scholarly journals A Pilot Basket Study to Evaluate Multi-Analyte Liquid Biopsies for Personalized Treatments in Advanced Refractory Cancers

2021 ◽  
Author(s):  
Rajnish Nagarkar ◽  
Timothy Crook ◽  
Nicholas Plowman ◽  
Andrew Gaya ◽  
Darshana Patil ◽  
...  
Keyword(s):  
Single Gene ◽  
Pilot Trial ◽  
Poor Response ◽  
Liquid Biopsies ◽  
Single Drug ◽  
Liquid Impact ◽  
Pathway Activation ◽  
Combination Regimens ◽  
Tumor Profiling ◽  
Selection Of

Prior attempts at personalizing anticancer treatments based on univariate tumor profiling (single gene variant) for selection of monotherapy with targeted agents (single drug) have generally yielded poor response rates. We report findings from the LIQUID IMPACT pilot trial where Multi-analyte Liquid Biopsy (MLB) profiling of circulating tumor analytes in peripheral blood was used to inform selection of personalized combination regimens in advanced refractory cancers. Among the 43 patients evaluable as per study protocol, 34 had targetable pathway activations. Partial Response (PR) was observed in 14 (41.1%) of the 34 patients with signaling pathway activation, including 5 (50%) of 10 cases with mTOR activation, 8 (44.4%) of 18 cases with activation of angiogenesis and 4 (50.0%) of 8 cases with EGFR / ERBB2 activation. PR was not reported among the 9 cases with no detectable pathway activation. Toxicities were manageable and there were no treatment related deaths. The study findings suggest that MLB may be able to inform safe and efficacious combination regimens in patients with advanced refractory cancers.

scholarly journals Effects of different combined regimens of cisplatin, metformin, and quercetin on nasopharyngeal carcinoma cells and subcutaneous xenografts

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Zhongwei Chen ◽  
Zhen Zeng ◽  
Shanshan Zhu ◽  
Ying Zeng ◽  
Qihuang Lin ◽  
...  
Keyword(s):  
Nasopharyngeal Carcinoma ◽  
Nude Mice ◽  
Drug Combination ◽  
Drug Application ◽  
Inhibitory Effects ◽  
Single Drug ◽  
Combined Application ◽  
Subcutaneous Xenograft ◽  
Recurrent Nasopharyngeal Carcinoma ◽  
Combination Regimens

AbstractCisplatin, metformin, and quercetin are all reliable anticancer drugs. However, it is unclear how effective their different combination regimens are on the growth of nasopharyngeal carcinoma cell line Sune-1 and subcutaneous xenograft in nude mice. This study evaluated the effects of single-drug, two-drug, and three-drug simultaneous or sequential combined application of these drugs on the growth of Sune-1 cells and subcutaneous xenograft tumors in nude mice. The results showed that the different combination regimens of cisplatin, metformin and quercetin all had significant inhibitory effects on the proliferation of Sune-1 cells and the growth of subcutaneous xenografts in nude mice (P < 0.01), and the inhibition rate of the three drugs simultaneous combined application was significant Higher than the two-drug combination or single-drug application (P < 0.05), the contribution level of each drug in the three-drug combination application from high to low were cisplatin > metformin > quercetin. In summary, our results indicate that the simultaneous combination of cisplatin, metformin, and quercetin may synergistically inhibit the growth of Sune-1 cells and subcutaneous xenografts in nude mice through their different anticancer mechanisms, which may be clinically refractory and provide reference for chemotherapy of patients with recurrent nasopharyngeal carcinoma.

scholarly journals Biomarkers for Liquid Biopsies of Pituitary Neuroendocrine Tumors

Biomedicines ◽  
2020 ◽  
Vol 8 (6) ◽  
pp. 148
Author(s):  
Wilhelm Gossing ◽  
Marcus Frohme ◽  
Lars Radke
Keyword(s):  
Neuroendocrine Tumors ◽  
Diagnostic Procedures ◽  
Epigenetic Changes ◽  
Early Screening ◽  
Liquid Biopsies ◽  
Marker Substances ◽  
Pile Up ◽  
Screening Efficiency ◽  
Key Nodes ◽  
Tumor Profiling

Pituitary neuroendocrine tumors (PitNET) do not only belong to the most common intracranial neoplasms but seem to be generally more common than has been thought. Minimally invasive liquid biopsies have the potential to improve their early screening efficiency as well as monitor prognosis by facilitating the diagnostic procedures. This review aims to assess the potential of using liquid biopsies of different kinds of biomarker species that have only been obtained from solid pituitary tissues so far. Numerous molecules have been associated with the development of a PitNET, suggesting that it often develops from the cumulative effects of many smaller genetic or epigenetic changes. These minor changes eventually pile up to switch critical molecules into tumor-promoting states, which may be the key regulatory nodes representing the most potent marker substances for a diagnostic test. Drugs targeting these nodes may be superior for the therapeutic outcome and therefore the identification of such pituitary-specific cellular key nodes will help to accelerate their application in medicine. The ongoing genetic degeneration in pituitary adenomas suggests that repeated tumor profiling via liquid biopsies will be necessary for personalized and effective treatment solutions.

SOCS1 Mutation Subtypes Predict Divergent Outcomes in DLBCL Patients

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 419-419
Author(s):  
Jochen K Lennerz ◽  
Birgit Schif ◽  
Christian W Kohler ◽  
Stefan Bentink ◽  
Markus Kreuz ◽  
...  
Keyword(s):  
B Cell ◽  
Conflicts Of Interest ◽  
Single Gene ◽  
Prognostic Significance ◽  
B Cell Lymphoma ◽  
Gene Signature ◽  
Full Length ◽  
Cytokine Signaling ◽  
Pathway Activation ◽  
Lymphoma Line

Abstract Abstract 419 Suppressor of cytokine signaling 1 (SOCS1) is frequently mutated in Hodgkin, primary mediastinal and diffuse large B-cell lymphomas (DLBCL). In the primary mediastinal B-cell lymphoma line MedB-1, mutated SOCS1 abnormally stabilizes phospho-JAK2, thereby enhances STAT signaling leading to continuous proliferation. Here, we evaluated the prognostic value of SOCS1 mutations by full-length gene sequencing of SOCS1 in 154 comprehensively characterized DLBCL cases. By sequence analysis, we identified 90 SOCS1 mutations in 16% of lymphomas. We defined two distinct subtypes with respect to putative mutational consequences: those predicting the full-length (minor) and a truncated protein (major), respectively. Neither the SOCS1 mutation group, nor minor/major subgroups can be distinguished by clinical phenotype; however, assignment of four established expression-based classifiers revealed significant associations of SOCS1 major cases with germinal center- and specific pathway activation pattern signatures. Above all, SOCS1 major cases had an excellent overall survival, even better than the GCB-like subgroup (see Figure). SOCS1 minor cases had a dismal survival, even worse than the ABC gene signature group (see Figure). SOCS1 mutation subsets retain prognostic significance in uni- and multivariate analyses. Thus, if a SOCS1 mutation is present, the mutation type is an important single gene prognostic biomarker in DLBCL. Disclosures: No relevant conflicts of interest to declare.

Multi-analyte liquid biopsies based treatment in advanced refractory cancers.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15623-e15623
Author(s):  
Sewanti Limaye ◽  
Darshana Patil ◽  
Dadasaheb B Akolkar ◽  
Timothy Crook ◽  
Anantbhushan Ranade ◽  
...  
Keyword(s):  
Treatment Response ◽  
Liquid Biopsy ◽  
Tumor Tissue ◽  
Single Gene ◽  
Objective Response ◽  
Specific Treatment ◽  
Patient Specific ◽  
Solid Organ ◽  
Liquid Biopsies ◽  
Blood Draw

e15623 Background: Tumor tissue profiling following invasive biopsies is presently the standard approach for indication-based therapy management in solid organ cancers. However, challenges in biopsy are traditionally described due to proximity to vital organs, or patients’ co-morbidities or unwillingness for an invasive procedure. Liquid biopsies for evaluation of cancers are also largely restricted to single gene testing for selection of targeted therapy agents. We developed a comprehensive liquid biopsy based multi-analyte (molecular and functional) investigation of the cancer (eLBx: Encyclopedic Liquid Biopsy) for selection and management of individualised treatments in a cohort of advanced refractory cancers. Methods: We obtained 20 mL blood from 65 patients with solid organ cancers where the disease had progressed following failure of at least two lines of systemic therapies and where biopsy to obtain tumor tissue for molecular profiling of tumor was unviable. Cell free tumor DNA (ctDNA) was interrogated for mutations, while exosomal mRNA was profiled for gene expression. Viable circulating tumor associated cells (C-TACs) were tested in vitro for chemoresistance and used to determine expression of cell surface signalling receptors by immunocytochemistry (ICC). The findings were integrated to generate patient-specific treatment regimens. In patients who received treatment, response was determined radiologically. Results: Fifty-one patients received eLBx-guided personalized treatments with combinations of cytotoxic, targeted and endocrine agents. No two patients received the same treatment regimen. Forty-three patients were evaluable for treatment response per protocol among whom Partial Response (PR) was observed in 14 patients yielding an Objective Response Rate (ORR) of 32.6%. Additionally, 23 patients showed Stable Disease thus yielding an overall Disease Control rate of 86.1%. Median Progression Free Survival (PFS) was 108 days. There were no Grade IV therapy related Adverse Events or therapy related deaths. Conclusions: The ability to make informed treatment choices from a convenient blood draw implies a reduced dependence on invasive biopsies for disease management. We demonstrate successful management of advanced refractory solid tumor malignancies using an integrational non-invasive multi-analyte liquid biopsy approach. Clinical trial information: CTRI/2019/02/017548.

scholarly journals Toward an Evidence-Based Nonclinical Road Map for Evaluating the Efficacy of New Tuberculosis (TB) Drug Regimens: Proceedings of a Critical Path to TB Drug Regimens-National Institute of Allergy and Infectious DiseasesIn VivoPharmacology Workshop for TB Drug Development

2016 ◽  
Vol 60 (3) ◽  
pp. 1177-1182 ◽  
Author(s):  
Eric Nuermberger ◽  
Christine Sizemore ◽  
Klaus Romero ◽  
Debra Hanna
Keyword(s):  
Infectious Diseases ◽  
Drug Development ◽  
Drug Combination ◽  
Critical Path ◽  
Evidence Based ◽  
Road Map ◽  
Drug Regimens ◽  
Combination Regimens ◽  
Selection Of

Novel tuberculosis (TB) drug regimens are urgently needed, and their development will be enabled by improved preclinical approaches that more effectively inform and ensure safe selection of clinical candidates and drug combination/regimens. An evidence-based approach for the assessment of nonclinical models supporting TB drug development has been proposed by a joint partnership between the National Institute of Allergy and Infectious Diseases (NIAID) and the Critical Path to TB Drug Regimens (CPTR) Consortium.

scholarly journals Inheritance of a Mild Reaction to Lettuce Mosaic

HortScience ◽  
1996 ◽  
Vol 31 (4) ◽  
pp. 612e-612 ◽  
Author(s):  
Edward J. Ryder
Keyword(s):  
Plant Resistance ◽  
Single Gene ◽  
Recessive Gene ◽  
Leaf Margin ◽  
Single Recessive Gene ◽  
Reaction Type ◽  
Vein Clearing ◽  
Resistant Lines ◽  
Selection Of

Resistance to lettuce mosaic (LMV) in current cultivars of lettuce is due to a single recessive gene, momo, in one of two allelic forms. The nature of the resistance may be described as resistance to multiplication and spread in the plant. Resistance is systemically manifested as small irregular yellowish areas on the leaf. This compares to the usual expression of susceptibility: vein clearing, followed by mottling, leaf margin recurving, and later stunting and yellowing. A cos-like stem lettuce from Egypt, `Balady Aswan', is susceptible to LMV, but reaction to the virus is a milder one than the usual susceptible reaction. Segregating generations from crosses with normal susceptible and resistant lines were analyzed. The data suggest a single gene for reaction type, with mild dominant or partially dominant to severe. Selection of lines from crosses with the resistant type allows the breeder to select resistant and mild alleles together, which confers a higher level of resistance than momo alone. Plants with the combined reaction either show no symptom or show the resistant symptom very late.

scholarly journals Tumor suppression in basal keratinocytes via dual non-cell-autonomous functions of a Na,K-ATPase beta subunit

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Julia Hatzold ◽  
Filippo Beleggia ◽  
Hannah Herzig ◽  
Janine Altmüller ◽  
Peter Nürnberg ◽  
...  
Keyword(s):  
Tumor Suppression ◽  
Single Gene ◽  
Tumor Development ◽  
Beta Subunit ◽  
Epithelial Polarity ◽  
Basal Cells ◽  
Loss Of Function ◽  
Basal Keratinocytes ◽  
Hypotonic Stress ◽  
Pathway Activation

The molecular pathways underlying tumor suppression are incompletely understood. Here, we identify cooperative non-cell-autonomous functions of a single gene that together provide a novel mechanism of tumor suppression in basal keratinocytes of zebrafish embryos. A loss-of-function mutation in atp1b1a, encoding the beta subunit of a Na,K-ATPase pump, causes edema and epidermal malignancy. Strikingly, basal cell carcinogenesis only occurs when Atp1b1a function is compromised in both the overlying periderm (resulting in compromised epithelial polarity and adhesiveness) and in kidney and heart (resulting in hypotonic stress). Blockade of the ensuing PI3K-AKT-mTORC1-NFκB-MMP9 pathway activation in basal cells, as well as systemic isotonicity, prevents malignant transformation. Our results identify hypotonic stress as a (previously unrecognized) contributor to tumor development and establish a novel paradigm of tumor suppression.

scholarly journals Immunodeficiency and Intermittent Dosing Promote Acquired Rifamycin Monoresistance in Murine Tuberculosis

2017 ◽  
Vol 61 (11) ◽  
Author(s):  
Sang-Won Park ◽  
Rokeya Tasneen ◽  
Paul J. Converse ◽  
Eric L. Nuermberger
Keyword(s):  
Nude Mice ◽  
Acquired Resistance ◽  
Isoniazid Resistance ◽  
Continuation Phase ◽  
Intensive Phase ◽  
Control Regimen ◽  
Rifampin Resistance ◽  
Resistant Mutants ◽  
Combination Regimens ◽  
Selection Of

ABSTRACT More-permissive preclinical models may be useful in evaluating antituberculosis regimens for their propensity to select drug-resistant mutants. To evaluate whether acquired rifamycin monoresistance could be recapitulated in mice and, if so, to evaluate the effects of immunodeficiency, intermittent dosing, and drug exposures, athymic nude and BALB/c mice were infected. Controls received daily rifapentine alone or 2 months of rifampin, isoniazid, pyrazinamide, and ethambutol, followed by 4 months of rifampin/isoniazid, either daily or twice weekly with one of two isoniazid doses. Test groups received the same intensive regimen followed by once-weekly rifapentine or isoniazid/rifapentine with rifapentine doses of 10, 15, or 20 mg/kg of body weight plus one of two isoniazid doses. All combination regimens rendered BALB/c mouse cultures negative but selected mutants resistant to isoniazid (8.5%, 12/140) or rifampin (3.5%, 5/140) in nude mice (P < 0.001). Intermittently dosed intensive-phase therapy selected isoniazid and rifampin resistance in 10% (8/80, P < 0.001) and 20% (16/80, P = 0.009) of nude mice, respectively, compared to 0% treated with a daily regimen. Once-weekly rifapentine-containing continuation-phase regimens selected rifampin-resistant mutants at a rate of 18.0% (18/100, P = 0.035 compared to rifampin/isoniazid regimens). Higher isoniazid doses in the intermittent-treatment control regimen and higher rifapentine doses in once-weekly regimens were associated with less selection of isoniazid resistance. Acquired resistance, including rifamycin monoresistance, was more likely to occur in nude mice despite administration of combination therapy. These results recapitulate clinical outcomes and indicate that nude mice may be useful for evaluating the ability of novel regimens to prevent the selection of resistance.

scholarly journals Regulation of Alternative Splicing by Reversible Protein Phosphorylation

2007 ◽  
Vol 283 (3) ◽  
pp. 1223-1227 ◽  
Author(s):  
Stefan Stamm
Keyword(s):  
Alternative Splicing ◽  
Protein Phosphorylation ◽  
Protein Phosphatase ◽  
Single Gene ◽  
Biological Properties ◽  
Regulatory Proteins ◽  
Protein Phosphatase 1 ◽  
Splice Sites ◽  
Reversible Protein Phosphorylation ◽  
Selection Of

The vast majority of human protein-coding genes are subject to alternative splicing, which allows the generation of more than one protein isoform from a single gene. Cells can change alternative splicing patterns in response to a signal, which creates protein variants with different biological properties. The selection of alternative splice sites is governed by the dynamic formation of protein complexes on the processed pre-mRNA. A unique set of these splicing regulatory proteins assembles on different pre-mRNAs, generating a “splicing” or “messenger ribonucleoprotein code” that determines exon recognition. By influencing protein/protein and protein/RNA interactions, reversible protein phosphorylation modulates the assembly of regulatory proteins on pre-mRNA and therefore contributes to the splicing code. Studies of the serine/arginine-rich protein class of regulators identified different kinases and protein phosphatase 1 as the molecules that control reversible phosphorylation, which controls not only splice site selection, but also the localization of serine/arginine-rich proteins and mRNA export. The involvement of protein phosphatase 1 explains why second messengers like cAMP and ceramide that control the activity of this phosphatase influence alternative splicing. The emerging mechanistic links between splicing regulatory proteins and known signal transduction pathways now allow in detail the understanding how cellular signals modulate gene expression by influencing alternative splicing. This knowledge can be applied to human diseases that are caused by the selection of wrong splice sites.

scholarly journals ddPCR-based detection of circulating tumour DNA from paediatric high grade and diffuse midline glioma patients

2021 ◽  
Author(s):  
Elisa Izquierdo ◽  
Paula Proszek ◽  
Giulia Pericoli ◽  
Sara Temelso ◽  
Matthew Clarke ◽  
...  
Keyword(s):  
Poor Response ◽  
Randomised Clinical Trial ◽  
Digital Pcr ◽  
High Grade ◽  
Sample Collection ◽  
Survival Times ◽  
Liquid Biopsies ◽  
Cystic Fluid ◽  
Dna Alterations ◽  
Circulating Tumour Dna

Abstract Background The use of liquid biopsy is of potential high importance for children with high grade (HGG) and diffuse midline gliomas (DMG), particularly where surgical procedures are limited, and invasive biopsy sampling not without risk. To date, however, the evidence that detection of cell-free DNA (cfDNA) or circulating tumour DNA (ctDNA) could provide useful information for these patients has been limited, or contradictory. Methods We optimised droplet digital PCR (ddPCR) assays for the detection of common somatic mutations observed in paediatric HGG/DMG, and applied them to liquid biopsies from plasma, serum, cerebrospinal fluid (CSF) and cystic fluid collected from 32 patients. Results Although detectable in all biomaterial types, ctDNA presented at significantly higher levels in CSF compared to plasma and/or serum. When applied to a cohort of 127 plasma specimens from 41 patients collected from 2011-2018 as part of a randomised clinical trial in pediatric non-brainstem HGG/DMG, ctDNA profiling by ddPCR was of limited use due to the small volumes (mean=0.49ml) available. In anecdotal cases where sufficient material was available, cfDNA concentration correlated with disease progression in two examples each of poor response in H3F3A_K27M-mutant DMG, and longer survival times in hemispheric BRAF_V600E-mutant cases. Conclusion Tumour-specific DNA alterations are more readily detected in CSF than plasma. Although we demonstrate the potential of the approach to assess tumour burden, our results highlight the necessity for adequate sample collection and approaches to improve detection if plasma samples are to be used.

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