Emerging therapies and latest development in the treatment of unresectable pancreatic neuroendocrine tumors: an update for clinicians.
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ABSTRACT:
SUBMITTER: Sharma J
PROVIDER: S-EPMC3808571 | biostudies-literature | 2013 Nov
REPOSITORIES: biostudies-literature
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Project description: Not available
| S-EPMC4849884 | biostudies-literature
Project description:Pemphigus represents a group of rare and severe autoimmune intra-epidermal blistering diseases affecting the skin and mucous membranes. These painful and debilitating diseases are driven by the production of autoantibodies that are mainly directed against the desmosomal adhesion proteins, desmoglein 3 (Dsg3) and desmoglein 1 (Dsg1). The search to define underlying triggers for anti-Dsg-antibody production has revealed genetic, environmental, and possible vaccine-driven factors, but our knowledge of the processes underlying disease initiation and pathology remains incomplete. Recent studies point to an important role of T cells in supporting auto-antibody production; yet the involvement of the myeloid compartment remains unexplored. Clinical management of pemphigus is beginning to move away from broad-spectrum immunosuppression and towards B-cell-targeted therapies, which reduce many patients' symptoms but can have significant side effects. Here, we review the latest developments in our understanding of the predisposing factors/conditions of pemphigus, the underlying pathogenic mechanisms, and new and emerging therapies to treat these devastating diseases.
| S-EPMC8855930 | biostudies-literature
Project description:Neuroendocrine tumors (NETs) are a heterogeneous class of diseases characterized by challenging management. Preclinical evidence shows that the PI3K/AKT/mTOR signaling pathway plays a central role in the pathogenesis and progression of NETs. Everolimus is a direct inhibitor of this pathway, and therefore this molecule appears to be a well-grounded strategy for the treatment of NETs, capable of changing clinical practice. The efficacy and safety of everolimus was demonstrated in the RADIANT trials. In this work, we comment on the results of the RADIANT trials, and other recent key evidence from fully published clinical trials on everolimus, and we discuss the current role of everolimus in the treatment of NETs.
| S-EPMC5349426 | biostudies-literature
Project description:Treatment options for neuroendocrine tumors (NETs) and carcinomas (NECs) are expanding. Early-phase studies have shown preliminary evidence of the antitumor activity of alpha-emitting peptide receptor radionuclide therapy (PRRT), and novel radiopeptides incorporating somatostatin receptor antagonists (rather than agonists) have been developed. Several tyrosine kinase inhibitors (TKIs) with antiangiogenic potential have been evaluated in patients with NETs, including lenvatinib, axitinib, cabozantinib and pazopanib. Recently, two phase 3 clinical trials have demonstrated the efficacy and safety of surufatinib, an inhibitor of vascular endothelial growth factor receptor (VEGFR)-1, -2, -3, fibroblast growth factor receptor (FGFR)-1 and colony stimulating factor-1 receptor (CSF-1R), in patients with pancreatic and extra-pancreatic NETs. Multiple clinical trials of combination immunotherapy have been recently completed, but interpretation of the results is hampered by small samples sizes and discordant outcomes. This review summarizes recent data on emerging treatments for neuroendocrine neoplasms.
| S-EPMC7696369 | biostudies-literature
Project description:BackgroundEverolimus, an oral inhibitor of mammalian target of rapamycin (mTOR), has shown antitumor activity in patients with advanced pancreatic neuroendocrine tumors, in two phase 2 studies. We evaluated the agent in a prospective, randomized, phase 3 study.MethodsWe randomly assigned 410 patients who had advanced, low-grade or intermediate-grade pancreatic neuroendocrine tumors with radiologic progression within the previous 12 months to receive everolimus, at a dose of 10 mg once daily (207 patients), or placebo (203 patients), both in conjunction with best supportive care. The primary end point was progression-free survival in an intention-to-treat analysis. In the case of patients in whom radiologic progression occurred during the study, the treatment assignments could be revealed, and patients who had been randomly assigned to placebo were offered open-label everolimus.ResultsThe median progression-free survival was 11.0 months with everolimus as compared with 4.6 months with placebo (hazard ratio for disease progression or death from any cause with everolimus, 0.35; 95% confidence interval [CI], 0.27 to 0.45; P<0.001), representing a 65% reduction in the estimated risk of progression or death. Estimates of the proportion of patients who were alive and progression-free at 18 months were 34% (95% CI, 26 to 43) with everolimus as compared with 9% (95% CI, 4 to 16) with placebo. Drug-related adverse events were mostly grade 1 or 2 and included stomatitis (in 64% of patients in the everolimus group vs. 17% in the placebo group), rash (49% vs. 10%), diarrhea (34% vs. 10%), fatigue (31% vs. 14%), and infections (23% vs. 6%), which were primarily upper respiratory. Grade 3 or 4 events that were more frequent with everolimus than with placebo included anemia (6% vs. 0%) and hyperglycemia (5% vs. 2%). The median exposure to everolimus was longer than exposure to placebo by a factor of 2.3 (38 weeks vs. 16 weeks).ConclusionsEverolimus, as compared with placebo, significantly prolonged progression-free survival among patients with progressive advanced pancreatic neuroendocrine tumors and was associated with a low rate of severe adverse events. (Funded by Novartis Oncology; RADIANT-3 ClinicalTrials.gov number, NCT00510068.).
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Project description:Gastric cancer is one of the most lethal cancers worldwide despite many advances and options in therapy. As it is often diagnosed at an advanced stage, prognosis is poor with a median overall survival of less than twelve months. Chemotherapy remains the mainstay of treatment for these patients but it confers only a moderate survival advantage. There remains a need for new targeted treatment options and a way to better define patient populations who will benefit from these agents. In the past few years, there has been a better understanding of the biology, molecular profiling, and heterogeneity of gastric cancer. Our increased knowledge has led to the identification of gastric cancer subtypes and to the development of new targeted therapeutic agents. There are now two new targeted agents, trastuzumab and ramucirumab, that have recently been approved for the treatment of advanced and metastatic gastric cancer. There are also many other actively investigated targets, including epidermal growth factor receptor, the phosphatadylinositol 3-kinase/protein kinase B/mammalian target of rapamycin pathway, c-Met, poly ADP-ribose polymerase, and immune checkpoint inhibition. In this review, we discuss the current management of advanced gastric cancer as well as emerging targeted therapies and immunotherapy.
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Project description:The development of biologic agents has ushered in a new era of precision medicine, opening the door to new therapeutic options designed to intelligently target cancer cells and their promoting factors, while leaving normal cells relatively unharmed. Biologics for the treatment of neuroendocrine tumors (NETs) have followed in the footsteps of regimens targeting pathways upregulated in other cancers, including the vascular endothelial growth factor (VEGF) and the mammalian target of rapamycin (mTOR). Through a number of clinical trials, the mTOR inhibitor everolimus and the receptor tyrosine kinase (RTK) inhibitor sunitinib were recently approved for NETs. Other biologics such as the VEGF-A inhibitor bevacizumab have also demonstrated promising clinical activity in NETs. Interestingly, though trials have demonstrated the efficacy of everolimus and sunitinib in extending progression-free survival (PFS) in NETs, objective response rates (RR) are uniformly low, indicating that the primary effect of these drugs is maintenance of stable disease. Due to the relatively indolent nature of the more common, well-differentiated variety of NETs, stable disease is often a reasonable goal for NET patients. Well-differentiated NETs have been shown to be poor responders to cytotoxic chemotherapy, underlining the important role of biologics in treating and managing NETs and their hormonal symptoms. Ongoing and future trials are investigating a wide variety of biologic compounds in NETs, including other RTK inhibitors, mTOR pathway inhibitors, and immune checkpoint inhibitors. Within this review, we will discuss major trials leading up to the FDA approval of everolimus and sunitinib for NETs, as well as other promising biologics currently under investigation in NET clinical trials.
| S-EPMC5506272 | biostudies-literature
Project description:Over the past decade, substantial insight into the biological function of the tumor suppressors neurofibromin (NF1) and Merlin (NF2) has been gained. The purpose of this review is to highlight some of the major advances in our understanding of the biology of neurofibromatosis type 1 (NF1) and neurofibromatosis type 2 (NF2) as they relate to the development of novel therapies for these disorders.The development of increasingly sophisticated preclinical models over the recent years has provided the platform from which to rationally develop molecular targeted therapies for both NF1 and NF2-related tumors, such as within the Department of Defense-sponsored Neurofibromatosis Clinical Trials Consortium.Clinical trials with molecular-targeted therapies have become a reality for neurofibromatosis patients, and hold substantial promise for improving the morbidity and mortality of individuals affected with these disorders.
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Project description:Thymic epithelial tumors (TETs), including thymomas and thymic carcinomas, are rare malignancies arising from the thymus gland. The optimal management requires a multidisciplinary approach. Standard first-line systemic treatment involves cytotoxic chemotherapeutic regimens; however, alternative options for systemic treatment are required. Current research focuses on the unique profile of immune-related pathogenic mechanisms of TETs, involving an overlap with certain autoimmune phenotypes, as well as on determining the landscape of oncogenic molecular alterations and the role of tumor angiogenesis. The aim of the present review is to summarize the current clinical investigation on immunotherapy and targeted agents in the management of TETs. Regarding immune checkpoint inhibitors, efficacy results are promising in certain subsets of patients; however, caution is required concerning their toxicity. Anti-angiogenic agents, mainly potent small-molecule inhibitors, have demonstrated antitumor activity in TETs, whereas other targeted agents, including KIT inhibitors and epigenetic agents, are associated with encouraging, yet still modest results for unselected populations, in the absence of predictive biomarkers. Future research should focus on identifying predictive biomarkers for patients with TETs, and should implement multicenter collaborations and appropriate clinical trials tailored for rare tumor types.
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Project description:Anaplastic thyroid cancer represents 1%-2% of thyroid cancers. For its aggressiveness, it is considered a systemic disease at the time of diagnosis. Surgery remains the cornerstone of therapy in resectable tumor. Traditional chemotherapy has little effect on metastatic disease. A multimodality approach, incorporating cytoreductive surgical resection, chemoradiation, either concurrently or sequentially, and new promising target therapies is advisable. Doxorubicin is the most commonly used agent, with a response rate of 22%. Recently, other chemotherapy agents have been used, such as paclitaxel and gemcitabine, with superimposable activity and response rates of 10%-20%. However, survival of patients with anaplastic thyroid cancer has changed little in the past 50 years, despite more aggressive systemic and radiotherapies. Several new agents are currently under investigation. Some of them, such as sorafenib, imatinib, and axitinib have been tested in small clinical trials, showing promising disease control rates ranging from 35%-75%. Referral of patients for participation in clinical trials is needed.
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