scholarly journals Pancreatic Neuroendocrine Tumors: Molecular Mechanisms and Therapeutic Targets

Cancers ◽  
2021 ◽  
Vol 13 (20) ◽  
pp. 5117
Author(s):  
Chandra K. Maharjan ◽  
Po Hien Ear ◽  
Catherine G. Tran ◽  
James R. Howe ◽  
Chandrikha Chandrasekharan ◽  
...  

Pancreatic neuroendocrine tumors (pNETs) are unique, slow-growing malignancies whose molecular pathogenesis is incompletely understood. With rising incidence of pNETs over the last four decades, larger and more comprehensive ‘omic’ analyses of patient tumors have led to a clearer picture of the pNET genomic landscape and transcriptional profiles for both primary and metastatic lesions. In pNET patients with advanced disease, those insights have guided the use of targeted therapies that inhibit activated mTOR and receptor tyrosine kinase (RTK) pathways or stimulate somatostatin receptor signaling. Such treatments have significantly benefited patients, but intrinsic or acquired drug resistance in the tumors remains a major problem that leaves few to no effective treatment options for advanced cases. This demands a better understanding of essential molecular and biological events underlying pNET growth, metastasis, and drug resistance. This review examines the known molecular alterations associated with pNET pathogenesis, identifying which changes may be drivers of the disease and, as such, relevant therapeutic targets. We also highlight areas that warrant further investigation at the biological level and discuss available model systems for pNET research. The paucity of pNET models has hampered research efforts over the years, although recently developed cell line, animal, patient-derived xenograft, and patient-derived organoid models have significantly expanded the available platforms for pNET investigations. Advancements in pNET research and understanding are expected to guide improved patient treatments.

2020 ◽  
Vol 27 (12) ◽  
pp. 1276-1287
Author(s):  
Brigida Anna Maiorano ◽  
Giovanni Schinzari ◽  
Sabrina Chiloiro ◽  
Felicia Visconti ◽  
Domenico Milardi ◽  
...  

Pancreatic neuroendocrine tumors (PanNETs) are rare tumors having usually an indolent behavior, but sometimes with unpredictable aggressiveness. PanNETs are more often non-functioning (NF), unable to produce functioning hormones, while 10-30% present as functioning (F) - PanNETs, such as insulinomas , gastrinomas , and other rare tumors. Diagnostic and prognostic markers, but also new therapeutic targets, are still lacking. Proteomics techniques represent therefore promising approaches for the future management of PanNETs. We conducted a systematic review to summarize the state of the art of proteomics in PanNETs. A total of 9 studies were included, focusing both on NF- and F-PanNETs. Indeed, proteomics is useful for the diagnosis, the prognosis and the detection of therapeutic targets. However, further studies are required. It is also warranted to standardize the analysis methods and the collection techniques, in order to validate proteins with a relevance in the personalized approach to PanNETs management.


Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2878
Author(s):  
Claudia Maria Hattinger ◽  
Maria Pia Patrizio ◽  
Leonardo Fantoni ◽  
Chiara Casotti ◽  
Chiara Riganti ◽  
...  

High-grade osteosarcoma (HGOS), the most common primary malignant tumor of bone, is a highly aggressive neoplasm with a cure rate of approximately 40–50% in unselected patient populations. The major clinical problems opposing the cure of HGOS are the presence of inherent or acquired drug resistance and the development of metastasis. Since the drugs used in first-line chemotherapy protocols for HGOS and clinical outcome have not significantly evolved in the past three decades, there is an urgent need for new therapeutic biomarkers and targeted treatment strategies, which may increase the currently available spectrum of cure modalities. Unresponsive or chemoresistant (refractory) HGOS patients usually encounter a dismal prognosis, mostly because therapeutic options and drugs effective for rescue treatments are scarce. Tailored treatments for different subgroups of HGOS patients stratified according to drug resistance-related biomarkers thus appear as an option that may improve this situation. This review explores drug resistance-related biomarkers, therapeutic targets and new candidate treatment strategies, which have emerged in HGOS. In addition to consolidated biomarkers, specific attention has been paid to the role of non-coding RNAs, tumor-derived extracellular vesicles, and cancer stem cells as contributors to drug resistance in HGOS, in order to highlight new candidate markers and therapeutic targets. The possible use of new non-conventional drugs to overcome the main mechanisms of drug resistance in HGOS are finally discussed.


Pancreas ◽  
2016 ◽  
Vol 45 (2) ◽  
pp. 187-192 ◽  
Author(s):  
Ki Byung Song ◽  
Song Cheol Kim ◽  
Ji Hun Kim ◽  
Dong-Wan Seo ◽  
Seung-Mo Hong ◽  
...  

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi215-vi216
Author(s):  
Melanie Schoof ◽  
Carolin Göbel ◽  
Dörthe Holdhof ◽  
Sina Al-Kershi ◽  
Ulrich Schüller

Abstract DNA methylation based classification of brain tumors has revealed a high heterogeneity between tumors and led to the description of multiple distinct subclasses. The increasing subdivision of tumors can help to understand molecular mechanisms of tumor development and to improve therapy if appropriate model systems for preclinical research are available. Multiple recent publications have described a subgroup of pediatric glioblastoma which is clearly separable from other pediatric and adult glioblastoma in its DNA methylation profile (GBM MYCN). Many cases in this group are driven by MYCN amplifications and harbor TP53 mutations. These tumors almost exclusively occur in children and were further described as highly aggressive with a median overall survival of only 14 months. In order to further investigate the biology and treatment options of these tumors, we generated hGFAP-cre::TP53 Fl/Fl ::lsl-MYCN mice. These mice carry a loss of TP53 and show aberrant MYCN expression in neural precursors of the central nervous system. The animals develop large forebrain tumors within the first 80 days of life with 100 % penetrance. These tumors resemble human GBM MYCN tumors histologically and are sensitive to AURKA and ATR inhibitors in vitro. We believe that further characterization of the model and in vivo treatment studies will pave the way to improve treatment of patients with these highly aggressive tumors.


2021 ◽  
Vol 11 ◽  
Author(s):  
Ying Liu ◽  
Xiang Ao ◽  
Guoqiang Ji ◽  
Yuan Zhang ◽  
Wanpeng Yu ◽  
...  

Gastric cancer (GC) is one of the most common malignant tumors of digestive systems worldwide, with high recurrence and mortality. Chemotherapy is still the standard treatment option for GC and can effectively improve the survival and life quality of GC patients. However, with the emergence of drug resistance, the clinical application of chemotherapeutic agents has been seriously restricted in GC patients. Although the mechanisms of drug resistance have been broadly investigated, they are still largely unknown. MicroRNAs (miRNAs) are a large group of small non-coding RNAs (ncRNAs) widely involved in the occurrence and progression of many cancer types, including GC. An increasing amount of evidence suggests that miRNAs may play crucial roles in the development of drug resistance by regulating some drug resistance-related proteins as well as gene expression. Some also exhibit great potential as novel biomarkers for predicting drug response to chemotherapy and therapeutic targets for GC patients. In this review, we systematically summarize recent advances in miRNAs and focus on their molecular mechanisms in the development of drug resistance in GC progression. We also highlight the potential of drug resistance-related miRNAs as biomarkers and therapeutic targets for GC patients.


2020 ◽  
Vol 21 (6) ◽  
pp. 2081 ◽  
Author(s):  
Pavel Klener ◽  
Magdalena Klanova

Non-Hodgkin lymphomas (NHL) are lymphoid tumors that arise by a complex process of malignant transformation of mature lymphocytes during various stages of differentiation. The WHO classification of NHL recognizes more than 90 nosological units with peculiar pathophysiology and prognosis. Since the end of the 20th century, our increasing knowledge of the molecular biology of lymphoma subtypes led to the identification of novel druggable targets and subsequent testing and clinical approval of novel anti-lymphoma agents, which translated into significant improvement of patients’ outcome. Despite immense progress, our effort to control or even eradicate malignant lymphoma clones has been frequently hampered by the development of drug resistance with ensuing unmet medical need to cope with relapsed or treatment-refractory disease. A better understanding of the molecular mechanisms that underlie inherent or acquired drug resistance might lead to the design of more effective front-line treatment algorithms based on reliable predictive markers or personalized salvage therapy, tailored to overcome resistant clones, by targeting weak spots of lymphoma cells resistant to previous line(s) of therapy. This review focuses on the history and recent advances in our understanding of molecular mechanisms of resistance to genotoxic and targeted agents used in clinical practice for the therapy of NHL.


Cancers ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 828 ◽  
Author(s):  
Amit Akirov ◽  
Vincent Larouche ◽  
Sameerah Alshehri ◽  
Sylvia L. Asa ◽  
Shereen Ezzat

The management of pancreatic neuroendocrine tumors (PanNETs) involves classification into non-functional or functional PanNET, and as localized or metastatic PanNET. In addition, while most PanNETs are sporadic, these endocrine neoplasms can also be manifestations of genetic syndromes. All these factors may assist in forming a risk stratification system permitting a tailored management approach. Most PanNETs are classified as non-functional because they are not associated with clinical sequelae of hormone excess. They are characterized by non-specific symptoms, such as abdominal pain or weight loss, resulting from mass effect related to the pancreatic tumor or secondary to distant metastases. Accurate staging of the disease is essential for determining the appropriate approach to therapy. As cure is only potentially possible with surgical resection of the tumor, it is recommended to remove all localized and limited metastatic disease. However, many patients present with metastatic and/or advanced local disease. In such instances, the goal of therapy is to control tumor growth and/or decrease tumor burden, lengthen survival, and palliate local symptoms and those of hormone excess. This typically requires a multimodal approach, including surgery, liver-directed treatment, and systemic medical therapy.


2016 ◽  
Vol 96 (3) ◽  
pp. 805-829 ◽  
Author(s):  
Andreas Wicki ◽  
Mario Mandalà ◽  
Daniela Massi ◽  
Daniela Taverna ◽  
Huifang Tang ◽  
...  

Although modern therapeutic strategies have brought significant progress to cancer care in the last 30 years, drug resistance to targeted monotherapies has emerged as a major challenge. Aberrant regulation of multiple physiological signaling pathways indispensable for developmental and metabolic homeostasis, such as hyperactivation of pro-survival signaling axes, loss of suppressive regulations, and impaired functionalities of the immune system, have been extensively investigated aiming to understand the diversity of molecular mechanisms that underlie cancer development and progression. In this review, we intend to discuss the molecular mechanisms of how conventional physiological signal transduction confers to acquired drug resistance in cancer patients. We will particularly focus on protooncogenic receptor kinase inhibition-elicited tumor cell adaptation through two major core downstream signaling cascades, the PI3K/Akt and MAPK pathways. These pathways are crucial for cell growth and differentiation and are frequently hyperactivated during tumorigenesis. In addition, we also emphasize the emerging roles of the deregulated host immune system that may actively promote cancer progression and attenuate immunosurveillance in cancer therapies. Understanding these mechanisms may help to develop more effective therapeutic strategies that are able to keep the tumor in check and even possibly turn cancer into a chronic disease.


Cancer ◽  
2013 ◽  
Vol 119 (23) ◽  
pp. 4094-4102 ◽  
Author(s):  
Kosuke Okuwaki ◽  
Mitsuhiro Kida ◽  
Tetuo Mikami ◽  
Hiroshi Yamauchi ◽  
Hiroshi Imaizumi ◽  
...  

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