Jeffrey Zhao, Carlos Galvez, Kathryn Eby Beckermann, Douglas B Johnson, Jeffrey A Sosman
{"title":"Novel insights into the pathogenesis and treatment of NRAS mutant melanoma.","authors":"Jeffrey Zhao, Carlos Galvez, Kathryn Eby Beckermann, Douglas B Johnson, Jeffrey A Sosman","doi":"10.1080/23808993.2021.1938545","DOIUrl":"10.1080/23808993.2021.1938545","url":null,"abstract":"<p><strong>Introduction: </strong>NRAS was the first mutated oncogene identified in melanoma and is currently the second most common driver mutation in this malignancy. For patients with NRAS<sup>mutant</sup> advanced stage melanoma refractory to immunotherapy or with contraindications to immune-based regimens, there are few therapeutic options including low-efficacy chemotherapy regimens and binimetinib monotherapy. Here, we review recent advances in preclinical studies of molecular targets for NRAS mutant melanoma as well as the failures and successes of early-phase clinical trials. While there are no targeted therapies for NRAS-driven melanoma, there is great promise in approaches combining MEK inhibition with inhibitors of the focal adhesion kinase (FAK), inhibitors of autophagy pathways, and pan-RAF inhibitors.</p><p><strong>Areas covered: </strong>This review surveys new developments in all aspects of disease pathogenesis and potential treatment - including those that have failed, stalled, or progressed through various phases of preclinical and clinical development.</p><p><strong>Expert opinion: </strong>There are no currently approved targeted therapies for BRAF wild-type melanoma patients harboring NRAS driver mutations though an array of agents are in early phase clinical trials. The diverse strategies taken exploit combined MAP kinase signaling blockade with inhibition of cell cycle mediators, inhibition of the autophagy pathway, and alteration of kinases involved in actin cytoskeleton signaling. Future advances of developmental therapeutics into late stage trials may yield new options beyond immunotherapy for patients with advanced stage disease and NRAS mutation status.</p>","PeriodicalId":12124,"journal":{"name":"Expert Review of Precision Medicine and Drug Development","volume":null,"pages":null},"PeriodicalIF":1.2,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8415440/pdf/nihms-1714276.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9349969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Personalizing liver targeted treatments and transplantation for patients with alpha-1 antitrypsin deficiency","authors":"A. Pye, S. Khan, T. Whitehouse, A. Turner","doi":"10.1080/23808993.2021.1862648","DOIUrl":"https://doi.org/10.1080/23808993.2021.1862648","url":null,"abstract":"ABSTRACT Introduction: There is currently no specific treatment for liver disease due to alpha-1 antitrypsin deficiency (AATD) other than care applied for other liver diseases including transplantation. This review describes the personalized approaches to liver disease in AATD, and the current stage of development of new therapeutic agents. Areas covered: We review the pathology, presentation and progression of AATD liver disease and the approaches being taken to understand the natural history of the disease to aid future therapeutic advances. Peri- and post-transplant care is described and we highlight the reasons that alternative approaches to avoid the need for liver transplantation are being explored. The role of patient selection for new therapies is addressed as this is likely to be of paramount importance to achieve better outcomes. Expert opinion: Treatments directed at both liver, and lung and liver combined, are now being trialed in patients with AATD. The next 5–10 years may determine a more reliable noninvasive measurement of liver fibrosis, together with predictors of who is most likely to progress and develop cirrhosis. Personalized approaches could optimize when and how to effectively manage an individual with a cost-effective treatment and avoid progression to liver transplantation.","PeriodicalId":12124,"journal":{"name":"Expert Review of Precision Medicine and Drug Development","volume":null,"pages":null},"PeriodicalIF":1.2,"publicationDate":"2020-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/23808993.2021.1862648","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43289188","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Givosiran, a novel treatment for acute hepatic porphyrias","authors":"Manish Thapar, S. Rudnick, H. Bonkovsky","doi":"10.1080/23808993.2021.1838275","DOIUrl":"https://doi.org/10.1080/23808993.2021.1838275","url":null,"abstract":"ABSTRACT Introduction Acute hepatic porphyrias (AHPs) are a group of rare genetic disorders that affect the enzymes of the heme biosynthetic pathway. Patients have a varied presentation, but attacks of severe abdominal pain are the cardinal feature. Until recently, IV hemin was the only definitive treatment option available. Areas covered We summarize salient features of AHP and the work leading to clinical studies of givosiran and to its approval by the US FDA and the EMA. Givosiran is a novel siRNA therapeutic agent that targets hepatic 5-aminolevulinic acid (ALA) synthase-1, the first and rate limiting enzyme in the heme biosynthetic pathway. It has been effective in decreasing the levels of hepatic ALA synthase-1 mRNA, levels of ALA, which likely is the chief neurotoxin, and the composite attack rates in patients with AHP. The drug can cause elevated liver enzymes, elevations in serum creatinine, and injection site reactions. Single doses, given to asymptomatic persons with AIP who are chronic high excretors of ALA and porphobilinogen, caused decreases in CYP1A2 and CYP2D6 activity, raising concern for drug interactions. Expert opinion Givosiran is expensive; insurance plans are likely to limit its availability to patients with well-documented AHP and frequent and severe acute attacks.","PeriodicalId":12124,"journal":{"name":"Expert Review of Precision Medicine and Drug Development","volume":null,"pages":null},"PeriodicalIF":1.2,"publicationDate":"2020-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/23808993.2021.1838275","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43244105","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Abiraterone acetate plus prednisone/prednisolone in hormone-sensitive and castration-resistant metastatic prostate cancer","authors":"J. Gschwend, K. Miller","doi":"10.1080/23808993.2021.1863781","DOIUrl":"https://doi.org/10.1080/23808993.2021.1863781","url":null,"abstract":"ABSTRACT Introduction: New-generation hormonal therapies such as abiraterone acetate (AA) in combination with prednisone or prednisolone (AAP) have improved the overall survival (OS) in patients with chemotherapy-pretreated and naïve metastatic castration-resistant prostate cancer (mCRPC). More recently, AAP has demonstrated efficacy in newly diagnosed high-risk metastatic hormone-sensitive prostate cancer (mHSPC) and has received expanded approval for this indication. Areas covered: This review is intended to provide a thorough overview of AA as the first-in-class and only currently approved steroid 17α-hydroxylase/C17,20-lyase (CYP17) inhibitor for prostate cancer. To the best of our knowledge, this is the most comprehensive review of AAP that covers all three indications: mCRPC in the pre- and post-chemotherapy setting, and mHSPC. We describe, among other things, the mechanism of action of AA and review data on its efficacy and safety from phase 1, 2 and the pivotal phase 3 clinical trials that support its use in the mentioned approved indications. Expert opinion: AAP has been established over the past 10 years and was added to the WHO list of essential medicines in 2019 through an evidence-based selection process in which quality, safety, efficacy, and cost-effectiveness are key criteria, highlighting its role in the current therapeutic landscape of prostate cancer management.","PeriodicalId":12124,"journal":{"name":"Expert Review of Precision Medicine and Drug Development","volume":null,"pages":null},"PeriodicalIF":1.2,"publicationDate":"2020-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/23808993.2021.1863781","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46163826","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Durvalumab for the treatment of PD-L1 non-small cell lung cancer","authors":"T. Naito, H. Shiraishi, Y. Fujiwara","doi":"10.1080/23808993.2021.1855075","DOIUrl":"https://doi.org/10.1080/23808993.2021.1855075","url":null,"abstract":"ABSTRACT Introduction: Immune checkpoint inhibitors, monoclonal antibodies directed against programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1), have broadened treatment options for patients with non-small cell lung cancer (NSCLC). Durvalumab is a selective, high-affinity, human IgG1 monoclonal anti-PD-L1 antibody that blocks interactions of PD-L1 with PD-1 and CD80. Areas covered: We reviewed clinical data supporting the use of durvalumab as a monotherapy and combination therapy for the treatment of locally advanced and advanced NSCLC. Expert commentary: Durvalumab as a monotherapy or combination therapy has shown well-tolerated safety profiles for NSCLC in several trials. Durvalumab monotherapy in advanced NSCLC patients with PD-L1 ≥ 25% as later line (ATLANTIC study) therapy led to clinically meaningful improvements compared to standard of care. Combination therapy comprising durvalumab plus tremelimumab for advanced NSCLC did not show clinical efficacy in three phase III trials. Durvalumab administered after chemoradiotherapy in stage III NSCLC (PACIFIC study) significantly improved progression-free survival and overall survival. This result has led to approval of durvalumab for patients with locally advanced NSCLC as the standard of care. Ongoing trials provide insight into how durvalumab fits into the rapidly evolving therapeutic landscape for locally advanced or advanced NSCLC.","PeriodicalId":12124,"journal":{"name":"Expert Review of Precision Medicine and Drug Development","volume":null,"pages":null},"PeriodicalIF":1.2,"publicationDate":"2020-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/23808993.2021.1855075","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47734184","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A. Ariani, N. Sverzellati, Andrea Becciolni, G. Milanese, Mario Silva
{"title":"Using quantitative computed tomography to predict mortality in patients with interstitial lung disease related to systemic sclerosis: implications for personalized medicine","authors":"A. Ariani, N. Sverzellati, Andrea Becciolni, G. Milanese, Mario Silva","doi":"10.1080/23808993.2021.1858053","DOIUrl":"https://doi.org/10.1080/23808993.2021.1858053","url":null,"abstract":"ABSTRACT Introduction: Interstitial lung disease (ILD) is the main cause of mortality in systemic sclerosis (SSc). Methods stratifying the prognosis of SSc-ILD are lacking in clinical practice. The quantification of ILD provides a paramount contribution to establishing prognosis and may assist in tailored treatment. Areas covered: In this review, we provide an overview of the main quantitative methods implemented in SSc-ILD (semi-quantitative assessment, volumetric, parametric, and textural quantitative evaluation). Even if they are different one from another, all of them have a prognostic value as they predict mortality as well as radiological and functional worsening. Expert opinion: Semi-quantitative rating of CT images (sQCT) is now the gold standard for SSc-ILD patient assessment and stratification. Furthermore, there are many software available for quantification objective quantification, and classification of ILD. These tools are barely burdened by inter- intra-reader variability and they are suitable for both trial and clinical application. It is therefore expected that in the next few years a better stratification of patients will be achieved by these tools, allowing to recognize patients with the worst prognosis. This, together with the availability of different treatments for pulmonary fibrosis, makes it possible to develop precision medicine also in the field of SSc-ILD.","PeriodicalId":12124,"journal":{"name":"Expert Review of Precision Medicine and Drug Development","volume":null,"pages":null},"PeriodicalIF":1.2,"publicationDate":"2020-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/23808993.2021.1858053","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42056501","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Precision medicine in osteoarthritis: not yet ready for prime time","authors":"B. Siaton, Beth H. Hogans, M. Hochberg","doi":"10.1080/23808993.2020.1842731","DOIUrl":"https://doi.org/10.1080/23808993.2020.1842731","url":null,"abstract":"","PeriodicalId":12124,"journal":{"name":"Expert Review of Precision Medicine and Drug Development","volume":null,"pages":null},"PeriodicalIF":1.2,"publicationDate":"2020-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/23808993.2020.1842731","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41806953","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nourhan Hossam, M. Matboli, H. Shehata, Marwa M. Aboelhussein, M. Hassan, S. Eissa
{"title":"Toll-like receptor immune modulatory role in personalized management of colorectal cancer, review of literature","authors":"Nourhan Hossam, M. Matboli, H. Shehata, Marwa M. Aboelhussein, M. Hassan, S. Eissa","doi":"10.1080/23808993.2020.1816136","DOIUrl":"https://doi.org/10.1080/23808993.2020.1816136","url":null,"abstract":"ABSTRACT Colorectal cancer (CRC) is characterized by high heterogeneity and a complex microenvironment that leads to high inter-patient variability. Personalized management of CRC could address this. Accumulating data highlights the interaction between the CRC microenvironment and the immune system through different cells and receptors with a focus on the toll-like receptors (TLRs). Multiple studies identified a bidirectional role played by TLRs in CRC with involvement in both carcinogenesis and therapy. Areas covered A study to highlight the interaction between TLRs and CRC microenvironment on different molecular levels was undertaken, addressing TLR gene polymorphism, TLR genetic and epigenetic deregulation and TLR ligand binders. In addition, the use of these TLRs and their interaction with CRC microenvironment were evaluated to identify novel CRC therapeutics. Expert commentary Previous literature has shown that TLRs are incriminated in CRC pathogenesis and thus research effort was directed to make use of these TLRs in drawing new therapeutic patterns for CRC. However, to date, these immune-therapeutic patterns of CRC have shown limited success in reducing tumor burden. This highlights the need for more studies that would better illustrate the interaction between TLRs and CRC microenvironment and the impact of TLR modifications to yield more efficient and precise CRC therapeutics.","PeriodicalId":12124,"journal":{"name":"Expert Review of Precision Medicine and Drug Development","volume":null,"pages":null},"PeriodicalIF":1.2,"publicationDate":"2020-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/23808993.2020.1816136","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42418712","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
M. Heiblig, Sabine Hachem-Khalife, C. Willekens, J. Micol, A. Paci, V. Penard-Lacronique, S. de Botton
{"title":"Enasidenib for the treatment of relapsed or refractory acute myeloid leukemia with an isocitrate dehydrogenase 2 mutation","authors":"M. Heiblig, Sabine Hachem-Khalife, C. Willekens, J. Micol, A. Paci, V. Penard-Lacronique, S. de Botton","doi":"10.1080/23808993.2020.1831909","DOIUrl":"https://doi.org/10.1080/23808993.2020.1831909","url":null,"abstract":"ABSTRACT Introduction Isocitrate dehydrogenase 2 (IDH2) is a key metabolic enzyme that converts isocitrate to α-ketoglutarate (αKG). Somatic point mutations in IDH2 confer a gain-of-function in blast cells resulting in overproduction of D-2-hydroxyglutarate (D-2HG). High intracellular concentrations of D-2HG inhibit α-ketoglutarate-dependent dioxygenases including histone, DNA and RNA demethylases, leading to histone, DNA and RNA hypermethylation, and cell differentiation blockade. In vitro and in vivo preclinical studies have demonstrated that inhibition of IDH2-mutant enzymes with enasidenib decrease intracellular D-2HG levels, reverse epigenetic dysregulation, and release the differentiation block. The US Food and Drug Administration (FDA) approved enasidenib, a mutant-IDH2 enzyme inhibitor for patients with relapsed or refractory (R/R) IDH2-mutated AML. Areas covered We review the biology and prognostic significance of IDH2 mutations in AML and discuss the pharmacology, clinical efficacy, and toxicity profile of enasidenib. We highlight areas of ongoing preclinical and clinical research. Expert opinion Enasidenib was FDA approved due to high response rates, durability of the responses that translated into an impressive OS in that heavily pretreated population. Promising ongoing clinical trials are evaluating combination therapies with enasidenib frontline.","PeriodicalId":12124,"journal":{"name":"Expert Review of Precision Medicine and Drug Development","volume":null,"pages":null},"PeriodicalIF":1.2,"publicationDate":"2020-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/23808993.2020.1831909","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47392961","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Personalized asthma management in pediatric patients based on treatment response","authors":"N. Navanandan, S. Szefler","doi":"10.1080/23808993.2020.1834843","DOIUrl":"https://doi.org/10.1080/23808993.2020.1834843","url":null,"abstract":"ABSTRACT Introduction Asthma is the most common chronic illness in the pediatric population and is characterized by substantial heterogeneity in phenotypes and treatment response. A precision medicine approach is required to advance asthma care and improve asthma morbidity in children. Areas covered We present a review of currently available biomarkers for the diagnosis and management of pediatric asthma. We discuss a core set of biomarkers recognized by the National Institute of Health Asthma Outcomes Task Force including eosinophil counts, IgE levels, and fraction of exhaled nitric oxide. We also review emerging biomarkers including periostin, thymic stromal lymphopoietin, and volatile organic compounds. These biomarkers have proven effective in differentiating asthma phenotypes and predicting and monitoring treatment response, and have led to the development of game-changing biologic therapies for pediatric asthma. Expert opinion Substantial progress has been made in the identification of key biomarkers to aid in the classification and management of pediatric asthma. However, for biomarkers to be used routinely in clinical practice, further investigations are needed to expand biomarker representation of additional asthma phenotypes. A systems biology approach is also required, combining the various ‘omic’ strategies, for precision medicine to reach its full potential in pediatric asthma management.","PeriodicalId":12124,"journal":{"name":"Expert Review of Precision Medicine and Drug Development","volume":null,"pages":null},"PeriodicalIF":1.2,"publicationDate":"2020-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/23808993.2020.1834843","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43820455","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}