scholarly journals Mechanisms of imipridones in targeting mitochondrial metabolism in cancer cells

2020 ◽  
Author(s):  
Erin R Bonner ◽  
Sebastian M Waszak ◽  
Michael A Grotzer ◽  
Sabine Mueller ◽  
Javad Nazarian
Keyword(s):  
Drug Targets ◽  
Molecular Mechanisms ◽  
Human Cancer ◽  
Meta Analysis ◽  
Single Agent ◽  
Predictive Biomarkers ◽  
Predictive Biomarker ◽  
Mitochondrial Metabolism ◽  
Response To Treatment ◽  
Human Cancer Cell Lines

Abstract ONC201 is the first member of the imipridone family of anticancer drugs to enter the clinic for the treatment of diverse solid and hematologic cancers. A subset of pediatric and adult patients with highly aggressive brain tumors has shown remarkable clinical responses to ONC201, and recently, the more potent derivative ONC206 entered clinical trials as a single agent for the treatment of CNS cancers. Despite the emerging clinical interest in the utility of imipridones, their exact molecular mechanisms are not fully described. In fact, the existing literature points to multiple pathways (e.g. TRAIL signaling, dopamine receptor antagonism, and mitochondrial metabolism) as putative drug targets. We have performed a comprehensive literature review and highlighted mitochondrial metabolism as the major target of imipridones. In support of this, we performed a meta-analysis of an ONC201 screen across 539 human cancer cell lines and showed that the mitochondrial protease ClpP is the most significant predictive biomarker of response to treatment. Herein, we summarize the main findings on the anticancer mechanisms of this potent class of drugs, provide clarity on their role, and identify clinically relevant predictive biomarkers of response.

scholarly journals CTNI-17. CLINICAL EFFICACY AND PREDICTIVE BIOMARKERS OF ONC201 IN H3 K27M-MUTANT DIFFUSE MIDLINE GLIOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii45-ii46
Author(s):  
Abed Rahman Kawakibi ◽  
Rohinton S Tarapore ◽  
Sharon Gardner ◽  
Chase Thomas ◽  
Rodrigo Cartaxo ◽  
...  
Keyword(s):  
Cell Lines ◽  
Human Cancer ◽  
Resistance Mechanism ◽  
Predictive Biomarkers ◽  
Predictive Biomarker ◽  
Clinical Analysis ◽  
Mechanism Analysis ◽  
Human Cancer Cell Lines ◽  
Best Response ◽  
Diffuse Midline Glioma

Abstract Patients with diffuse midline glioma (DMG) harboring H3 K27M mutation rarely survive longer than two years and have no proven therapies following first-line radiation. ONC201, a bitopic DRD2 antagonist and allosteric ClpP agonist, has shown encouraging efficacy in early phase studies in H3 K27M-mutant DMG. In order to define response rates in H3 K27M DMG patients and to clarify the genomic, anatomic and molecular predictors of response, we performed an integrated pre-clinical and clinical analysis of ONC201 treatment. ONC201 was effective in intra-uterine electroporation (IUE)-generated H3 K27M-mutant murine glioma models with excellent CNS penetration and survival benefit. Patients with H3 K27M-mutant DMG treated with ONC201 on active clinical trials (n=50, 27 thalamic, 23 brainstem) showed an overall survival (OS) of 28.1 (range: 5.9–105) months from diagnosis (enrollment by 4/29/19, data cut-off 12/28/19), compared to historical median OS of 12 months. Median OS for non-recurrent patients has not been reached (n=16, median follow-up: 16.8 from diagnosis). For non-recurrent thalamic patients (n=8), median PFS is 20.1 (range: 9.3–27.6) months from diagnosis (median time on drug: 14.5 months). Best response for thalamic patients by RANO: 1 CR, 5 PR, 7 SD, 8 PD, 6 not reported. Decreased H3 K27M cell-free tumor DNA in plasma and CSF at 6 months correlated with long-term response. Baseline tumor gene expression profiling in patients treated with ONC201 (n=14) identified EGFR and the cortical developmental transcription factor FOXG1 as the strongest biomarkers of radiographic response to ONC201. Analysis of 541 ONC201-treated human cancer cell lines from DepMap, provided evidence for an EGFR-dependent ONC201 resistance mechanism. Analysis of 38 glioma cell lines further supports FOXG1 as a glioma-specific predictive biomarker of ONC201 response. The unprecedented survival results and radiographic responses to ONC201 in H3K27M DMG make a compelling case for later phase and combinatorial studies.

Updated meta-analysis (MA) of salvage therapy for metastatic urothelial cancer (mUC): Comparing outcomes of immunotherapy (IT) versus single agent and doublet chemotherapy (CT).

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 341-341 ◽  
Author(s):  
Andrea Necchi ◽  
Daniele Raggi ◽  
Guru Sonpavde ◽  
Patrizia Giannatempo ◽  
Luigi Mariani ◽  
...  
Keyword(s):  
Salvage Therapy ◽  
Meta Analysis ◽  
Single Agent ◽  
Predictive Biomarkers ◽  
Progression Free Survival ◽  
Random Effects Models ◽  
Level Data ◽  
Metastatic Urothelial Cancer ◽  
Programmed Cell Death 1 ◽  
Ecog Ps

341 Background: Doublet CT demonstrated improved overall response rate (ORR) and progression-free survival (PFS) compared to single agent CT in a MA of patients (pts) receiving II line CT in trials of mUC ( Raggi et al, Ann Oncol 2016). We aimed to update the analyses adding trials of salvage IT. Methods: We searched for arms of phase 2 or 3 studies of salvage single agent anti-programmed cell death-1/Ligand-1 (PD-1/PD-L1) agents pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab, single agent CT and doublet CT. Random-effects models were used to pool trial level data according to treatment arm, including ORR, median PFS (mPFS), median overall survival (mOS). Univariable (UVA) and multivariable (MVA) analyses were performed, adjusting for ECOG-PS 2 and liver metastases. Results: 7 IT trials were analyzed (n=1,041), 22 arms received single agent CT (n=1,202), and 24 doublet CT (n=708). The pooled ORR was: 21.2% (95%CI: 14.9-29.2) with IT, 14.2% (95%CI: 11.1-17.9) with single agent CT and 31.9% (95%CI: 27.3-36.9) with doublet CT. Pooled mPFS was 1.8, 2.69 and 4.05 months, respectively. Pooled mOS was 8.27, 6.98 and 8.50 months. Pooled median ORR and mOS of IT for PD-L1+ pts were: 30.7% (95%CI: 23.2-39.2) and 11.60 months. Results of UVA and MVA are shown in the table. Only UVA was possible for PD-L1+ pts. Conclusions: Among trials of salvage therapy for mUC, IT was associated with significantly higher ORR and mOS in PD-L1+ pts compared with single agent or doublet CT, while significant differences were not seen in unselected pts. These results are hypothesis-generating and suggest the importance of developing companion predictive biomarkers. [Table: see text]

scholarly journals A pathogen-responsive gene cluster for the production of highly modified fatty acids in tomato

2018 ◽  
Author(s):  
Ju Eun Jeon ◽  
Jung-Gun Kim ◽  
Curt R. Fischer ◽  
Cosima Dufour-Schroif ◽  
Kimberly Wemmer ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Gene Cluster ◽  
Human Cancer ◽  
Lipid Production ◽  
Biosynthetic Gene Cluster ◽  
Response To Treatment ◽  
Direct Role ◽  
Human Cancer Cell Lines ◽  
Chemical Complexity ◽  
Modified Fatty Acids

AbstractIn response to biotic stress, plants reshape their complement of lipids to produce suites of highly modified fatty acids that bear unusual chemical functionality. Despite their chemical complexity, proposed roles in pathogen defense and presence in crop plants, little is known about the biosynthesis of these decorated fatty acids. Falcarindiol is a prototypical member of a suite of acetylenic lipids from carrot, tomato, and celery that inhibits growth of several fungal strains and human cancer cell lines. Here we report a set of clustered genes in tomato (Solanum lycopersicum) that are required for the production of falcarindiol in leaves in response to treatment with an adapted fungal pathogen, Cladosporium fulvum. Our approach is based on correlation of untargeted transcriptomic and metabolomic data sets in order to rapidly identify a candidate biosynthetic pathway. By reconstituting the initial biosynthetic steps in a heterologous host (Nicotiana benthamiana) and generating stable transgenic pathway mutants in tomato, we demonstrate a direct role for three genes in the cluster in falcarindiol biosynthesis. This work reveals a mechanism by which plants sculpt their lipid pool in response to pathogens, and provides critical insight into the biochemistry of alkynyl lipid production.One Sentence SummaryA biosynthetic gene cluster for the production of falcarindiol, a highly modified antifungal oxylipin found in edible plants.

scholarly journals Bimodality of gene expression in cancer patient tumors as interpretable biomarkers for drug sensitivity

2020 ◽  
Author(s):  
Wail Ba-Alawi ◽  
Sisira Kadambat Nair ◽  
Bo Li ◽  
Anthony Mammoliti ◽  
Petr Smirnov ◽  
...  
Keyword(s):  
Machine Learning ◽  
Large Scale ◽  
Human Cancer ◽  
Predictive Biomarkers ◽  
Precision Oncology ◽  
Human Cancer Cell Lines ◽  
Validation Rate ◽  
Approved Drugs ◽  
Pharmacogenomic Studies

ABSTRACTIdentifying biomarkers predictive of cancer cells’ response to drug treatment constitutes one of the main challenges in precision oncology. Recent large-scale cancer pharmacogenomic studies have boosted the research for finding predictive biomarkers by profiling thousands of human cancer cell lines at the molecular level and screening them with hundreds of approved drugs and experimental chemical compounds. Many studies have leveraged these data to build predictive models of response using various statistical and machine learning methods. However, a common challenge in these methods is the lack of interpretability as to how they make the predictions and which features were the most associated with response, hindering the clinical translation of these models. To alleviate this issue, we develop a new machine learning pipeline based on the recent LOBICO approach that explores the space of bimodally expressed genes in multiple large in vitro pharmacogenomic studies and builds multivariate, nonlinear, yet interpretable logic-based models predictive of drug response. Using our method, we used a compendium of three of the largest pharmacogenomic data sets to build robust and interpretable models for 101 drugs that span 17 drug classes with high validation rate in independent datasets.

De-adoption of epidermal growth factor receptor (EGFR) inhibitors following recommendations for KRAS testing to guide treatment of metastatic colorectal cancer (mCRC).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e14021-e14021
Author(s):  
Efrat Dotan ◽  
Tianyu Li ◽  
Michael J. Hall ◽  
Neal J. Meropol ◽  
Robert J Beck ◽  
...  
Keyword(s):  
Single Agent ◽  
Growth Factor Receptor ◽  
Predictive Biomarkers ◽  
Clinical Trial Data ◽  
Predictive Biomarker ◽  
Chemotherapy Agent ◽  
Line Therapy ◽  
Epidermal Growth ◽  
Oncology Practice ◽  
Egfr Antibody

e14021 Background: KRAS mutation status is a predictive biomarker for resistance to EGFR antibodies among mCRC pts, and is recommended for use by ASCO and the FDA. Little is known about the uptake of clinical recommendations in oncology practice. We sought to study the effect of ASCO and FDA guidelines on the use of EGFR antibodies among a commercially insured population. Methods: The LifeLink Health Plan Claims Database (formerly the PharMetrics Patient-Centric Database) was used to create a cohort of >18 yo mCRC pts treated between 2004-2010. We identified treatment and diagnosis using ICD-9 or HCPCS (J) codes. We defined 1st line therapy as any chemotherapy +/- bevacizumab given after the pt had a claim for mCRC, excluding pts treated with EGFR antibodies in the 1st line. 2nd line therapy was defined as the initiation of a new chemotherapy agent (irinotecan/oxaliplatin) +/- EGFR antibody. We examined pts in two-month time intervals and calculated the fraction of pts in each interval who received EGFR antibody at any point beyond their 1st line treatment. Chi2 tests were used to compare treatment rates at the time points shown in the Table. Results: 5099 pts received 2nd line therapy of which 2603 pts received an EGFR antibody. Median age was 61 years, with 57% males. 59% received an EGFR antibody as a single agent. The remainder received this in combination with one or more of the following agents: fluorouracil 13.5%, irinotecan 36.7%, oxaliplatin 3.9%, and bevacizumab 6.1%. Rates of EGFR antibody use are outlined in the Table. Conclusions: The utilization of EGFR antibodies for mCRC treatment decreased following the presentation of clinical trial data, publication of ASCO guidelines and FDA label change. These data suggest that oncologists respond rapidly to new evidence and professional guidelines, and readily accept the use of predictive biomarkers in clinical practice. [Table: see text]

Strategies To Identify Effective Treatments For Proteasome Inhibitor Resistant Multiple Myeloma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 278-278
Author(s):  
Brian Van Ness ◽  
Holly A. F. Stessman ◽  
Linda B. Baughn ◽  
Aatif Mansoor ◽  
Amit Mitra ◽  
...  
Keyword(s):  
Data Base ◽  
Cell Lines ◽  
Research Funding ◽  
Human Cancer ◽  
Expression Profiles ◽  
Single Agent ◽  
Cross Resistance ◽  
Human Cancer Cell Lines ◽  
Chemical Structures

Abstract Despite the introduction of effective new agents in the treatment of myeloma, the disease is still mostly incurable. Among the most significant issues is the heterogeneity of the disease, with accumulation of multiple genetic abnormalities among patients, resulting in disease refractory to some highly active agents, or the emergence of resistance leading to aggressive relapse. We have focused efforts on modeling drug sensitivity, and generating both genetic and biomarker signatures of response and resistance to the proteasome inhibitors (PIs): bortezomib (Btz), MLN2238 (Takeda) and carfilzomob (Onyx). Using mouse and human myeloma cell lines we dose escalated with bortezomib and selected bortezomib-resistant (Btz-R) lines (that showed cross resistance to MLN2238 and carfilzomib). We previously reported the identification of gene expression signatures that distinguish sensitivity or resistance to bortezomib (Stessman, et al., Mol Cancer Ther 12:1140, 2013). We then took three approaches to identify effective strategies to treat bortezomib resistance: 1) The connectivity map (CMAP) data base contains treatment induced transcriptional signatures from over 1300 bioactive compounds in human cancer cell lines. We queried our Btz-R expression profiles against the CMAP data base and developed a correlation analysis to identify potential drugs that would be predicted to show toxicity to Btz-R lines. We identified HDAC-inhibitor and topoisomerase-inhibitor sensitivity profiles that were able to predict Btz-R tumor responsiveness to these drugs in vitro. 2) We found that Btz-R was associated with loss of PC maturation markers (CD69, CD93, BLIMP, CXCR4, spliced XBP-1), and were able to re-sensitize Btz-R cells to Btz sensitivity by inducing PC maturation. The correlation of expression markers we identified stratified survival outcomes in bortezomib containing clinical trials; thus demonstrating the markers we identified in the in vitro modeling are relevant to patient outcomes. 3) Finally, we designed a cell-based high throughput drug screening approach that led to the identification of several chemical structures with selective activity against Btz-R cells. Topoisomerase-inhibitors were among the top hits, a finding that independently supported our CMAP screening results. We also identified a more novel chemical lead (Velcade Re-sensitizing Compound 2; VRC-2) that showed modest but significant selectivity for Btz-R cells as a single agent, and most notably, exhibited potent Btz re-sensitizing activity when the 2 drugs were combined. The Btz re-sensitizing activity of VRC-2 was confirmed using multiple human and mouse Btz-R cell lines. The initial successes of the in vitro approaches that will be presented demonstrate the value of profiling resistant tumors as a means to identify secondary therapies, and demonstrate there are powerful screening approaches that can be used to effectively treat or reverse drug resistance. Disclosures: Van Ness: Millenium Pharnaceutical: Honoraria, Research Funding; Onyx Pharmaceutical: Research Funding.

scholarly journals Managing sarcoma: where have we come from and where are we going?

2017 ◽  
Vol 9 (10) ◽  
pp. 637-659 ◽  
Author(s):  
Jenna S. Bleloch ◽  
Reyna D. Ballim ◽  
Serah Kimani ◽  
Jeannette Parkes ◽  
Eugenio Panieri ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Single Agent ◽  
Treatment Strategies ◽  
Specific Treatment ◽  
Primary Treatment ◽  
Response To Treatment ◽  
Molecular Characteristics ◽  
Mortality And Morbidity ◽  
Children And Young Adults ◽  
Robust Response

Sarcomas are a heterogeneous group of neoplasms of mesenchymal origin. Approximately 80% arise from soft tissue and 20% originate from bone. To date more than 100 sarcoma subtypes have been identified and they vary in molecular characteristics, pathology, clinical presentation and response to treatment. While sarcomas represent <1% of adult cancers, they account for approximately 21% of paediatric malignancies and thus pose some of the greatest risks of mortality and morbidity in children and young adults. Metastases occur in one-third of all patients and approximately 10–20% of sarcomas recur locally. Surgery in combination with preoperative and postoperative therapies is the primary treatment for localized sarcoma tumours and is the most promising curative possibility. Metastasized sarcomas, on the other hand, are treated primarily with single-agent or combination chemotherapy, but this rarely leads to a complete and robust response and often becomes a palliative form of treatment. The heterogeneity of sarcomas results in variable responses to current generalized treatment strategies. In light of this and the lack of curative strategies for metastatic and unresectable sarcomas, there is a need for novel subtype-specific treatment strategies. With the more recent understanding of the molecular mechanisms underlying the pathogenesis of some of these tumours, the treatment of sarcoma subtypes with targeted therapies is a rapidly evolving field. This review discusses the current management of sarcomas as well as promising new therapies that are currently underway in clinical trials.

scholarly journals CTLA4 promoter methylation predicts response and progression-free survival in stage IV melanoma treated with anti-CTLA-4 immunotherapy (ipilimumab)

2020 ◽  
Author(s):  
Simon Fietz ◽  
Romina Zarbl ◽  
Dennis Niebel ◽  
Christian Posch ◽  
Peter Brossart ◽  
...  
Keyword(s):  
Protein Expression ◽  
Promoter Methylation ◽  
Single Agent ◽  
Stage Iv ◽  
Predictive Biomarkers ◽  
Progression Free Survival ◽  
Immune Checkpoint Blockade ◽  
Response To Treatment ◽  
Free Survival ◽  
Stage Iv Melanoma

AbstractAnti-CTLA-4-antibodies can induce long-lasting tumor remissions. However, only a few patients respond, necessitating the development of predictive companion biomarkers. Increasing evidence suggests a major role of epigenetics, including DNA methylation, in immunology and resistance to immune checkpoint blockade. Here, we tested CTLA4 promoter methylation and CTLA-4 protein expression as predictive biomarkers for response to anti-CTLA-4 immunotherapy. We identified retrospectively N = 30 stage IV melanoma patients treated with single-agent anti-CTLA-4 immunotherapy (ipilimumab). We used quantitative methylation-specific PCR and immunohistochemistry to quantify CTLA4 methylation and protein expression in pre-treatment samples. CTLA4 methylation was significantly higher in progressive as compared to responding tumors and significantly associated with progression-free survival. A subset of infiltrating lymphocytes and tumor cells highly expressed CTLA-4. However, CTLA-4 protein expression did not predict response to treatment. We conclude that CTLA4 methylation is a predictive biomarker for response to anti-CTLA-4 immunotherapy.

scholarly journals The Chinese Herb Isolate Isorhapontigenin Induces Apoptosis in Human Cancer Cells by Down-regulating Overexpression of Antiapoptotic Protein XIAP

2012 ◽  
Vol 287 (42) ◽  
pp. 35234-35243 ◽  
Author(s):  
Yong Fang ◽  
Yonghui Yu ◽  
Qi Hou ◽  
Xiao Zheng ◽  
Min Zhang ◽  
...  
Keyword(s):  
Cancer Cell ◽  
Molecular Mechanisms ◽  
Human Cancer ◽  
Chinese Herb ◽  
Down Regulation ◽  
Human Cancer Cell Lines ◽  
Xiap Expression ◽  
Apoptosis Protein ◽  
Anti Cancer ◽  
Cancer Activity

Although the Chinese herb Gnetum cleistostachyum has been used as a remedy for cancers for hundred years, the active compounds and molecular mechanisms underlying its anti-cancer activity have not been explored. Recently a new derivative of stilbene compound, isorhapontigenin (ISO), was isolated from this Chinese herb. In the present study, we examined the potential of ISO in anti-cancer activity and the mechanisms involved in human cancer cell lines. We found that ISO exhibited significant inhibitory effects on human bladder cancer cell growth that was accompanied by marked apoptotic induction as well as down-regulation of the X-linked inhibitor of apoptosis protein (XIAP). Further studies have shown that ISO down-regulation of XIAP protein expression was only observed in endogenous XIAP, but not in constitutionally exogenously expressed XIAP in the same cells, excluding the possibility of ISO regulating XIAP expression at the level of protein degradation. We also identified that ISO down-regulated XIAP gene transcription via inhibition of Sp1 transactivation. There was no significant effect of ISO on apoptosis and colony formation of cells transfected with exogenous HA-tagged XIAP. Collectively, current studies, for the first time to the best of our knowledge, identify ISO as a major active compound for the anti-cancer activity of G. cleistostachyum by down-regulation of XIAP expression and induction of apoptosis through specific targeting of a SP1 pathway, and cast new light on the treatment of the cancer patients with XIAP overexpression.

Sign in / Sign up

Export Citation Format

Share Document