scholarly journals Neurofibromatosis: Molecular Pathogenesis and Natural Compounds as Potential Treatments

2021 ◽  
Vol 11 ◽  
Author(s):  
Anusha Amaravathi ◽  
Janet L. Oblinger ◽  
D. Bradley Welling ◽  
A. Douglas Kinghorn ◽  
Long-Sheng Chang

The neurofibromatosis syndromes, including NF1, NF2, and schwannomatosis, are tumor suppressor syndromes characterized by multiple nervous system tumors, particularly Schwann cell neoplasms. NF-related tumors are mainly treated by surgery, and some of them have been treated by but are refractory to conventional chemotherapy. Recent advances in molecular genetics and genomics alongside the development of multiple animal models have provided a better understanding of NF tumor biology and facilitated target identification and therapeutic evaluation. Many targeted therapies have been evaluated in preclinical models and patients with limited success. One major advance is the FDA approval of the MEK inhibitor selumetinib for the treatment of NF1-associated plexiform neurofibroma. Due to their anti-neoplastic, antioxidant, and anti-inflammatory properties, selected natural compounds could be useful as a primary therapy or as an adjuvant therapy prior to or following surgery and/or radiation for patients with tumor predisposition syndromes, as patients often take them as dietary supplements and for health enhancement purposes. Here we review the natural compounds that have been evaluated in NF models. Some have demonstrated potent anti-tumor effects and may become viable treatments in the future.

2009 ◽  
Vol 19 (Suppl 2) ◽  
pp. S55-S62 ◽  
Author(s):  
Michael A. Bookman

Introduction:Advanced-stage epithelial ovarian cancer is generally managed with cytoreductive surgery and chemotherapy consisting of carboplatin and paclitaxel. Although initially responsive, most tumors recur and demonstrate progressive chemotherapy resistance. During the last 20 years, many thousands of women have participated in international front-line phase 3 trials that have contributed to our understanding of ovarian cancer biology and helped to define optimal treatment strategies. Emerging data from these trials need to be interpreted within an evolving paradigm of cancer biology, disease management, and availability of clinical resources.Methods:Survey of recent phase 3 trials and emerging principles of ovarian tumor biology.Results:There is no evidence that adding a third cytotoxic agent improves clinical outcomes. However, weekly dose-dense scheduling of paclitaxel appears superior to standard dosing.Conclusion:Primary therapy with carboplatin and paclitaxel remains a well-tolerated standard regimen, including the option of weekly paclitaxel dosing. Data are awaited from completed trials incorporating bevacizumab. Emerging biological paradigms will contribute to individualized treatment options in the future.


2019 ◽  
Vol 50 (05) ◽  
pp. 300-303 ◽  
Author(s):  
Pia Vaassen ◽  
Nikola Dürr ◽  
Andreas Röhrig ◽  
Rainer Willing ◽  
Thorsten Rosenbaum

AbstractPlexiform neurofibromas are congenital peripheral nerve sheath tumors characteristic of neurofibromatosis type 1 (NF1)—a frequent neurocutaneous disorder caused by mutations of the NF1 tumor suppressor gene. Since plexiform neurofibromas are a major cause of the burden of disease and may also progress to malignancy, many efforts have been undertaken to find a cure for these tumors. However, neither surgery nor medication has so far produced a breakthrough therapeutic success. Recently, a clinical phase I study reported significant shrinkage of plexiform neurofibromas following treatment with the MEK inhibitor selumetinib. Here, we report an 11-year-old NF1 patient with a large plexiform neurofibroma of the neck that had led to a sharp-angled kinking of the cervical spine and subsequent myelopathy. Although surgical stabilization of the cervical vertebral column was urgently recommended, the vertebral column was inaccessible due to extensive tumor growth. In this situation, treatment with the MEK inhibitor trametinib was initiated which resulted in a 22% reduction in tumor volume after 6 months of therapy and finally enabled surgery. These data show that MEK inhibitors may not lead to complete disappearance of NF1-associated plexiform neurofibromas but can be an essential step in a multimodal therapeutic approach for these tumors. The course of our patient suggests that MEK inhibitors are likely to play a significant role in providing a cure for one of the most devastating manifestations of NF1.


Hematology ◽  
2007 ◽  
Vol 2007 (1) ◽  
pp. 398-404 ◽  
Author(s):  
Magda Melchert ◽  
Alan F. List

Abstract Strategies for the management of anemia in patients with myelodysplastic syndrome (MDS) have evolved following the U.S. Food and Drug Administration (FDA) approval of three new therapeutics from one of symptom amelioration with red blood cell (RBC) transfusions to one of active treatment. Most patients develop transfusion-dependent anemia over the course of their disease, however, and its adverse consequence on the natural history of disease has only recently been appreciated. Although severe anemia contributes to symptoms of fatigue and reduced quality of life, transfusion dependence increases the risk of organ complications from iron overload coupled with an increased risk of leukemia transformation. Among World Health Organization categories without elevation in bone marrow myeloblasts, an incremental rise in RBC transfusion burden is associated with a proportionate reduction in both overall survival and leukemia-free survival, implying that anemia severity is an important variable limiting the otherwise favorable natural history of patients with lower risk disease. Moreover, therapeutic strategies that successfully restore effective erythropoiesis, such as erythropoetic stimulating agents, immunomodulatory agents, immunosuppressive therapies, or hypomethylating agents, may favorably affect the natural history of this disease, creating perhaps a new urgency for the initiation of erythropoietic promoters that have durable clinical benefit. Selection of primary therapy for the management of anemia should consider four response determinants: age, RBC transfusion burden and duration, endogenous erythropoietin production, and karyotype.


2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 148-148
Author(s):  
Bryan Anthony Chan ◽  
Hao-Wen Sim ◽  
Akina Natori ◽  
Stephanie Moignard ◽  
Daniel Yokom ◽  
...  

148 Background: In gastric/GEJ cancer, 40% of patients (pts) are metastatic at diagnosis ( de novo stage IV) and up to 70% with locoregional disease recur (relapsed stage IV). We compared survival outcomes between de novo vs relapsed stage IV. Methods: A retrospective observational study of stage IV gastric/GEJ pts was conducted (2012-2015). Overall survival (OS) was from date of stage IV diagnosis. PFS1 defined the period from stage IV diagnosis to first progression. PFS2 was from first to second progression. For relapsed stage IV pts, disease-free interval (DFI) was the period from initial diagnosis to metastatic relapse. Cox proportional hazards models compared OS, PFS1 and PFS2 between de novo vs relapsed stage IV pts, stratified by DFI [ < 6, 6-12 and > 12 months (mo)] and controlled for baseline patient characteristics. Results: Of 198 pts, 62% were male and median age was 64 years (26-93), with 64% gastric and 36% GEJ adenocarcinomas. Primary therapy for locoregional pts included surgery (75%), perioperative chemotherapy (42%) and radiotherapy (42%). De novo and relapsed stage IV pts represented 68% and 32% of the cohort respectively. Median follow-up was 13 mo. Controlled for age, performance status and Charlson comorbidity index, there were no significant differences in OS (median OS 12.5 ( de novo) vs 12.2 mo (relapsed); HR 1.22, 95% CI 0.83-1.77, p = 0.31), PFS1 (6.8 vs 7.4 mo; HR 1.00, 95% CI 0.65-1.56, p = 0.98) or PFS2 (3.8 vs 3.0 mo; HR 1.03, 95% CI 0.44-2.41, p = 0.95). Median OS for relapsed stage IV patients were different by DFI groups (log-rank p = 0.02): 22.9 mo (for DFI > 12mo; n = 31), 11.2 mo (DFI 6-12; n = 19) and 7.5 mo (DFI < 6; n = 14). Additionally, OS was significantly better if the DFI was greater than 12 mo, compared with de novo stage IV (HR 0.50, 95% CI 0.28-0.88, p = 0.02). Conclusions: There was no observed difference in the natural history of de novo vs relapsed stage IV gastric/GEJ pts. DFI was strongly prognostic with median OS (from date of relapse) approaching 2 years for relapsed pts with DFI > 12 mo. In addition to implications for treatment strategy, tumor biology within subgroups should be examined to identify novel biomarkers and potential therapeutic targets.


2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Rakshamani Tripathi ◽  
Zulong Liu ◽  
Aditi Jain ◽  
Anastasia Lyon ◽  
Christina Meeks ◽  
...  

Abstract Metastatic melanoma remains an incurable disease for many patients due to the limited success of targeted and immunotherapies. BRAF and MEK inhibitors reduce metastatic burden for patients with melanomas harboring BRAF mutations; however, most eventually relapse due to acquired resistance. Here, we demonstrate that ABL1/2 kinase activities and/or expression are potentiated in cell lines and patient samples following resistance, and ABL1/2 drive BRAF and BRAF/MEK inhibitor resistance by inducing reactivation of MEK/ERK/MYC signaling. Silencing/inhibiting ABL1/2 blocks pathway reactivation, and resensitizes resistant cells to BRAF/MEK inhibitors, whereas expression of constitutively active ABL1/2 is sufficient to promote resistance. Significantly, nilotinib (2nd generation ABL1/2 inhibitor) reverses resistance, in vivo, causing prolonged regression of resistant tumors, and also, prevents BRAFi/MEKi resistance from developing in the first place. These data indicate that repurposing the FDA-approved leukemia drug, nilotinib, may be effective for prolonging survival for patients harboring BRAF-mutant melanomas.


2021 ◽  
Author(s):  
Eran Cohen‐Barak ◽  
Hagit Toledano Alhadief ◽  
Nada Danial‐Farran ◽  
Ido Livneh ◽  
Banan Mwassi ◽  
...  

2020 ◽  
Author(s):  
Karin S. Walsh ◽  
Pamela L. Wolters ◽  
Brigitte C. Widemann ◽  
Allison A. del Castillo ◽  
Maegan D. Sady ◽  
...  

AbstractObjectiveNF1-associated cognitive impairments carry significant life-long morbidity. The lack of targeted biologic treatments remains a significant unmet need. We examine changes in cognition in patients with NF1 in the first 48 weeks of MEK inhibitor (MEKi) treatment.Methods59 NF1 patients ages 5-27 on a MEKi clinical trial treating plexiform neurofibroma underwent pre-treatment and follow-up cognitive assessments over 48-weeks of treatment. Performance tasks (Cogstate) and observer-reported functioning (BRIEF) were primary outcomes. Group-level (paired t-tests) and individual-level analyses (reliable change index; RCI) were used.ResultsAnalysis showed statistically significant improvements on BRIEF compared to baseline (24-week BRI: t(58)=3.03, p=.004, d=0.24; 48-week MCI: t(39)=2.70, p=.01, d=0.27). RCI indicated more patients had clinically significant improvement at 48-weeks than expected by chance (Chi Square=11.95, p=.001, OR=6.3). Group-level analyses indicated stable performance on Cogstate (p>.05). RCI statistics showed high proportions of improved working memory (24-weeks Chi Square=8.36, p=.004, OR=4.6 and 48-weeks Chi Square=9.34, p=.004, OR=5.3) but not visual learning/memory. Patients with baseline impairments on BRIEF were more likely to show significant improvement than non-impaired patients (24-weeks 46% v. 8%; Chi Square=9.54, p=.008, OR=9.22; 48-weeks 63% v. 16%; Chi Square=7.50, p=.02, OR=9.0).InterpretationOur data shows no evidence of neurotoxicity in 48-weeks of treatment with a MEKi and a potential clinical signal supporting future research of MEKi as a cognitive intervention.


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