scholarly journals Therapeutic Potential of PARP Inhibitors in the Treatment of Gastrointestinal Cancers

Biomedicines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 1024
Author(s):  
Abdullah Alhusaini ◽  
Aoife Cannon ◽  
Stephen G. Maher ◽  
John V. Reynolds ◽  
Niamh Lynam-Lennon
Keyword(s):  
Treatment Response ◽  
Therapeutic Potential ◽  
Predictive Biomarker ◽  
Parp Inhibitors ◽  
Current Evidence ◽  
Combination Strategies ◽  
Gi Cancer ◽  
Brca1 Brca2 ◽  
Novel Therapeutic Strategies

Gastrointestinal (GI) malignancies are a major global health burden, with high mortality rates. The identification of novel therapeutic strategies is crucial to improve treatment and survival of patients. The poly (ADP-ribose) polymerase (PARP) enzymes involved in the DNA damage response (DDR) play major roles in the development, progression and treatment response of cancer, with PARP inhibitors (PARPi) currently used in the clinic for breast, ovarian, fallopian, primary peritoneal, pancreatic and prostate cancers with deficiencies in homologous recombination (HR) DNA repair. This article examines the current evidence for the role of the DDR PARP enzymes (PARP1, 2, 3 and 4) in the development, progression and treatment response of GI cancers. Furthermore, we discuss the role of HR status as a predictive biomarker of PARPi efficacy in GI cancer patients and examine the pre-clinical and clinical evidence for PARPi and cytotoxic therapy combination strategies in GI cancer. We also include an analysis of the genomic and transcriptomic landscape of the DDR PARP genes and key HR genes (BRCA1, BRCA2, ATM, RAD51, MRE11, PALB2) in GI patient tumours (n = 1744) using publicly available datasets to identify patients that may benefit from PARPi therapeutic approaches.

scholarly journals Immune Check-Point Inhibitors in Breast Cancer: Current Evidence and Future Directions

2021 ◽  
Vol 8 (3) ◽  
Author(s):  
Mosteiro M ◽  
◽  
Cejuela M ◽  
Pernas S ◽  
◽  
...  
Keyword(s):  
Breast Cancer ◽  
Advanced Breast Cancer ◽  
Triple Negative ◽  
New Combination ◽  
Current Evidence ◽  
Check Point ◽  
Future Directions ◽  
Combination Strategies ◽  
Check Point Inhibitors

Check-point inhibitors have erupted as a treatment option for numerous kinds of neoplasms. Although there have been some achievements, the evidence supporting their use in breast cancer is scarce. Combinations with chemotherapy seem to provide better outcomes, and triple negative is the subtype most likely to benefit from them. New combination strategies are undergoing research to improve these results. Other approaches to determining biomarkers that identify which populations clearly benefit from these therapies are needed. Here, we review the clinical data of the role of immune check-point inhibitors in early and advanced breast cancer and present emerging strategies.

scholarly journals MicroRNA in Pancreatic Cancer: From Biology to Therapeutic Potential

Genes ◽  
2019 ◽  
Vol 10 (10) ◽  
pp. 752 ◽  
Author(s):  
Rawat ◽  
Kadian ◽  
Gupta ◽  
Kumar ◽  
Chain ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Patients ◽  
Therapeutic Potential ◽  
Critical Role ◽  
Mirna Biogenesis ◽  
Effective Management ◽  
Future Directions ◽  
Novel Therapeutic Strategies ◽  
Conclusion Section

Pancreatic cancer is one of the most aggressive malignancies, accounting for more than 45,750 deaths annually in the U.S. alone. The aggressive nature and late diagnosis of pancreatic cancer, coupled with the limitations of existing chemotherapy, present the pressing need for the development of novel therapeutic strategies. Recent reports have demonstrated a critical role of microRNAs (miRNAs) in the initiation, progression, and metastasis of cancer. Furthermore, aberrant expressions of miRNAs have often been associated with the cause and consequence of pancreatic cancer, emphasizing the possible use of miRNAs in the effective management of pancreatic cancer patients. In this review, we provide a brief overview of miRNA biogenesis and its role in fundamental cellular process and miRNA studies in pancreatic cancer patients and animal models. Subsequent sections narrate the role of miRNA in, (i) cell cycle and proliferation; (ii) apoptosis; (iii) invasions and metastasis; and (iv) various cellular signaling pathways. We also describe the role of miRNA’s in pancreatic cancer; (i) diagnosis; (ii) prognosis and (iii) therapeutic intervention. Conclusion section describes the gist of review with future directions.

scholarly journals Poly-ADP-ribose polymerase inhibitor use in ovarian cancer: expanding indications and novel combination strategies

2019 ◽  
Vol 29 (5) ◽  
pp. 956-968 ◽  
Author(s):  
Emily Hinchcliff ◽  
Shannon Neville Westin ◽  
Graziela Dal Molin ◽  
Christopher J LaFargue ◽  
Robert L. Coleman
Keyword(s):  
Ovarian Cancer ◽  
Drug Administration ◽  
Food And Drug Administration ◽  
Parp Inhibitors ◽  
Parp Inhibition ◽  
Combination Therapies ◽  
Combination Strategies ◽  
Polymerase Inhibitor

The use of poly(ADP-ribose) polymerase (PARP) inhibition is transforming care for the treatment of ovarian cancer, with three different PARP inhibitors (PARPi) gaining US Food and Drug Administration approval since 2014. Given the rapidly expanding use of PARPi, this review aims to summarize the key evidence for their use and therapeutic indications. Furthermore, we provide an overview of the development of PARPi resistance and the emerging role of PARPi combination therapies, including those with anti-angiogenic and immunotherapeutic agents.

Neutrophils in cystic fibrosis

2016 ◽  
Vol 397 (6) ◽  
pp. 485-496 ◽  
Author(s):  
Julie Laval ◽  
Anjali Ralhan ◽  
Dominik Hartl
Keyword(s):  
Cystic Fibrosis ◽  
Lung Disease ◽  
Structural Damage ◽  
Fungal Pathogens ◽  
Therapeutic Potential ◽  
Inflammatory Cells ◽  
Current Evidence ◽  
Infection And Inflammation ◽  
Shed Light

Abstract Cystic fibrosis (CF) lung disease is characterized by chronic infection and inflammation. Among inflammatory cells, neutrophils represent the major cell population accumulating in the airways of CF patients. While neutrophils provide the first defensive cellular shield against bacterial and fungal pathogens, in chronic disease conditions such as CF these short-lived immune cells release their toxic granule contents that cause tissue remodeling and irreversible structural damage to the host. A variety of human and murine studies have analyzed neutrophils and their products in the context of CF, yet their precise functional role and therapeutic potential remain controversial and incompletely understood. Here, we summarize the current evidence in this field to shed light on the complex and multi-faceted role of neutrophils in CF lung disease.

scholarly journals Post-Translational S-Nitrosylation of Proteins in Regulating Cardiac Oxidative Stress

Antioxidants ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 1051 ◽  
Author(s):  
Xiaomeng Shi ◽  
Hongyu Qiu
Keyword(s):  
Therapeutic Potential ◽  
Heart Diseases ◽  
Redox Homeostasis ◽  
Redox Status ◽  
Cardiac Protection ◽  
Cellular Functions ◽  
Post Translational Modifications ◽  
Cellular Redox ◽  
Novel Therapeutic Strategies

Like other post-translational modifications (PTMs) of proteins, S-nitrosylation has been considered a key regulatory mechanism of multiple cellular functions in many physiological and disease conditions. Emerging evidence has demonstrated that S-nitrosylation plays a crucial role in regulating redox homeostasis in the stressed heart, leading to discoveries in the mechanisms underlying the pathogenesis of heart diseases and cardiac protection. In this review, we summarize recent studies in understanding the molecular and biological basis of S-nitrosylation, including the formation, spatiotemporal specificity, homeostatic regulation, and association with cellular redox status. We also outline the currently available methods that have been applied to detect S-nitrosylation. Additionally, we synopsize the up-to-date studies of S-nitrosylation in various cardiac diseases in humans and animal models, and we discuss its therapeutic potential in cardiac protection. These pieces of information would bring new insights into understanding the role of S-nitrosylation in cardiac pathogenesis and provide novel avenues for developing novel therapeutic strategies for heart diseases.

scholarly journals Cannabis sativa and Skin Health: Dissecting the Role of Phytocannabinoids

Planta Medica ◽  
2021 ◽  
Author(s):  
Giulia Martinelli ◽  
Andrea Magnavacca ◽  
Marco Fumagalli ◽  
Mario DellʼAgli ◽  
Stefano Piazza ◽  
...  
Keyword(s):  
Clinical Studies ◽  
Skin Diseases ◽  
Cannabis Sativa ◽  
Therapeutic Potential ◽  
Current Evidence ◽  
Skin Disorders ◽  
Anti Inflammatory

AbstractThe use of Cannabis sativa is currently recognized to ease certain types of chronic pain, reduce chemotherapy-induced nausea, and improve anxiety. Nevertheless, few studies highlighted the therapeutic potential of C. sativa extracts and related phytocannabinoids for a variety of widespread skin disorders including acne, atopic dermatitis, psoriasis, pruritus, and pain. This review summarized the current evidence on the effects of phytocannabinoids at the cutaneous level through the collection of in vitro, in vivo, and clinical studies published on PubMed, Scopus, Embase, and Web of Science until October 2020. Phytocannabinoids have demonstrated potential anti-inflammatory, antioxidant, anti-aging, and anti-acne properties by various mechanisms involving either CB1/2-dependent and independent pathways. Not only classical immune cells, but also several skin-specific actors, such as keratinocytes, fibroblasts, melanocytes, and sebocytes, may represent a target for phytocannabinoids. Cannabidiol, the most investigated compound, revealed photoprotective, antioxidant, and anti-inflammatory mechanisms at the cutaneous level, while the possible impact on cell differentiation, especially in the case of psoriasis, would require further investigation. Animal models and pilot clinical studies supported the application of cannabidiol in inflammatory-based skin diseases. Also, one of the most promising applications of non-psychotropic phytocannabinoids is the treatment of seborrheic disorders, especially acne. In conclusion, the incomplete knowledge of the role of the endocannabinoid system in skin disorders emerged as an important limit for pharmacological investigations. Moreover, the limited studies conducted on C. sativa extracts suggested a higher potency than single phytocannabinoids, thus stimulating new research on phytocannabinoid interaction.

scholarly journals Peptidylarginine Deiminase 2 in Host Immunity: Current Insights and Perspectives

2021 ◽  
Vol 12 ◽  
Author(s):  
Zhenyu Wu ◽  
Patrick Li ◽  
Yuzi Tian ◽  
Wenlu Ouyang ◽  
Jessie Wai-Yan Ho ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Host Immunity ◽  
Preclinical Research ◽  
Post Translational Modifications ◽  
Different Types ◽  
Arginine Residues ◽  
Cell Death Signaling ◽  
Underlying Mechanisms ◽  
Novel Therapeutic Strategies

Peptidylarginine deiminases (PADs) are a group of enzymes that catalyze post-translational modifications of proteins by converting arginine residues into citrullines. Among the five members of the PAD family, PAD2 and PAD4 are the most frequently studied because of their abundant expression in immune cells. An increasing number of studies have identified PAD2 as an essential factor in the pathogenesis of many diseases. The successes of preclinical research targeting PAD2 highlights the therapeutic potential of PAD2 inhibition, particularly in sepsis and autoimmune diseases. However, the underlying mechanisms by which PAD2 mediates host immunity remain largely unknown. In this review, we will discuss the role of PAD2 in different types of cell death signaling pathways and the related immune disorders contrasted with functions of PAD4, providing novel therapeutic strategies for PAD2-associated pathology.

Poly(ADP-Ribose) Polymerase in Cervical Cancer Pathogenesis: Mechanism and Potential Role for PARP Inhibitors

2016 ◽  
Vol 26 (4) ◽  
pp. 763-769 ◽  
Author(s):  
Ioannis C. Kotsopoulos ◽  
Ali Kucukmetin ◽  
Asima Mukhopadhyay ◽  
John Lunec ◽  
Nicola J. Curtin
Keyword(s):  
Cervical Cancer ◽  
Therapeutic Potential ◽  
Treatment Options ◽  
Invasive Cervical Cancer ◽  
Locally Advanced ◽  
Intraepithelial Neoplasia ◽  
Parp Inhibitors ◽  
Chemotherapeutic Agents ◽  
Cancer Pathogenesis

AbstractTreatment options for disease recurrence of women treated for locally advanced and advanced cervical cancer are very limited—largely palliative chemotherapy. The low efficacy of the currently available drugs raises the need for new targeted agents. Poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors (PARPi) have emerged as a promising class of chemotherapeutic agents in cancers associated with defects in DNA repair. Their therapeutic potential in cervical cancer is currently being evaluated in 3 ongoing clinical trials. Here we review the available information regarding all the aspects of PARP in cervical intraepithelial neoplasia and invasive cervical cancer, from expression and the mechanism of action to the role of the polymorphisms in the pathogenesis of the disease, as well as the potential of the inhibitors. We finally propose a new unifying theory regarding the role of PARPs in the development of cervical carcinomas.

Treatment response comparisons between ATM and BRCA2 germline carriers for mCRPC.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 63-63
Author(s):  
Alexandra Sokolova ◽  
Catherine Handy Marshall ◽  
Rebeca Lozano ◽  
Petros Grivas ◽  
Celestia S. Higano ◽  
...  
Keyword(s):  
Treatment Response ◽  
Treatment Strategies ◽  
Parp Inhibitors ◽  
Gleason Grade ◽  
Retrospective Case ◽  
Individual Gene ◽  
Novel Treatment Strategies ◽  
Brca1 Brca2 ◽  
Control Study ◽  
Gene Alterations

63 Background: Over 10% of men with metastatic prostate cancer (PC) have germline DNA damage response gene alterations; most studies have reported BRCA2 alone or an aggregate of BRCA1, BRCA2 and ATM. Emerging data suggest ATM mutations have distinct effects and warrant individual gene evaluation. We hypothesize that, compared to patients (pts) carrying germline BRCA2 mutations (g BRCA2mut), pts carrying germline ATM mutations (g ATMmut) may have different treatment response to androgen-receptor-targeted agents, docetaxel, platinum therapy and PARP inhibitors (PARPi). Methods: This is an international, multicenter, retrospective case-control study of pts with PC who underwent clinical germline genetic testing between 2014-2019. We identified pts with g ATMmut and matched pts with g BRCA2mut by stage at diagnosis and year of testing. IRB-approved medical records review, χ² and log rank tests were performed. Results: 39 g ATMmut cases and 39 matched g BRCA2mut cases were identified for total of 78. A third (13/39) of pts in each cohort had metastases at diagnosis. Of those diagnosed with localized stage, 81% (21/26) of gATMmut and 73% (19/26) of g BRCA2mut developed metastasis (median times to metastasis 69 vs 49 months, respectively (p=0.1)). Pts in g ATMmut and g BRCA2mut cohorts had similar age, Gleason grade, and PSA at diagnosis. We did not observe a difference in PSA50 response rates to abiraterone, enzalutamide, docetaxel, or carboplatin for mCRPC (Table). g BRCA2mut pts were more likely to respond to PARPi for mCRPC; where available, somatic loss of heterozygosity (LOH) data will be reported at final presentation. Conclusions: While response to standard therapies appears similar between g ATMmut and g BRCA2mut cohorts, response to PARPi in g ATMmut appears to be attenuated compared to g BRCA2mut. More studies are needed and pts with g ATMmut warrant prioritization for novel treatment strategies.[Table: see text]

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