scholarly journals Recent Advances in Enhancing the Therapeutic Index of PARP Inhibitors in Breast Cancer

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 4132
Author(s):  
Camille Franchet ◽  
Jean-Sébastien Hoffmann ◽  
Florence Dalenc
Keyword(s):  
Treatment Strategies ◽  
Therapeutic Index ◽  
Parp Inhibitors ◽  
Resistance Mechanisms ◽  
High Rate ◽  
Parp Inhibition ◽  
Breast Cancers ◽  
Synthetic Lethal ◽  
Novel Treatment Strategies

As poly-(ADP)-ribose polymerase (PARP) inhibition is synthetic lethal with the deficiency of DNA double-strand (DSB) break repair by homologous recombination (HR), PARP inhibitors (PARPi) are currently used to treat breast cancers with mutated BRCA1/2 HR factors. Unfortunately, the increasingly high rate of PARPi resistance in clinical practice has dented initial hopes. Multiple resistance mechanisms and acquired vulnerabilities revealed in vitro might explain this setback. We describe the mechanisms and vulnerabilities involved, including newly identified modes of regulation of DSB repair that are now being tested in large cohorts of patients and discuss how they could lead to novel treatment strategies to improve the therapeutic index of PARPi.

scholarly journals Molecular mechanisms underpinning sarcomas and implications for current and future therapy

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Victoria Damerell ◽  
Michael S. Pepper ◽  
Sharon Prince
Keyword(s):  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Treatment Strategies ◽  
Mesenchymal Transition ◽  
Mesenchymal To Epithelial Transition ◽  
Cells Of Origin ◽  
Novel Treatment Strategies ◽  
Future Therapy

AbstractSarcomas are complex mesenchymal neoplasms with a poor prognosis. Their clinical management is highly challenging due to their heterogeneity and insensitivity to current treatments. Although there have been advances in understanding specific genomic alterations and genetic mutations driving sarcomagenesis, the underlying molecular mechanisms, which are likely to be unique for each sarcoma subtype, are not fully understood. This is in part due to a lack of consensus on the cells of origin, but there is now mounting evidence that they originate from mesenchymal stromal/stem cells (MSCs). To identify novel treatment strategies for sarcomas, research in recent years has adopted a mechanism-based search for molecular markers for targeted therapy which has included recapitulating sarcomagenesis using in vitro and in vivo MSC models. This review provides a comprehensive up to date overview of the molecular mechanisms that underpin sarcomagenesis, the contribution of MSCs to modelling sarcomagenesis in vivo, as well as novel topics such as the role of epithelial-to-mesenchymal-transition (EMT)/mesenchymal-to-epithelial-transition (MET) plasticity, exosomes, and microRNAs in sarcomagenesis. It also reviews current therapeutic options including ongoing pre-clinical and clinical studies for targeted sarcoma therapy and discusses new therapeutic avenues such as targeting recently identified molecular pathways and key transcription factors.

BINDING OF 17-SUBSTITUTED 16-NITRILE 16,17-SECOESTRANE COMPOUNDS TO ESTROGEN RECEPTORS – „IN VITRO“ AND „IN SILICO“ STUDY

2021 ◽  
Author(s):  
Suzana S. Jovanović-Šanta ◽  
◽  
Esma Isenović ◽  
Julijana A. Petrović ◽  
Yaraslau U. Dzichenka
Keyword(s):  
Amino Acids ◽  
Estrogen Receptors ◽  
Nuclear Translocation ◽  
Binding Mode ◽  
High Rate ◽  
Dynamics Simulation ◽  
Breast Cancers ◽  
Number Of Binding Sites ◽  
Almost All

About 75% of breast cancers express estrogen receptors (ERs), which is a good base for an efficient endocrine therapy. This gives the opportunity for the treatment of patients with antiestrogens, compounds that bind to the ERs and thus compete to estradiol (E2), preventing its action in progression of estrogen-depending cancers. Here we present results of testing the effect of the modified steroids, namely 17-substituted 16-nitrile 16,17-secoestrane compounds on the E2-ER complex forming, its stability, nuclear translocation and binding to DNA. Almost all compounds in moderate to high rate induced lower forming of this complex, destabilizing it – they increased Kd of this complex and decreased number of binding sites. Complex formed in the presence of some test secosteroids could pass to the nucleus, while other compounds inhibited translocation. In the presence of some compounds binding of the formed complex E2-ER to DNA was noticed. Docking followed molecular dynamics simulation was performed to reveal binding mode of E2 to ER in the presence of test secosteroids. Amino acids important for binding process and complex stabilization were detected. Analysis of the simulation data allowed identifying key amino acids and type of binding of the secoestrane compounds, important for high affinity binding of the steroidal compounds.

GSK3β Inhibition Synergizes with PARP Inhibitors through the Induction of Homologous Recombination Deficiency in Colorectal Cancer

2020 ◽  
Author(s):  
Ning Zhang ◽  
Yu-Nan Tian ◽  
Li-Na Zhou ◽  
Meng-Zhu Li ◽  
Shan-Shan Song ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Homologous Recombination ◽  
High Throughput Screening ◽  
Glycogen Synthase ◽  
Objective Response ◽  
Xenograft Model ◽  
Parp Inhibitors ◽  
High Rate ◽  
Parp Inhibition ◽  
Mouse Xenograft Model

Abstract Background: Monotherapy with poly ADP-ribose polymerase (PARP) inhibitors results in limited objective response rate (≤ 60% in most cases) in patients with homologous recombination repair (HRR)-deficient cancer, which suggests a high rate of resistance in this subset of patients to PARP inhibitors (PARPi). To overcome resistance to PARPi and to broaden their clinical use, we performed high-throughput screening of 99 anticancer drugs in combination with PARPi to identify potential therapeutic combinations. Methods: The effects of PARPi combined with glycogen synthase kinase 3 (GSK3) inhibitors were investigated in vitro with respect to cell viability, cell cycle and apoptosis. The synergy was assessed by calculation of the combination index (CI). GSK3α null and GSK3β null cells were generated using CRISPR/Cas9 technique. The underlying mechanism was examined by western blotting, flow cytometry, qRT-PCR and fluorescence microscopy. This combination was also evaluated in the mouse xenograft model; tumor growth and tumor lysates were analyzed, and the immunohistochemistry assay was performed. All data are presented as mean ± SD. Comparison between two groups was performed with the Student’s t-test.Result: The data showed that ~25% of oncological drugs and kinase inhibitors that were evaluated displayed synergy with PARPi in HCT-15 cells. Among the tested agents, GSK3 inhibitors (GSK3i) exhibited the strongest synergistic effect with PARPi. Moreover, the synergistic antitumor effect of GSK3 and PARP inhibition was confirmed in a panel of colorectal cancer (CRC) cell lines with diverse genetic backgrounds. Additionally, inhibition or genetic depletion of GSK3β was found to impair HRR of DNA and reduce the mRNA and protein level of BRCA1. Finally, we demonstrated that inhibition or depletion of GSK3β could enhance the in vivo sensitivity to simmiparib without toxicity.Conclusion: Our results provide a mechanistic understanding of combination of PARP and GSK3 inhibition, and support the clinical development of this combination therapy for CRC patients.

scholarly journals PARP Inhibitor Resistance Mechanisms and Implications for Post-Progression Combination Therapies

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2054
Author(s):  
Elizabeth K. Lee ◽  
Ursula A. Matulonis
Keyword(s):  
Synthetic Lethality ◽  
Parp Inhibitor ◽  
Parp Inhibitors ◽  
Resistance Mechanisms ◽  
Parp Inhibition ◽  
Combination Therapies ◽  
Mechanisms Of Resistance ◽  
Damage Repair ◽  
Inhibitor Resistance

The use of PARP inhibitors (PARPi) is growing widely as FDA approvals have shifted its use from the recurrence setting to the frontline setting. In parallel, the population developing PARPi resistance is increasing. Here we review the role of PARP, DNA damage repair, and synthetic lethality. We discuss mechanisms of resistance to PARP inhibition and how this informs on novel combinations to re-sensitize cancer cells to PARPi.

scholarly journals Antimicrobial activity of a novel bioengineered honey against non-typeable Haemophilus influenzae biofilms: an in vitro study

2018 ◽  
Vol 71 (6) ◽  
pp. 554-558 ◽  
Author(s):  
Rachel S Newby ◽  
Matthew Dryden ◽  
Raymond N Allan ◽  
Rami J Salib
Keyword(s):  
Haemophilus Influenzae ◽  
Treatment Strategies ◽  
In Vitro Study ◽  
Opportunistic Pathogen ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Chronic Respiratory Diseases ◽  
Novel Treatment ◽  
Novel Treatment Strategies

The opportunistic pathogen non-typeable Haemophilus influenzae (NTHi) plays an important role in many chronic respiratory diseases including otitis media, chronic rhinosinusitis, cystic fibrosis and chronic obstructive pulmonary disease. Biofilm formation has been implicated in NTHi colonisation, persistence of infection and recalcitrance towards antimicrobials. There is therefore a pressing need for the development of novel treatment strategies that are effective against NTHi biofilm-associated diseases. SurgihoneyRO is a honey-based product that has been bioengineered to enable the slow release of H2O2, a reactive oxygen species to which H. influenzae is susceptible. Treatment of established NTHi biofilms with SurgihoneyRO significantly reduced biofilm viability through enhanced H2O2 production and was shown to be more effective than the conventional antibiotic co-amoxiclav.

scholarly journals Resistance-Guided Treatment of Gonorrhea: A Prospective Clinical Study

2020 ◽  
Author(s):  
Jeffrey D Klausner ◽  
Claire C Bristow ◽  
Olusegun O Soge ◽  
Akbar Shahkolahi ◽  
Toni Waymer ◽  
...  
Keyword(s):  
Single Dose ◽  
Clinical Study ◽  
Scale Up ◽  
Treatment Strategies ◽  
Prospective Clinical Study ◽  
Dose Oral ◽  
Novel Treatment Strategies ◽  
Oral Ciprofloxacin ◽  
Culture Positive

Abstract Background Novel treatment strategies to slow the continued emergence and spread of antimicrobial resistance in Neisseria gonorrhoeae are urgently needed. A molecular assay that predicts in vitro ciprofloxacin susceptibility is now available but has not been systematically studied in human infections. Methods Using a genotypic polymerase chain reaction assay to determine the status of the N. gonorrhoeae gyrase subunit A serine 91 codon, we conducted a multisite prospective clinical study of the efficacy of a single oral dose of ciprofloxacin 500 mg in patients with culture-positive gonorrhea. Follow-up specimens for culture were collected to determine microbiological cure 5–10 days post-treatment. Results Of the 106 subjects possessing culture-positive infections with wild-type gyrA serine N. gonorrhoeae genotype, the efficacy of single-dose oral ciprofloxacin treatment in the per-protocol population was 100% (95% 1-sided confidence interval, 97.5–100%). Conclusions Resistance-guided treatment of N. gonorrhoeae infections with single-dose oral ciprofloxacin was highly efficacious. The widespread introduction and scale-up of gyrA serine 91 genotyping in N. gonorrhoeae infections could have substantial medical and public health benefits in settings where the majority of gonococcal infections are ciprofloxacin susceptible. Clinical Trials Registration NCT02961751.

scholarly journals Therapeutic Effects of Curcumin—From Traditional Past to Present and Future Clinical Applications

2019 ◽  
Vol 20 (15) ◽  
pp. 3757 ◽  
Author(s):  
Beatrice Bachmeier ◽  
Dieter Melchart
Keyword(s):  
Molecular Mechanisms ◽  
Malignant Tumors ◽  
Scientific Evidence ◽  
Treatment Strategies ◽  
Therapeutic Effects ◽  
Microbial Infection ◽  
Therapeutic Benefits ◽  
Novel Treatment Strategies

The efficacy of the plant-derived polyphenol curcumin, in various aspects of health and wellbeing, is matter of public interest. An internet search of the term “Curcumin” displays about 12 million hits. Among the multitudinous information presented on partly doubtful websites, there are reports attracting the reader with promises ranging from eternal youth to cures for incurable diseases. Unfortunately, many of these reports are not based on scientific evidence, but they feed the desideratum of the reader for a “miracle cure”. This circumstance makes it very difficult for researchers, who work in a scientifically sound and evidence-based manner on the therapeutic benefits (or side effects) of curcumin, to demarcate their results from sensational reports that circulate in the web and in other media. This is only one of many obstacles making it difficult to pave curcumin’s way into clinical application; others are its nonpatentability and low economic usability. A further impediment comes from scientists who never worked with curcumin or any other natural plant-derived compound in their own labs. They have never tested these compounds in any scientific assay, neither in vitro nor in vivo; however, they claim, in a sometimes polemic manner, that everything that has so far been published on curcumin’s molecular effects is based on artefacts. The here presented Special Issue comprises a collection of five scientifically sound articles and nine reviews reporting on the therapeutic benefits and the molecular mechanisms of curcumin or of chemically modified curcumin in various diseases ranging from malignant tumors to chronic diseases, microbial infection, and even neurodegenerative diseases. The excellent results of the scientific projects that underlie the five original papers give reason to hope that curcumin will be part of novel treatment strategies in the near future—either as monotherapy or in combination with other drugs or therapeutic applications.

scholarly journals Antibiotic collateral sensitivity is contingent on the repeatability of evolution

2017 ◽  
Author(s):  
Daniel Nichol ◽  
Joseph Rutter ◽  
Christopher Bryant ◽  
Andrea M Hujer ◽  
Sai Lek ◽  
...  
Keyword(s):  
Experimental Evolution ◽  
Treatment Strategies ◽  
Therapeutic Benefit ◽  
Cross Resistance ◽  
Health Crisis ◽  
Collateral Sensitivity ◽  
Drug Regimens ◽  
Novel Treatment Strategies ◽  
Increased Susceptibility

AbstractAntibiotic resistance represents a growing health crisis that necessitates the immediate discovery of novel treatment strategies. One such strategy is the identification of collateral sensitivities, wherein evolution under a first drug induces susceptibility to a second. Here, we report that sequential drug regimens derived from in vitro evolution experiments may have overstated therapeutic benefit, predicting a collaterally sensitive response where cross resistance ultimately occurs. We quantify the likelihood of this phenomenon by use of a mathematical model parametrised with combinatorially complete fitness landscapes for Escherichia coli. Through experimental evolution we then verify that a second drug can indeed stochastically exhibit either increased susceptibility or increased resistance when following a first. Genetic divergence is confirmed as the driver of this differential response through targeted and whole genome sequencing. Taken together, these results highlight that the success of evolutionarily-informed therapies is predicated on a rigorous probabilistic understanding of the contingencies that arise during the evolution of drug resistance.

scholarly journals Identifying chemogenetic interactions from CRISPR knockout screens with drugZ

2017 ◽  
Author(s):  
Medina Colic ◽  
Gang Wang ◽  
Michal Zimmermann ◽  
Keith Mascall ◽  
Megan McLaughlin ◽  
...  
Keyword(s):  
Gene Mutations ◽  
Drug Efficacy ◽  
Chemical Compounds ◽  
Parp Inhibitors ◽  
Resistance Mechanisms ◽  
Synthetic Lethal ◽  
Drug Mechanism ◽  
Damage Repair ◽  
Synthetic Lethal Interactions ◽  
Additional Cell

AbstractChemogenetic profiling enables the identification of gene mutations that enhance or suppress the activity of chemical compounds. This knowledge provides insights into drug mechanism-of-action, genetic vulnerabilities, and resistance mechanisms, all of which may help stratify patient populations and improve drug efficacy. CRISPR-based screening enables sensitive detection of drug-gene interactions directly in human cells, but until recently has largely been used to screen only for resistance mechanisms. We present drugZ, an algorithm for identifying both synergistic and suppressor chemogenetic interactions from CRISPR screens. DrugZ identifies synthetic lethal interactions between PARP inhibitors and both known and novel members of the DNA damage repair pathway. Additionally, drugZ confirms KEAP1 loss as a resistance factor for ERK inhibitors in oncogenic KRAS backgrounds and identifies additional cell-specific mechanisms of drug resistance. The software is available at github.com/hart-lab/drugz.

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