Current and emerging therapies for patients with advanced pancreatic ductal adenocarcinoma: a bright future

Christenson, Eric S.; Jaffee, Elizabeth M.; Azad, Nilofer S.

doi:10.1016/s1470-2045(19)30795-8

Cited by 175 publications

(135 citation statements)

References 70 publications

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“…Gene fusion is rare but oncogenic in KRAS wild-type cell lines [77]. The frequency of NTRK fusion and NRG1 fusion is 0.3% and 0.5%, respectively [78]. Chromosomal rearrangement of the NTRK gene family promotes the expression of tropomyosin receptor kinases with chimeric rearrangements, which are characterized by ligand-independent constitutive activation [77].…”

Section: Gene Fusions As Promising Targets In Kras Wild-type Pdacmentioning

confidence: 99%

Molecular alterations and targeted therapy in pancreatic ductal adenocarcinoma

et al. 2020

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Pancreatic ductal adenocarcinoma (PDAC) is a malignancy characterized by a poor prognosis and high mortality rate. Genetic mutations and altered molecular pathways serve as targets in precise therapy. Using next-generation sequencing (NGS), these aberrant alterations can be identified and used to develop strategies that will selectively kill cancerous cells in patients with PDAC. The realization of targeted therapies in patients with PDAC may be summarized by three approaches. First, because oncogenes play a pivotal role in tumorigenesis, inhibition of dysregulated oncogenes is a promising method (Table 3). Numerous researchers are developing strategies to target oncogenes, such as KRAS, NRG1, and NTRK and related molecules, although most of the results are unsatisfactory. Accordingly, emerging strategies are being developed to target these oncogenes, including simultaneously inhibiting multiple molecules or pathways, modification of mutant residues by small molecules, and RNA interference. Second, researchers have attempted to reactivate inactivated tumour suppressors or modulate related molecules. TP53, CDKN2A and SMAD4 are three major tumour suppressors involved in PDAC. Advances have been achieved in clinical and preclinical trials of therapies targeting these three genes, and further investigations are warranted. The TGF-β-SMAD4 signalling pathway plays a dual role in PDAC tumorigenesis and participates in mediating tumour-stroma crosstalk and modulating the tumour microenvironment (TME); thus, molecular subtyping of pancreatic cancer according to the SMAD4 mutation status may be a promising precision oncology technique. Finally, genes such as KDM6A and BRCA have vital roles in maintaining the structural stability and physiological functions of normal chromosomes and are deficient in some patients with PDAC, thus serving as potential targets for correcting these deficiencies and precisely killing these aberrant tumour cells. Recent clinical trials, such as the POLO (Pancreas Cancer Olaparib Ongoing) trial, have reported encouraging outcomes. In addition to genetic event-guided treatment, immunotherapies such as chimeric antigen receptor T cells (CAR-T), antibody-drug conjugates, and immune checkpoint inhibitors also exhibit the potential to target tumours precisely, although the clinical value of immunotherapies as treatments for PDAC is still limited. In this review, we focus on recent preclinical and clinical advances in therapies targeting aberrant genes and pathways and predict the future trend of precision oncology for PDAC.

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Section: Gene Fusions As Promising Targets In Kras Wild-type Pdacmentioning

confidence: 99%

Molecular alterations and targeted therapy in pancreatic ductal adenocarcinoma

et al. 2020

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“…Notably, the classification of an inflammatory cancer subtype emphasizes the importance of the tumor microenvironment affecting PDAC characteristics. The substantial and complex impact of the inflammatory tumor microenvironment on tumor biology and therapy efficiency is excellently reviewed in [32,33]. In a previous study, we could show that the immune microenvironment in PDAC can be of prognostic value and we provided a signature comprising different leukocyte subpopulations and stromal composition to stratify patients using progression free survival as the primary outcome [34].…”

Section: Novel Preclinical Strategies For Precision Medicinementioning

confidence: 99%

Current Strategies and Future Perspectives for Precision Medicine in Pancreatic Cancer

Regel

Mayerle

Mahajan

2020

Cancers

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Current standard-of-care for patients with pancreatic ductal adenocarcinoma (PDAC) focusses on chemotherapeutic regimens and pancreatic cancer surgery. However, limited treatment options, late diagnosis in advanced tumor stages and the aggressive behavior of PDAC contribute to the high mortality of the disease. Consequently, there is an urgent need of precision medicine for pancreatic cancer patients. All over the world, numerous initiatives started in recent years to translate novel scientific discoveries into prospective clinical trials. One major approach pursues the stratification of PDAC patients according the tumor transcriptome to predict treatment response. Other strategies concentrate on genomic alterations and the identification of individualized targeted therapies. Further experimental studies are ongoing to detect novel biomarkers for cancer diagnosis, subtyping, treatment response prediction or clinical outcome. However, the challenge remains to transfer the knowledge into clinical practice. In this review, we summarize current literature and knowledge and highlight novel concepts of basic and clinical research uncovering suitable biomarkers and targeted therapies. Thus, we provide an overview of preclinical and clinical efforts of precision medicine in pancreatic cancer.

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“… 8 This could be attributed to the widespread distribution of angiotensin converting enzyme-2 (ACE-2), the primary receptor for SARS coronaviruses, in multiple organs. 9 , 10 ACE-2 is expressed as a cell-surface molecule in the respiratory tract (epithelium, arterial and venous endothelium), the small intestinal epithelium, and arterial smooth muscle cells. 11 …”

Section: Introductionmentioning

confidence: 99%

Understanding the epidemiology, pathophysiology, diagnosis and management of SARS-CoV-2

et al. 2020

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The emergence of coronavirus disease 2019 (COVID-19) in December 2019 has resulted in over 20 million cases and 741,808 deaths globally, affecting more than 200 countries. COVID-19 was declared a pandemic on 11 March 2020 by the World Health Organization. The disease is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). There is limited information on COVID-19, and treatment has so far focused on supportive care and use of repurposed drugs. COVID-19 can be transmitted via person-to-person contact through droplet spread. Some of the recommended precautionary measures to reduce the rate of disease spread include social distancing, good hygiene practices, and avoidance of crowded areas. These measures are effective because the droplets are heavy and can only travel approximately 1 meter in the air, settling quickly on fixed surfaces. Promising strategies to combat SARS-CoV-2 include discovery of therapeutic targets/drugs and vaccines. In this review, we summarize the epidemiology, pathophysiology, and diagnosis of COVID-19. We also address the mechanisms of action of approved repurposed drugs for therapeutic management of the disease.

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Current and emerging therapies for patients with advanced pancreatic ductal adenocarcinoma: a bright future

Cited by 175 publications

References 70 publications

Molecular alterations and targeted therapy in pancreatic ductal adenocarcinoma

Molecular alterations and targeted therapy in pancreatic ductal adenocarcinoma

Current Strategies and Future Perspectives for Precision Medicine in Pancreatic Cancer

Understanding the epidemiology, pathophysiology, diagnosis and management of SARS-CoV-2

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