinically, FEN1 is induced upon cisplatin treatment, and nuclear translocation of FEN1 is dependent on physical interaction with importin β. FEN1 depletion, gene inactivation, or inhibition re-sensitizes platinum-resistant ovarian cancer cells to cisplatin. BRCA2 deficient cells exhibited synthetic lethality upon treatment with a FEN1 inhibitor. FEN1 inhibitor-resistant PEO1R cells were generated, and these reactivated BRCA2 and overexpressed the key repair proteins, POLβ and XRCC1. FEN1i treatment was selectively toxic to POLβ deficient but not XRCC1 deficient ovarian cancer cells. High throughput screening of 391,275 compounds identified several FEN1 inhibitor hits that are suitable for further drug development. We conclude that FEN1 is a valid target for ovarian cancer therapy.

scholarly journals Thiazole Ring—A Biologically Active Scaffold

Molecules ◽  
2021 ◽  
Vol 26 (11) ◽  
pp. 3166
Author(s):  
Anthi Petrou ◽  
Maria Fesatidou ◽  
Athina Geronikaki
Keyword(s):  
Recent Literature ◽  
Biological Activities ◽  
Literature Survey ◽  
Biologically Active ◽  
Thiazole Ring ◽  
Peer Reviews ◽  
Experimental Drugs ◽  
Wide Range ◽  
Approved Drugs ◽  
Fda Approved Drugs

Background: Thiazole is a good pharmacophore nucleus due to its various pharmaceutical applications. Its derivatives have a wide range of biological activities such as antioxidant, analgesic, and antimicrobial including antibacterial, antifungal, antimalarial, anticancer, antiallergic, antihypertensive, anti-inflammatory, and antipsychotic. Indeed, the thiazole scaffold is contained in more than 18 FDA-approved drugs as well as in numerous experimental drugs. Objective: To summarize recent literature on the biological activities of thiazole ring-containing compounds Methods: A literature survey regarding the topics from the year 2015 up to now was carried out. Older publications were not included, since they were previously analyzed in available peer reviews. Results: Nearly 124 research articles were found, critically analyzed, and arranged regarding the synthesis and biological activities of thiazoles derivatives in the last 5 years.

scholarly journals Silver (I) N-Heterocyclic Carbene Complexes: A Winning and Broad Spectrum of Antimicrobial Properties

2021 ◽  
Vol 22 (5) ◽  
pp. 2497
Author(s):  
Filippo Prencipe ◽  
Anna Zanfardino ◽  
Michela Di Napoli ◽  
Filomena Rossi ◽  
Stefano D’Errico ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Antimicrobial Agents ◽  
Antimicrobial Properties ◽  
Resistance Mechanisms ◽  
Heterocyclic Carbenes ◽  
Significant Activity ◽  
Bacterial Strains ◽  
Development Of Resistance ◽  
Starting Point ◽  
Catalytic Chemistry

The evolution of antibacterial resistance has arisen as the main downside in fighting bacterial infections pushing researchers to develop novel, more potent and multimodal alternative drugs.Silver and its complexes have long been used as antimicrobial agents in medicine due to the lack of silver resistance and the effectiveness at low concentration as well as to their low toxicities compared to the most commonly used antibiotics. N-Heterocyclic Carbenes (NHCs) have been extensively employed to coordinate transition metals mainly for catalytic chemistry. However, more recently, NHC ligands have been applied as carrier molecules for metals in anticancer applications. In the present study we selected from literature two NHC-carbene based on acridinescaffoldand detailed nonclassicalpyrazole derived mono NHC-Ag neutral and bis NHC-Ag cationic complexes. Their inhibitor effect on bacterial strains Gram-negative and positivewas evaluated. Imidazolium NHC silver complex containing the acridine chromophore showed effectiveness at extremely low MIC values. Although pyrazole NHC silver complexes are less active than the acridine NHC-silver, they represent the first example of this class of compounds with antimicrobial properties. Moreover all complexesare not toxic and they show not significant activity againstmammalian cells (Hek lines) after 4 and 24 h. Based on our experimental evidence, we are confident that this promising class of complexes could represent a valuable starting point for developing candidates for the treatment of bacterial infections, delivering great effectiveness and avoiding the development of resistance mechanisms.

17 Activity sensors for noninvasive monitoring of immune response and tumor resistance during immune checkpoint blockade therapy

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A17-A17
Author(s):  
Quoc Mac ◽  
James Bowen ◽  
Hathaichanok Phuengkham ◽  
Anirudh Sivakumar ◽  
Congmin Xu ◽  
...  
Keyword(s):  
T Cell ◽  
Treatment Response ◽  
Immune Checkpoint ◽  
Tumor Regression ◽  
Growth Curves ◽  
Resistance Mechanisms ◽  
Immune Checkpoint Blockade ◽  
Tumor Resistance ◽  
Activity Sensors ◽  
Therapeutic Responses

BackgroundDespite the curative potential of immune checkpoint blockade (ICB) therapy, only small subsets of patients achieve tumor regression while many responders relapse and acquire resistance. Monitoring treatment response and detecting the onset of resistance are critical for improving patient prognoses. Here we engineered ICB antibody-sensor conjugates known as ICB-Dx by coupling peptides sensing the activity of granzyme B (GzmB), a T cell cytotoxic protease, directly on αPD1 antibody to monitor therapeutic responses by producing a fluorescent reporter into urine. To develop biomarkers that indicate mechanisms of resistance to ICB, we generated B2m-/- and Jak1-/- tumor models and performed transcriptomic analyses to identify unique protease signatures of these resistance mechanisms. We then built a multiplexed library of αPD1-Dx capable of detecting early therapeutic response and illuminating resistance mechanisms during ICB therapy.MethodsFITC-labeled GzmB substrates were synthesized (CEM) and conjugated to αPD1 antibody. B2m-/- and Jak1-/- tumors were generated from WT MC38 cells using CRISPR/Cas9. For tumor studies, 106 cells were inoculated s.c. in B6 mice. Tumor mice were treated with αPD1 or IgG1 isotype conjugates (0.1 mg), and urine was collected at 3 hours. Tumor RNA was isolated with RNEasy kit (Qiagen) and prepared for sequencing with TruSeq mRNA kit (Illumina).ResultsTo synthesize αPD1-Dx, we coupled FITC-labeled GzmB substrates to αPD1 antibody (figure 1a). In MC38 tumors, systemic administration of αPD1-Dx lowered tumor burden relative to control treatment while producing significantly elevated urine signals that preceded tumor regression (figure 1b, c). To investigate the ability to monitor tumor resistance to ICB, we developed knockout tumors to model B2m and Jak1 mutations, which are observed in human patients. in vivo, B2m-/- and Jak1-/- MC38 tumors were resistant to αPD1 monotherapy (figure 1d). Tumor RNA sequencing revealed that gene expression was altered during αPD1 treatment only in WT tumors. Importantly, B2m-/- tumors showed very different expression profiles than Jak1-/- tumors during αPD1 treatment, indicative of unique regulation of resistance (figure 1e). We used differential expression analyses to discover unique protease signatures associated with these two resistance mechanisms. Finally, a multiplexed library of αPD1-Dx engineered to monitor both tumor and immune proteases detected early on-treatment responses and stratified B2m-/- from Jak1-/- resistance with high diagnostic validity (figure 1f).Abstract 17 Figure 1Monitoring response and resistance with ICB-Dx(a) αPD1-Dx can reinvigorate T cell response and monitor protease activities in the tumor microenvironment. (b) Growth curves of WT MC38 tumors treated with αPD1- or IgG1-Dx (ANOVA). (c) Urine signals detect treatment response to αPD1 monotherapy (ANOVA). (d) Growth curves of B2m-/- and Jak1-/- tumors treated with αPD1- or IgG1-Dx (ANOVA). (e) TSNE plot showing RNA profiles of WT, B2m-/-, Jak1-/- tumors treated with αPD1 or isotype control. (f) ROC curves of random forest classifiers built from urine signals that differentiate on-treatment response from on-treatment resistance and B2m-/- from Jak1-/- resistance.ConclusionsWe have engineered activity sensors that accurately detect therapeutic responses and stratify resistance mechanisms noninvasively from urine, thereby potentially expanding the precision of ICB therapy to benefit cancer patients.Ethics ApprovalAll animal studies were approved by Georgia Tech IACUC (A100193)

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