scholarly journals RARE-18. NF1-MUTATED TUMORS EXHIBIT INCREASED SENSITIVITY TO AUTOPHAGY INHIBITION ALONE AND IN COMBINATION WITH MEK INHIBITION

2021 ◽  
Vol 23 (Supplement_1) ◽  
pp. i44-i44
Author(s):  
Eliza Baird-Daniel ◽  
Shadi Zahedi ◽  
Andrew Morin ◽  
Michelle Desmarais ◽  
Kyle Williams ◽  
...  
Keyword(s):  
Mapk Pathway ◽  
Clinical Investigation ◽  
Cns Tumors ◽  
Adjunctive Treatment ◽  
Cns Tumor ◽  
Mek Inhibition ◽  
Increased Sensitivity ◽  
Tumor Types ◽  
Autophagy Inhibition ◽  
Pathway Dysregulation

Abstract Background Autophagy inhibition is a potential treatment for central nervous system (CNS) tumors. Autophagy, a heavily regulated process by which cellular waste is transferred to lysosomes for degradation and processing, is an integral part of tumor cell survival under stressful conditions including nutrient deprivation and chemotherapy. While the efficacy of autophagy inhibition has been demonstrated in CNS tumors with BRAFV600e mutations, it has yet to be explored in other CNS tumor types with MAPK pathway dysregulation including NF1-mutated tumors. Many tumors associated with the NF1 phenotype can be difficult to treat surgically thus development of further pharmacologic interventions is necessary. Methods A CRISPR/Cas9 mediated NF1 KO was derived from human immortalized Schwann cells and utilized as a tumor model. Autophagy inhibition was achieved pharmacologically by chloroquine (CQ) and genetically via shRNAi of ATG5 and ATG7. Trametinib was used for MEK inhibition. Cell growth and viability were determined by Incucyte, Cell Titer-Glo luminescent assay, and colony-formation assays. Protein expression was measured by western blot. Results We demonstrate increased autophagic activity in NF1 KO cell as compared to control lines both at baseline and in response to cellular stress. Furthermore, we describe that NF1 KO cells exhibit increased sensitivity to CQ alone, CQ in combination with trametinib, and shRNAi-mediated autophagy inhibition in combination with trametinib. Conclusion Here, we describe increased autophagic dependence of NF1 mutated tumors and demonstrate increased tumor sensitivity to autophagy inhibition both alone and in combination with MEK inhibition. These findings indicate that autophagy inhibition via CQ may be an effective adjunctive treatment for NF1 mutated tumors and suggests that diverse CNS tumor types with MAPK pathway dysregulation are susceptible to autophagy inhibition. Clinical investigation of combined MEK and autophagy inhibition has the potential to improve outcomes for NF1 patients with CNS tumors.

scholarly journals Co-Deregulated miRNA Signatures in Childhood Central Nervous System Tumors: In Search for Common Tumor miRNA-Related Mechanics

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 3028
Author(s):  
George I. Lambrou ◽  
Apostolos Zaravinos ◽  
Maria Braoudaki
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Cns Tumors ◽  
Normal Brain ◽  
Cns Tumor ◽  
Different Types ◽  
Receiver Operator Curve Analysis ◽  
The Central Nervous System ◽  
Tumor Types ◽  
Operator Curve

Despite extensive experimentation on pediatric tumors of the central nervous system (CNS), related to both prognosis, diagnosis and treatment, the understanding of pathogenesis and etiology of the disease remains scarce. MicroRNAs are known to be involved in CNS tumor oncogenesis. We hypothesized that CNS tumors possess commonly deregulated miRNAs across different CNS tumor types. Aim: The current study aims to reveal the co-deregulated miRNAs across different types of pediatric CNS tumors. Materials: A total of 439 CNS tumor samples were collected from both in-house microarray experiments as well as data available in public databases. Diagnoses included medulloblastoma, astrocytoma, ependydoma, cortical dysplasia, glioblastoma, ATRT, germinoma, teratoma, yoc sac tumors, ocular tumors and retinoblastoma. Results: We found miRNAs that were globally up- or down-regulated in the majority of the CNS tumor samples. MiR-376B and miR-372 were co-upregulated, whereas miR-149, miR-214, miR-574, miR-595 and miR-765 among others, were co-downregulated across all CNS tumors. Receiver-operator curve analysis showed that miR-149, miR-214, miR-574, miR-595 and miR765 could distinguish between CNS tumors and normal brain tissue. Conclusions: Our approach could prove significant in the search for global miRNA targets for tumor diagnosis and therapy. To the best of our knowledge, there are no previous reports concerning the present approach.

scholarly journals MEK inhibition causes Bim stabilization and sensitivity to Bcl2 family member inhibitors in RAS-MAPK mutated neuroblastoma

2020 ◽  
Author(s):  
Thomas F Eleveld ◽  
Lindy Vernooij ◽  
Linda Schild ◽  
Bianca Koopmans ◽  
Lindy K Alles ◽  
...  
Keyword(s):  
Family Member ◽  
Tumor Regression ◽  
Mapk Pathway ◽  
Neuroblastoma Cells ◽  
Mek Inhibition ◽  
Bcl2 Family ◽  
Increased Sensitivity ◽  
Bcl2 Family Member

AbstractMutations affecting the RAS-MAPK pathway occur frequently in relapsed neuroblastoma tumors and are associated with response to MEK inhibition in vitro. However, these inhibitors alone do not lead to tumor regression in vivo, indicating the need for combination therapy. Through high throughput combination screening we identify Trametinib and inhibitors of the BCL2 family (Navitoclax and Venetoclax) as a promising combination in neuroblastoma cells with RAS-MAPK mutations. In these lines, inhibiting the RAS-MAPK pathway leads to Bim stabilization and increased sensitivity to compounds inhibiting Bim binding to Bcl2 family members. Combining Trametinib with BCL2 inhibitors causes increased growth inhibition compared to Trametinib only in NRAS mutant SKNAS xenografts, while BCL2 inihibitors alone do not affect growth of these tumors. These results show that MEK inhibitors and specific Bcl2 family member inhibitors are a potent combination for RAS-MAPK mutated neuroblastoma tumors.

scholarly journals PATH-11. PROSPECTIVE (EPI-)GENETIC CLASSIFICATION OF > 1,000 PEDIATRIC CNS TUMORS—THE MNP 2.0 STUDY

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii426-iii426
Author(s):  
Dominik Sturm ◽  
Felix Sahm ◽  
Felipe Andreiuolo ◽  
David Capper ◽  
Marco Gessi ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Gene Panel ◽  
Cns Tumors ◽  
Lower Grade ◽  
High Grade ◽  
Sequencing Data ◽  
Cns Tumor ◽  
Gene Panel Sequencing ◽  
Tumor Entities ◽  
Panel Sequencing

Abstract The large variety of CNS tumor entities affecting children and adolescents, some of which are exceedingly rare, results in very diverging patient outcomes and renders accurate diagnosis challenging. To assess the diagnostic utility of routine DNA methylation-based CNS tumor classification and gene panel sequencing, the Molecular Neuropathology 2.0 study prospectively integrated these (epi-)genetic analyses with reference neuropathological diagnostics as an international trial for newly-diagnosed pediatric patients. In a four-year period, 1,215 patients with sufficient tissue were enrolled from 65 centers, receiving a reference neuropathological diagnosis according to the WHO classification in >97%. Using 10 FFPE sections as input, DNA methylation analysis was successfully performed in 95% of cases, of which 78% with sufficient tumor cell content were assigned to a distinct epigenetic tumor class. The remaining 22% did not match any of 82 represented classes, indicating novel rare tumor entities. Targeted gene panel sequencing of >130 genes performed for 96% of patients with matched blood samples detected diagnostically, prognostically, or therapeutically relevant somatic alterations in 48%. Germline DNA sequencing data indicated potential predisposition syndromes in ~10% of patients. Discrepant results by neuropathological and epigenetic classification (29%) were enriched in histological high-grade gliomas and implicated clinical relevance in 5% of all cases. Clinical follow-up suggests improved survival for some patients with high-grade glioma histology and lower-grade molecular profiles. Routine (epi-)genetic profiling at the time of primary diagnosis adds a valuable layer of information to neuropathological diagnostics and will improve clinical management of CNS tumors.

scholarly journals Long-term medical imaging use in children with central nervous system tumors

PLoS ONE ◽  
2021 ◽  
Vol 16 (4) ◽  
pp. e0248643
Author(s):  
Erin J. A. Bowles ◽  
Diana L. Miglioretti ◽  
Marilyn L. Kwan ◽  
Ute Bartels ◽  
Adam Furst ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Medical Imaging ◽  
Tumor Grade ◽  
Tumor Diagnosis ◽  
Cns Tumors ◽  
Cns Tumor ◽  
Longitudinal Imaging ◽  
The U.S

Background Children with central nervous system (CNS) tumors undergo frequent imaging for diagnosis and follow-up, but few studies have characterized longitudinal imaging patterns. We described medical imaging in children before and after malignant CNS tumor diagnosis. Procedure We conducted a retrospective cohort study of children aged 0–20 years diagnosed with CNS tumors between 1996–2016 at six U.S. integrated healthcare systems and Ontario, Canada. We collected computed topography (CT), magnetic resonance imaging (MRI), radiography, ultrasound, nuclear medicine examinations from 12 months before through 10 years after CNS diagnosis censoring six months before death or a subsequent cancer diagnosis, disenrollment from the health system, age 21 years, or December 31, 2016. We calculated imaging rates per child per month stratified by modality, country, diagnosis age, calendar year, time since diagnosis, and tumor grade. Results We observed 1,879 children with median four years follow-up post-diagnosis in the U.S. and seven years in Ontario, Canada. During the diagnosis period (±15 days of diagnosis), children averaged 1.10 CTs (95% confidence interval [CI] 1.09–1.13) and 2.14 MRIs (95%CI 2.12–2.16) in the U.S., and 1.67 CTs (95%CI 1.65–1.68) and 1.86 MRIs (95%CI 1.85–1.88) in Ontario. Within one year after diagnosis, 19% of children had ≥5 CTs and 45% had ≥5 MRIs. By nine years after diagnosis, children averaged one MRI and one radiograph per year with little use of other imaging modalities. Conclusions MRI and CT are commonly used for CNS tumor diagnosis, whereas MRI is the primary modality used during surveillance of children with CNS tumors.

scholarly journals Combined BRAF and MEK Inhibition with Vemurafenib and Cobimetinib for Patients with Advanced Melanoma

2017 ◽  
Vol 13 (01) ◽  
pp. 1
Author(s):  
Antonio M Grimaldi ◽  
Ester Simeone ◽  
Lucia Festino ◽  
Vito Vanella ◽  
Paolo A Ascierto ◽  
...  
Keyword(s):  
Mapk Pathway ◽  
Combined Therapy ◽  
Acquired Resistance ◽  
Braf Inhibitor ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Phase Iii ◽  
Free Survival ◽  
Mek Inhibition ◽  
Braf Mutant

Acquired resistance is the most common cause of BRAF inhibitor monotherapy treatment failure, with the majority of patients experiencing disease progression with a median progression-free survival of 6-8 months. As such, there has been considerable focus on combined therapy with dual BRAF and MEK inhibition as a means to improve outcomes compared with monotherapy. In the COMBI-d and COMBI-v trials, combined dabrafenib and trametinib was associated with significant improvements in outcomes compared with dabrafenib or vemurafenib monotherapy, in patients with BRAF-mutant metastatic melanoma. The combination of vemurafenib and cobimetinib has also been investigated. In the phase III CoBRIM study in patients with unresectable stage III-IV BRAF-mutant melanoma, treatment with vemurafenib and cobimetinib resulted in significantly longer progression-free survival and overall survival (OS) compared with vemurafenib alone. One-year OS was 74.5% in the vemurafenib and cobimetinib group and 63.8% in the vemurafenib group, while 2-year OS rates were 48.3% and 38.0%, respectively. The combination was also well tolerated, with a lower incidence of cutaneous squamous-cell carcinoma and keratoacanthoma compared with monotherapy. Dual inhibition of both MEK and BRAF appears to provide a more potent and durable anti-tumour effect than BRAF monotherapy, helping to prevent acquired resistance as well as decreasing adverse events related to BRAF inhibitor-induced activation of the MAPK-pathway. Combined BRAF and MEK inhibition is the standard of care in patients with advanced BRAF-mutant melanoma.

scholarly journals Therapeutic Targeting of Autophagy in Pancreatic Ductal Adenocarcinoma

2021 ◽  
Vol 12 ◽  
Author(s):  
Alexander G. Raufi ◽  
Nicholas R. Liguori ◽  
Lindsey Carlsen ◽  
Cassandra Parker ◽  
Liz Hernandez Borrero ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Alternative Energy ◽  
Mapk Pathway ◽  
Ductal Adenocarcinoma ◽  
Therapeutic Targeting ◽  
Aggressive Disease ◽  
Alternative Energy Sources ◽  
Novel Treatment ◽  
Late Detection ◽  
Autophagy Inhibition

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease characterized by early metastasis, late detection, and poor prognosis. Progress towards effective therapy has been slow despite significant efforts. Novel treatment approaches are desperately needed and autophagy, an evolutionary conserved process through which proteins and organelles are recycled for use as alternative energy sources, may represent one such target. Although incompletely understood, there is growing evidence suggesting that autophagy may play a role in PDAC carcinogenesis, metastasis, and survival. Early clinical trials involving autophagy inhibiting agents, either alone or in combination with chemotherapy, have been disappointing. Recently, evidence has demonstrated synergy between the MAPK pathway and autophagy inhibitors in PDAC, suggesting a promising therapeutic intervention. In addition, novel agents, such as ONC212, have preclinical activity in pancreatic cancer, in part through autophagy inhibition. We discuss autophagy in PDAC tumorigenesis, metabolism, modulation of the immune response, and preclinical and clinical data with selected autophagy modulators as therapeutics.

scholarly journals Effect of early-stage autophagy inhibition in BRAFV600E autophagy-dependent brain tumor cells

2019 ◽  
Vol 10 (9) ◽  
Author(s):  
Shadi Zahedi ◽  
Brent E. Fitzwalter ◽  
Andrew Morin ◽  
Sydney Grob ◽  
Michele Desmarais ◽  
...  
Keyword(s):  
Cell Survival ◽  
Tumor Cells ◽  
Late Stage ◽  
Early Stage ◽  
Specific Effect ◽  
Cns Tumors ◽  
Autophagic Flux ◽  
Dependent Manner ◽  
Tumor Cell Death ◽  
Autophagy Inhibition

Abstract Autophagy is a multistage process. Progress within the field has led to the development of agents targeting both early (initiation) and late (fusion) stages of this process. The specific stage of autophagy targeted may influence cancer treatment outcomes. We have previously shown that central nervous system (CNS) tumors with the BRAFV600E mutation are autophagy dependent, and late-stage autophagy inhibition improves the response to targeted BRAF inhibitors (BRAFi) in sensitive and resistant cells. Drugs directed toward initiation of autophagy have been shown to reduce tumor cell death in some cancers, but have not been assessed in CNS tumors. We investigated early-stage inhibition for autophagy-dependent CNS tumors. BRAFi-sensitive and resistant AM38 and MAF794 cell lines were evaluated for the response to pharmacologic and genetic inhibition of ULK1 and VPS34, two crucial subunits of the autophagy initiation complexes. Changes in autophagy were monitored by western blot and flow cytometry. Survival was evaluated in short- and long-term growth assays. Tumor cells exhibited a reduced autophagic flux with pharmacologic and genetic inhibition of ULK1 or VPS34. Pharmacologic inhibition reduced cell survival in a dose-dependent manner for both targets. Genetic inhibition reduced cell survival and confirmed that it was an autophagy-specific effect. Pharmacologic and genetic inhibition were also synergistic with BRAFi, irrespective of RAFi sensitivity. Inhibition of ULK1 and VPS34 are potentially viable clinical targets in autophagy-dependent CNS tumors. Further evaluation is needed to determine if early-stage autophagy inhibition is equal to late-stage inhibition to determine the optimal clinical target for patients.

scholarly journals Double PIK3CA mutations in cis increase oncogenicity and sensitivity to PI3Kα inhibitors

Science ◽  
2019 ◽  
Vol 366 (6466) ◽  
pp. 714-723 ◽  
Author(s):  
Neil Vasan ◽  
Pedram Razavi ◽  
Jared L. Johnson ◽  
Hong Shao ◽  
Hardik Shah ◽  
...  
Keyword(s):  
Membrane Lipid ◽  
Lipid Binding ◽  
Breast Cancers ◽  
Pik3ca Mutations ◽  
Downstream Signaling ◽  
Activating Mutations ◽  
Increased Sensitivity ◽  
Phosphoinositide 3 Kinase ◽  
Tumor Types ◽  
In Cis

Activating mutations in PIK3CA are frequent in human breast cancer, and phosphoinositide 3-kinase alpha (PI3Kα) inhibitors have been approved for therapy. To characterize determinants of sensitivity to these agents, we analyzed PIK3CA-mutant cancer genomes and observed the presence of multiple PIK3CA mutations in 12 to 15% of breast cancers and other tumor types, most of which (95%) are double mutations. Double PIK3CA mutations are in cis on the same allele and result in increased PI3K activity, enhanced downstream signaling, increased cell proliferation, and tumor growth. The biochemical mechanisms of dual mutations include increased disruption of p110α binding to the inhibitory subunit p85α, which relieves its catalytic inhibition, and increased p110α membrane lipid binding. Double PIK3CA mutations predict increased sensitivity to PI3Kα inhibitors compared with single-hotspot mutations.

Impact of metformin on outcomes in patients (pts) with metastatic renal cell carcinoma (mRCC): Results from a pooled clinical trials database.

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 531-531
Author(s):  
Lana Hamieh ◽  
Rana R. McKay ◽  
Suzanne S Mickey ◽  
Xun Lin ◽  
Ronit Simantov ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Cox Regression ◽  
Mapk Pathway ◽  
Risk Groups ◽  
Diabetic Patients ◽  
First Line Therapy ◽  
Kaplan Meier ◽  
Tumor Types ◽  
Phase Ii And Iii

531 Background: Metformin has been shown to confer anti-neoplastic properties in several tumor types. Its effect on outcomes in mRCC patients has not been completely characterized. In this study, we evaluated the role of metformin on survival outcomes in pts with mRCC. Methods: We conducted a retrospective study of pts with mRCC treated on several phase II and III clinical trials from 2003-2013. We analyzed overall survival (OS) in the metformin users versus non-users using the Cox regression model and the Kaplan-Meier method. Results: We identified 4,736 pts with mRCC including 486 diabetic pts of whom 218 (4.6%) were metformin users. The majority were <65 years of age (69%), male (71%), with clear-cell histology (89%) and prior nephrectomy (70%). With regard to IMDC risk groups, 14%, 42%, and 24% had favorable, intermediate, and poor-risk disease, respectively. Pts received treatment with sunitinib (n=1,059), sorafenib (n=772), axitinib (n=896), temsirolimus (TEM) (n=457), TEM + interferon (IFN)-α (n=208), bevacizumab (BEV) + TEM (n=393), BEV + IFN-α (n=391), or IFN-α (n=560); overall 3,044 (64%) received first-line therapy. In the total cohort, metformin use did not impact OS when compared to users of other anti-diabetic agents (p=0.17) or non-diabetics (p=0.69). In diabetic pts, metformin use did not confer a survival advantage when stratified by type of therapy and IMDC risk group. However, in the cohort of diabetic pts receiving sunitinib (n=128), metformin use was associated with an improvement in OS when compared to users of non-metformin anti-diabetic agents (29.3 versus 20.9 months, respectively, p=0.0008, HR 0.051, 95% CI 0.009, 0.292). Conclusions: This is the largest study to date investigating the role of metformin on outcomes in mRCC pts. In this analysis, we demonstrate that concomitant use of metformin may improve survival in diabetic pts with mRCC treated with sunitinib. Based on preclinical data, we hypothesize that the mechanism underlying this survival benefit may be related to synergistic inhibition of the MAPK pathway. However, the study is limited by the small number of diabetic patients. Larger prospective studies are warranted to validate these results.

Effect of bypass kinase pathways on acquired CDK4/6 inhibitor resistance.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 379-379
Author(s):  
Renee De Leeuw ◽  
Christopher McNair ◽  
Matthew Joseph Schiewer ◽  
Neermala Poudel Neupane ◽  
Michael Augello ◽  
...  
Keyword(s):  
Mapk Pathway ◽  
Early Stage ◽  
Mapk Signaling ◽  
Cross Resistance ◽  
Mek Inhibitors ◽  
Mesenchymal Transition ◽  
Inhibitor Resistance ◽  
Tumor Types

379 Background: Cyclin Dependent Kinase-4/6 (CDK4/6) kinase inhibitors have shown clinical benefit in treatment of solid tumor types, including breast cancer. However, resistance is common, and the underpinning mechanisms of action are not well understood. Given the dependence of CDK4/6 inhibitors on retinoblastoma tumor suppressor (RB) function for activity, this class of agents may be particularly effective in tumor types for which RB loss is infrequent or occurs late in tumor progression. Methods: Here, models of acquired palbociclib resistance were generated in early stage, RB positive cancers, wherein it was shown acquired palbociclib resistance resulted in cross-resistance to other CDK4/6 inhibitors under clinical testing. Results: Cells showing acquired resistance exhibited aggressive in vitro and in vivo phenotypes without genetic loss of RB or RB pathway members, including enhanced proliferative capacity, migratory potential, and characteristics of epithelial to mesenchymal transition. Further analyses through integration of RNA sequencing and phospho-proteomics identified activation of the MAPK signaling pathway as a mediator of CDK4/6 inhibitor resistance, capable of bypassing CDK4/6 activity. However, this altered kinase dependence resulted in sensitization to MEK inhibitors, suggestive of new clinical opportunities in CDK4/6 resistant tumors. Conclusions: In sum, the studies herein not only identify activation of the MAPK pathway as capable of bypassing the CDK4/6 requirement and promoting aggressive tumor characteristics, but nominate MEK inhibitors as potential mechanisms to treat or prevent CDK4/6 inhibitor resistance.

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