Morphologic and Molecular Landscape of Pancreatic Cancer Variants as the Basis of New Therapeutic Strategies for Precision Oncology

To date, pancreatic cancer is still one of the most lethal cancers in the world, mainly due to the lack of early diagnosis and personalized treatment strategies. In this context, the possibility and the opportunity of identifying genetic and molecular biomarkers are crucial to improve the feasibility of precision medicine. In 2019, the World Health Organization classified pancreatic ductal adenocarcinoma cancer (the most common pancreatic tumor type) into eight variants, according to specific histomorphological features. They are: colloid carcinoma, medullary carcinoma, adenosquamous carcinoma, undifferentiated carcinoma, including also rhabdoid carcinoma, undifferentiated carcinoma with osteoclast-like giant cells, hepatoid carcinoma, and signet-ring/poorly cohesive cells carcinoma. Interestingly, despite the very low incidence of these variants, innovative high throughput genomic/transcriptomic techniques allowed the investigation of both somatic and germline mutations in each specific variant, paving the way for their possible classification according also to specific alterations, along with the canonical mutations of pancreatic cancer (KRAS, TP53, CDKN2A, SMAD4). In this review, we aim to report the current evidence about genetic/molecular profiles of pancreatic cancer variants, highlighting their role in therapeutic and clinical impact.

Download Full-text

Novel 3D µtissues Mimicking the Fibrotic Stroma in Pancreatic Cancer to Study Cellular Interactions and Stroma-Modulating Therapeutics

Cancers ◽

10.3390/cancers13195006 ◽

2021 ◽

Vol 13 (19) ◽

pp. 5006

Author(s):

Kunal P. Pednekar ◽

Marcel A. Heinrich ◽

Joop van Baarlen ◽

Jai Prakash

Keyword(s):

Pancreatic Cancer ◽

Tumor Cells ◽

Treatment Options ◽

Treatment Strategies ◽

Collagen Gel ◽

Current Treatment ◽

Ductal Adenocarcinoma ◽

Tumor Type ◽

Cellular Interactions

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive tumor type with low patient survival due to the low efficacy of current treatment options. Cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) create a dense fibrotic environment around the tumor cells, preventing therapies from reaching their target. Novel 3D in vitro models are needed that mimic this fibrotic barrier for the development of therapies in a biologically relevant environment. Here, novel PDAC microtissues (µtissues) consisting of pancreatic cancer cell core surrounded by a CAF-laden collagen gel are presented, that is based on the cells own contractility to form a hard-to-penetrate barrier. The contraction of CAFs is demonstrated facilitating the embedding of tumor cells in the center of the µtissue as observed in patients. The µtissues displayed a PDAC-relevant gene expression by comparing their gene profile with transcriptomic patient data. Furthermore, the CAF-dependent proliferation of cancer cells is presented, as well as the suitability of the µtissues to serve as a platform for the screening of CAF-modulating therapies in combination with other (nano)therapies. It is envisioned that these PDAC µtissues can serve as a high-throughput platform for studying cellular interactions in PDAC and for evaluating different treatment strategies in the future.

Download Full-text

The Evolving Understanding of the Molecular and Therapeutic Landscape of Pancreatic Ductal Adenocarcinoma

Diseases ◽

10.3390/diseases6040103 ◽

2018 ◽

Vol 6 (4) ◽

pp. 103 ◽

Cited By ~ 3

Author(s):

Ashleigh Parkin ◽

Jennifer Man ◽

Angela Chou ◽

Adnan Nagrial ◽

Jaswinder Samra ◽

...

Keyword(s):

Pancreatic Cancer ◽

Treatment Strategies ◽

Current Status ◽

Ductal Adenocarcinoma ◽

Molecular Heterogeneity ◽

Precision Oncology ◽

Molecular Stratification ◽

Therapeutic Landscape ◽

Genomic Fingerprint ◽

Novel Treatment Strategies

Pancreatic cancer is the third leading cause of cancer-related deaths, characterised by poor survival, marked molecular heterogeneity and high intrinsic and acquired chemoresistance. Only 10–20% of pancreatic cancer patients present with surgically resectable disease and even then, 80% die within 5 years. Our increasing understanding of the genomic heterogeneity of cancer suggests that the failure of definitive clinical trials to demonstrate efficacy in the majority of cases is likely due to the low proportion of responsive molecular subtypes. As a consequence, novel treatment strategies to approach this disease are urgently needed. Significant developments in the field of precision oncology have led to increasing molecular stratification of cancers into subtypes, where individual cancers are selected for optimal therapy depending on their molecular or genomic fingerprint. This review provides an overview of the current status of clinically used and emerging treatment strategies, and discusses the advances in and the potential for the implementation of precision medicine in this highly lethal malignancy, for which there are currently no curative systemic therapies.

Download Full-text

Immune Cell Modulation of the Extracellular Matrix Contributes to the Pathogenesis of Pancreatic Cancer

Biomolecules ◽

10.3390/biom11060901 ◽

2021 ◽

Vol 11 (6) ◽

pp. 901

Author(s):

Ramiz S. Ahmad ◽

Timothy D. Eubank ◽

Slawomir Lukomski ◽

Brian A. Boone

Keyword(s):

Pancreatic Cancer ◽

Extracellular Matrix ◽

Immune Cells ◽

Immune Cell ◽

Treatment Strategies ◽

Stellate Cells ◽

Pancreatic Stellate Cells ◽

Ductal Adenocarcinoma ◽

Cellular Mechanisms ◽

Novel Treatment Strategies

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a five-year survival rate of only 9%. PDAC is characterized by a dense, fibrotic stroma composed of extracellular matrix (ECM) proteins. This desmoplastic stroma is a hallmark of PDAC, representing a significant physical barrier that is immunosuppressive and obstructs penetration of cytotoxic chemotherapy agents into the tumor microenvironment (TME). Additionally, dense ECM promotes hypoxia, making tumor cells refractive to radiation therapy and alters their metabolism, thereby supporting proliferation and survival. In this review, we outline the significant contribution of fibrosis to the pathogenesis of pancreatic cancer, with a focus on the cross talk between immune cells and pancreatic stellate cells that contribute to ECM deposition. We emphasize the cellular mechanisms by which neutrophils and macrophages, specifically, modulate the ECM in favor of PDAC-progression. Furthermore, we investigate how activated stellate cells and ECM influence immune cells and promote immunosuppression in PDAC. Finally, we summarize therapeutic strategies that target the stroma and hinder immune cell promotion of fibrogenesis, which have unfortunately led to mixed results. An enhanced understanding of the complex interactions between the pancreatic tumor ECM and immune cells may uncover novel treatment strategies that are desperately needed for this devastating disease.

Download Full-text

Adjuvant and Neoadjuvant Therapy for Pancreatic Adenocarcinoma

10.2310/7800.16076 ◽

2017 ◽

Author(s):

Gregory C Wilson ◽

Brent T Xia ◽

Syed A Ahmed

Keyword(s):

Pancreatic Cancer ◽

Adjuvant Therapy ◽

Neoadjuvant Therapy ◽

Pancreatic Adenocarcinoma ◽

Locally Advanced ◽

Neoadjuvant Treatment ◽

Advanced Pancreatic Cancer ◽

Treatment Strategies ◽

Ductal Adenocarcinoma ◽

Borderline Resectable

Despite decades of advancement and research into the multimodal care of pancreatic cancer, mortality after the diagnosis of pancreatic ductal adenocarcinoma remains grim. The role of adjuvant therapy following surgical resection has been well established in the literature. However, adjuvant therapy is imperfect, and outside of a clinical trial, there are high rates of omission or delayed initiation of therapy. Neoadjuvant treatment strategies continue to be explored in the management of resectable, borderline-resectable, and locally advanced unresectable pancreatic adenocarcinoma. With improved resection rates and the possibility for tumor downstaging, neoadjuvant therapy has become standard for patients with borderline-resectable and locally advanced unresectable tumors. Additional benefits of neoadjuvant therapy in the treatment of resectable tumors include improved completion rates of systemic therapy and R0 resection rates. Future clinical trials, including the use of novel treatment agents and combination treatment strategies in both neoadjuvant and adjuvant regimens, will add value to the treatment of pancreatic adenocarcinoma. Key words: adjuvant therapy, borderline-resectable pancreatic cancer, locally advanced pancreatic cancer, neoadjuvant therapy, pancreatic adenocarcinoma, resectable disease

Download Full-text

Missing links — epigenetic regulators of the pancreatic cancer–associated inflammation

Clinical Science ◽

10.1042/cs20210181 ◽

2021 ◽

Vol 135 (10) ◽

pp. 1289-1293

Author(s):

Gregor Werba ◽

Tamas A. Gonda

Keyword(s):

Pancreatic Cancer ◽

Noncoding Rna ◽

Current Knowledge ◽

Treatment Strategies ◽

Therapeutic Interventions ◽

Ductal Adenocarcinoma ◽

Gastrointestinal Cancers ◽

Novel Treatment ◽

Epigenetic Regulator ◽

Novel Treatment Strategies

Abstract Pancreatic ductal adenocarcinoma (PDAC) features a hostile tumor microenvironment (TME) that renders it remarkably resistant to most therapeutic interventions. Consequently, survival remains among the poorest compared with other gastrointestinal cancers. Concerted efforts are underway to decipher the complex PDAC TME, break down barriers to efficacious therapies and identify novel treatment strategies. In the recent Clinical Science, Li and colleagues identify the long noncoding RNA KLHDC7B-DT as a crucial epigenetic regulator of IL-6 transcription in PDAC and illustrate its potent influences on the pancreatic TME. In this commentary, we introduce epigenetics in pancreatic cancer and put the findings by Li et al. in context with current knowledge.

Download Full-text

Conversion Surgery for Advanced Pancreatic Cancer

Journal of Clinical Medicine ◽

10.3390/jcm8111945 ◽

2019 ◽

Vol 8 (11) ◽

pp. 1945

Author(s):

Thomas Hank ◽

Oliver Strobel

Keyword(s):

Pancreatic Cancer ◽

Locally Advanced ◽

Palliative Therapy ◽

Advanced Pancreatic Cancer ◽

Treatment Strategies ◽

Ductal Adenocarcinoma ◽

Conversion Surgery ◽

Radiological Criteria ◽

Intention To Treat ◽

Conversion Rates

While primarily unresectable locally advanced pancreatic cancer (LAPC) used to be an indication for palliative therapy, a strategy of neoadjuvant therapy (NAT) and conversion surgery is being increasingly used after more effective chemotherapy regimens have become available for pancreatic ductal adenocarcinoma. While high-level evidence from prospective studies is still sparse, several large retrospective studies have recently reported their experience with NAT and conversion surgery for LAPC. This review aims to provide a current overview about different NAT regimens, conversion rates, survival outcomes and determinants of post-resection outcomes, as well as surgical strategies in the context of conversion surgery after NAT. FOLFIRINOX is the predominant regimen used and associated with the highest reported conversion rates. Conversion rates considerably vary between less than 5% and more than half of the study population with heterogeneous long-term outcomes, owing to a lack of intention-to-treat analyses in most studies and a high heterogeneity in resectability criteria, treatment strategies, and reporting among studies. Since radiological criteria of local resectability are no longer applicable after NAT, patients without progressive disease should undergo surgical exploration. Surgery after NAT has to be aimed at local radicality around the peripancreatic vessels and should be performed in expert centers. Future studies in this rapidly evolving field need to be prospective, analyze intention-to-treat populations, report stringent and objective inclusion criteria and criteria for resection. Innovative regimens for NAT in combination with a radical surgical approach hold high promise for patients with LAPC in the future.

Download Full-text

Meningiomas

10.1093/med/9780190696696.003.0011 ◽

2018 ◽

Author(s):

K. E. Hovinga ◽

Y. Esquenazi ◽

P. H. Gutin

Keyword(s):

Treatment Strategies ◽

Brain Structures ◽

World Health ◽

Spinal Tumors ◽

Central Nervous System Tumors ◽

Clinical Scenarios ◽

The World ◽

Specific Factors ◽

Health Organization ◽

Slow Growing

Meningiomas are the most common primary central nervous system tumors and account for about one third of all primary brain and spinal tumors. They are classified according to the World Health Organization into 3 groups (I–III). Treatment strategies range from observation, surgery, and/or a radiation therapy. Many meningiomas are slow growing and discovered incidentally. Symptoms can vary widely, depending on the location. Patient’s specific factors and the location of the meningioma in relation to critical brain structures are all important factors in determining the optimal treatment. This chapter presents common clinical scenarios of meningioma. Differential diagnosis, perioperative workup, surgical nuances, and postoperative complications are discussed.

Download Full-text

From Genetic Alterations to Tumor Microenvironment: The Ariadne’s String in Pancreatic Cancer

Cells ◽

10.3390/cells9020309 ◽

2020 ◽

Vol 9 (2) ◽

pp. 309 ◽

Cited By ~ 3

Author(s):

Chiara Bazzichetto ◽

Fabiana Conciatori ◽

Claudio Luchini ◽

Francesca Simionato ◽

Raffaela Santoro ◽

...

Keyword(s):

Pancreatic Cancer ◽

Tumor Microenvironment ◽

Current Knowledge ◽

Myeloid Cells ◽

Genetic Alterations ◽

Molecular Characteristics ◽

Precision Oncology ◽

Cancer Type ◽

Tumor Type ◽

Driver Genes

The threatening notoriety of pancreatic cancer mainly arises from its negligible early diagnosis, highly aggressive progression, failure of conventional therapeutic options and consequent very poor prognosis. The most important driver genes of pancreatic cancer are the oncogene KRAS and the tumor suppressors TP53, CDKN2A, and SMAD4. Although the presence of few drivers, several signaling pathways are involved in the oncogenesis of this cancer type, some of them with promising targets for precision oncology. Pancreatic cancer is recognized as one of immunosuppressive phenotype cancer: it is characterized by a fibrotic-desmoplastic stroma, in which there is an intensive cross-talk between several cellular (e.g., fibroblasts, myeloid cells, lymphocytes, endothelial, and myeloid cells) and acellular (collagen, fibronectin, and soluble factors) components. In this review; we aim to describe the current knowledge of the genetic/biological landscape of pancreatic cancer and the composition of its tumor microenvironment; in order to better direct in the intrinsic labyrinth of this complex tumor type. Indeed; disentangling the genetic and molecular characteristics of cancer cells and the environment in which they evolve may represent the crucial step towards more effective therapeutic strategies

Download Full-text

Overcoming erlotinib resistance with STAT3 inhibition in pancreatic cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.4_suppl.304 ◽

2017 ◽

Vol 35 (4_suppl) ◽

pp. 304-304 ◽

Cited By ~ 2

Author(s):

Matthew Philip Salzberg ◽

Nipun B. Merchant

Keyword(s):

Pancreatic Cancer ◽

Kinase Inhibitor ◽

Treatment Strategies ◽

Phase Iii ◽

Human Pancreatic Cancer ◽

Ductal Adenocarcinoma ◽

Dependent Manner ◽

Egfr Inhibition ◽

Stat3 Signaling ◽

Stat3 Inhibition

304 Background: Pancreatic ductal adenocarcinoma (PDAC) remains a major therapeutic challenge. Cytotoxic chemotherapy remains the standard approach in PDAC, but results in minimal survival benefit for patients, highlighting a desperate need for novel treatment strategies. Epidermal growth factor receptor (EGFR) is overexpressed in 25-90% of PDACs and has been shown to be an adverse prognostic marker for survival, making it a rational target. To date, the combination of the EGFR tyrosine kinase inhibitor, erlotinib, with gemcitabine remains the only approved targeted therapy based on a significant, yet modest, improved overall survival when compared to gemcitabine alone in a phase III clinical trial. We have previously shown that constitutively activated signal transducer and activator of transcription 3 (STAT3) signaling is a biomarker of resistance to both gemcitabine and erlotinib. Therefore, we hypothesized that combined STAT3 and EGFR inhibition would overcome resistance to erlotinib and gemcitabine in PDAC. Methods: Human pancreatic cancer cell lines MiaPaca2 ( KRASG12C ; TP53mut ; EGFRwt) or BxPC-3 ( KRASwt ; TP53mut ; EGFRwt) were treated in a dose dependent manner with erlotinib in the presence or absence of gemcitabine. PDAC cells were additionally treated with EC50doses of a STAT3 inhibitor (AZD1480), erlotinib, and/or gemcitabine. Lysates were then collected and western blot analysis was performed to detect total and phosphorylated extracellular signal regulated kinase (ERK) or STAT3. Results: EGFR inhibition with erlotinib, with or without gemcitabine, results in decreased ERK activation, however, causes an increased activation of STAT3 signaling in both MiaPaca2 and BxPC-3 cells. Combined STAT3 and EGFR inhibition results in sustained attenuation of both phosphorylated ERK and STAT3 levels. Conclusions: Our study demonstrates that activated STAT3 signaling appears to be a mechanism of resistance to erlotinib and gemicitabine treatment in PDAC. Combining STAT3 inhibition with EGFR inhibition overcomes this resistance.

Download Full-text

Report of an International Psychogeriatric Association Special Meeting Work Group; Under the Cosponsorship of Alzheimer's Disease International, the European Federation of Neurological Societies, the World Health Organization, and the World Psychiatric Association

International Psychogeriatrics ◽

10.1017/s1041610297004675 ◽

1997 ◽

Vol 9 (S1) ◽

pp. 11-38 ◽

Cited By ~ 16

Author(s):

Barry Reisberg ◽

Alistair Burns ◽

Henry Brodaty ◽

Robin Eastwood ◽

Martin Rossor ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Current Knowledge ◽

Work Group ◽

Treatment Strategies ◽

Diagnostic Procedures ◽

World Health ◽

Diagnostic Process ◽

European Federation ◽

The World

Current knowledge with respect to the diagnosis of Alzheimer's disease (AD) is reviewed. There is agreement that AD is a characteristic clinicopathologic entity that is amenable to diagnosis. The diagnosis of AD should no longer be considered one of exclusion. Rather, the diagnostic process is one of recognition of the characteristic features of AD and of conditions that can have an impact on presentation or mimic aspects of the clinicopathologic picture. The present availability of improved prognosis, management, and treatment strategies makes the proper, and state-of-the-art, diagnosis of AD a clinical imperative in all medical settings. Concurrently, information regarding the relevance and applicability of current diagnostic procedures in diverse cultural settings must continue to accrue.

Download Full-text