scholarly journals Expression rate of ALK tyrosine kinase and TAG-72 oncoprotein in primary skin melanoma

2018 ◽  
Vol 17 (3) ◽  
pp. 50-54
Author(s):  
K. S. Titov ◽  
D. L. Rotin ◽  
A. M. Kazakov ◽  
O. U. Micheeva ◽  
I. M. Telezhnikova ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Correlation Coefficient ◽  
Detection System ◽  
Simultaneous Detection ◽  
Primary Melanoma ◽  
Diagnostic Value ◽  
Positive Sign ◽  
Skin Melanoma ◽  
Alk Positive ◽  
Lymphoid Infiltration

Objective.Determine the frequency of occurrence of tyrosine kinase expression of the mutated ALK and TAG-72 gene among patients with primary melanoma of the skin, to identify their association with a number of histological parameters, and to assess the diagnostic value of the determination of ALK and TAG-72.Materials and methods.Paraffin blocks with surgical material from 40 patients with primary skin melanoma. For routine histological examination, the material was fixed with 10 % neutral formalin for 24 h, poured into paraffin, sections were prepared with a thickness of 4–5 μm, stained with hematoxylin and eosin. IHC study with monoclonal antibodies D57.3 to ALK was performed on an immunostender – Ventana, with antibodies B72.3 to TAG-72 – on Thermo Fischer. As a detection system used: Envision – for TAG-72 and Ventana – for ALK.Results.ALK mutation was detected in 7 (12 %), TAG-72 – 4 (10 %) cases. Evaluation of the correlation force between the presence of ALK and TAG-72 showed a direct average coupling strength (correlation coefficient was 0.31). A direct correlation of the mean force between the presence of TAG-72 oncoprotein, ALK mutation and ulceration in the patient was found – the correlation coefficient was 0.53 and 0.68, respectively. There was a statistically significant association between the presence of ALK and lymphoid infiltration, which in most cases (57 %) was pronounced (p <0.05).Conclusion.Comparing the positive sign of the expression of ALK – 17.5 % and TAG-72 – 10 %, and the positive of their simultaneous detection – 7.5 %, it can be concluded that further studies to determine their diagnostic value are promising. The presence of severe lymphoid infiltration in ALK-positive patients claims a diagnostic value in primary skin melanoma.

scholarly journals Canadian perspectives: update on inhibition of ALK-positive tumours in advanced non-small-cell lung cancer

2018 ◽  
Vol 25 (5) ◽  
Author(s):  
B. Melosky ◽  
P. Cheema ◽  
J. Agulnik ◽  
R. Albadine ◽  
D. G. Bebb ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Single Agent ◽  
Small Cell ◽  
Phase Iii ◽  
Small Cell Lung ◽  
Anaplastic Lymphoma ◽  
Alk Inhibitor ◽  
Alk Positive

BackgroundInhibition of the anaplastic lymphoma kinase (alk) oncogenic driver in advanced non-small-cell lung carcinoma (nsclc) improves survival. In 2015, Canadian thoracic oncology specialists published a consensus guideline about the identification and treatment of ALK-positive patients, recommending use of the alk inhibitor crizotinib in the first line. New scientific literature warrants a consensus update.MethodsClinical trials of alk inhibitor were reviewed to assess benefits, risks, and implications relative to current Canadian guidance in patients with ALK-positive nsclc.ResultsRandomized phase iii trials have demonstrated clinical benefit for single-agent alectinib and ceritinib used in treatment-naïve patients and as second-line therapy after crizotinib. Phase ii trials have demonstrated activity for single-agent brigatinib and lorlatinib in further lines of therapy. Improved responses in brain metastases were observed for all second- and next/third-generation alk tyrosine kinase inhibitors in patients progressing on crizotinib. Canadian recommendations are therefore revised as follows:Patients with advanced nonsquamous nsclc have to be tested for the presence of an ALKrearrangement.Treatment-naïve patients with ALK-positive disease should initially be offered single-agent alectinib or ceritinib, or both sequentially.Crizotinib-refractory patients should be treated with single-agent alectinib or ceritinib, or both sequentially.Further treatments could include single-agent brigatinib or lorlatinib, or both sequentially.Patients progressing on alk tyrosine kinase inhibitors should be considered for pemetrexed-based chemotherapy.Other systemic therapies should be exhausted before immunotherapy is considered.SummaryMultiple lines of alk inhibition are now recommended for patients with advanced nsclc with an ALKrearrangement.

scholarly journals Emerging Paradigms in the Development of Resistance to Tyrosine Kinase Inhibitors in Lung Cancer

2013 ◽  
Vol 31 (31) ◽  
pp. 3987-3996 ◽  
Author(s):  
Justin F. Gainor ◽  
Alice T. Shaw
Keyword(s):  
Lung Cancer ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Genetic Alterations ◽  
Anaplastic Lymphoma ◽  
Development Of Resistance ◽  
Tki Resistance ◽  
Alk Positive ◽  
Egfr Mutant

The success of tyrosine kinase inhibitors (TKIs) in select patients with non–small-cell lung cancer (NSCLC) has transformed management of the disease, placing new emphasis on understanding the molecular characteristics of tumor specimens. It is now recognized that genetic alterations in the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) define two unique subtypes of NSCLC that are highly responsive to genotype-directed TKIs. Despite this initial sensitivity, however, the long-term effectiveness of such therapies is universally limited by the development of resistance. Identifying the mechanisms underlying this resistance is an area of intense, ongoing investigation. In this review, we provide an overview of recent experience in the field, focusing on results from preclinical resistance models and studies of patient-derived, TKI-resistant tumor specimens. Although diverse TKI resistance mechanisms have been identified within EGFR-mutant and ALK-positive patients, we highlight common principles of resistance shared between these groups. These include the development of secondary mutations in the kinase target, gene amplification of the primary oncogene, and upregulation of bypass signaling tracts. In EGFR-mutant and ALK-positive patients alike, acquired resistance may also be a dynamic and multifactorial process that may necessitate the use of treatment combinations. We believe that insights into the mechanisms of TKI resistance in patients with EGFR mutations or ALK rearrangements may inform the development of novel treatment strategies in NSCLC, which may also be generalizable to other kinase-driven malignancies.

scholarly journals Preclinical Evaluation of Gilteritinib on NPM1-ALK Driven Anaplastic Large Cell Lymphoma Cells

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2865-2865
Author(s):  
Sudhakiranmayi Kuravi ◽  
Janice Cheng ◽  
Kishore Polireddy ◽  
Gabrielle Fangman ◽  
Roy A Jensen ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Large Cell ◽  
Advisory Board ◽  
Advisory Committees ◽  
Apoptotic Protein ◽  
Large Cell Lymphoma ◽  
Alk Positive

Anaplastic large cell lymphoma (ALCL) is an aggressive type of non-Hodgkin's lymphoma (NHL) comprising 2-8% of adult and 10-20% of pediatric and adolescent NHL. More than three-fourths of anaplastic lymphoma kinase (ALK)-positive ALCL express (nucleophosmin1) NPM1-ALK fusion gene as a result of t(2;5) chromosomal translocation. The self-dimerization of fusion kinase NPM1-ALK mediates constitutive activation of the chimeric tyrosine kinase activity leading to downstream signaling pathways responsible for lymphoma cell proliferation and survival. The current standard treatment regimen for ALK+ ALCL is CHOP (cyclophosphamide, hydroxy doxorubicin, vincristine, prednisone) chemotherapy. Oftentimes, resistance and failure of remission occur with CHOP therapy, making it a suboptimal treatment regimen for many patients. Therefore, an alternative therapeutic approach is warranted to better address the needs of the ALK+ ALCL population. Gilteritinib is a recently FDA approved tyrosine kinase inhibitor for the treatment of FMS-like tyrosine kinase (FLT3) mutation-positive acute myeloid leukemia. Along with inhibition of FLT3, gilteritinib also inhibits other tyrosine kinases such as AXL and ALK. In this study, for the first time, we demonstrated gilteritinib mediated growth inhibitory effects on NPM1-ALK driven ALCL cells. We have used a total of five cell lines in our study: NPM1-ALK endogenously expressing human ALCL cell lines (SUDHL-1, SUP-M2, SR-786, and DEL), and our laboratory generated ectopically overexpressing Ba/F3-FG-NPM1-ALK, a murine cell line. Gilteritinib treatment (5-20 nM) inhibited NPM1-ALK fusion kinase phosphorylation, which resulted in downregulation of downstream survival signaling pathways including AKT, ERK1/2, and STAT3 leading to induced apoptosis and decreased clonogenic survival. Gilteritinib mediated apoptosis was associated with caspase 3/9 and poly (ADP-ribose) polymerase cleavage with increased pro-apoptotic protein BAD and decreased anti-apoptotic protein MCL-1. Increased expression of c-Myc is associated with ALK-positive ALCL and gilteritinib treatment decreased c-Myc levels in a dose dependent manner. Cell cycle analysis demonstrated gilteritinib treatment induced cell cycle arrest at the G0/G1 phase with a concomitant decrease in G2/M and S phases. In summary, our preclinical results suggest gilteritinib has therapeutic potential for the treatment of ALCL cells expressing NPM1-ALK and other ALK /ALK-fusion driven hematologic or solid malignancies. Disclosures Lin: Jazz Pharmaceuticals: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees. Ganguly:Daiichi Sankyo: Research Funding; Seattle Genetics: Speakers Bureau; Janssen: Honoraria, Other: Advisory Board; Kite Pharma: Honoraria, Other: Advisory Board. McGuirk:ArticulateScience LLC: Other: Assistance with manuscript preparation; Juno Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bellicum Pharmaceuticals: Research Funding; Astellas: Research Funding; Novartis: Research Funding; Fresenius Biotech: Research Funding; Pluristem Ltd: Research Funding; Gamida Cell: Research Funding; Kite Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Polarization Calibration for Multi-Spectral Aperture-Divided Simultaneous Detection System

2017 ◽  
Vol 37 (2) ◽  
pp. 0228001
Author(s):  
范慧敏 Fan Huimin ◽  
康 晴 Kang Qing ◽  
裘桢炜 Qiu Zhenwei ◽  
袁银麟 Yuan Yinlin ◽  
洪 津 Hong Jin
Keyword(s):  
Detection System ◽  
Simultaneous Detection

scholarly journals Study of the Female Sex Survival Advantage in Melanoma—A Focus on X-Linked Epigenetic Regulators and Immune Responses in Two Cohorts

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2082
Author(s):  
Abdullah Al Emran ◽  
Jérémie Nsengimana ◽  
Gaya Punnia-Moorthy ◽  
Ulf Schmitz ◽  
Stuart J. Gallagher ◽  
...  
Keyword(s):  
Immune Responses ◽  
Interaction Analysis ◽  
Prognostic Significance ◽  
Primary Melanoma ◽  
The Cancer Genome Atlas ◽  
Oncogenic Pathways ◽  
Cancer Genome Atlas ◽  
Epigenetic Regulators ◽  
New Treatment ◽  
Lymphoid Infiltration

Background: Survival from melanoma is strongly related to patient sex, with females having a survival rate almost twice that of males. Many explanations have been proposed but have not withstood critical scrutiny. Prior analysis of different cancers with a sex bias has identified six X-linked genes that escape X chromosome inactivation in females and are, therefore, potentially involved in sex differences in survival. Four of the genes are well-known epigenetic regulators that are known to influence the expression of hundreds of other genes and signaling pathways in cancer. Methods: Survival and interaction analysis were performed on the skin cutaneous melanoma (SKCM) cohort in The Cancer Genome Atlas (TCGA), comparing high vs. low expression of KDM6A, ATRX, KDM5C, and DDX3X. The Leeds melanoma cohort (LMC) on 678 patients with primary melanoma was used as a validation cohort. Results: Analysis of TCGA data revealed that two of these genes—KDM6A and ATRX—were associated with improved survival from melanoma. Tumoral KDM6A was expressed at higher levels in females and was associated with inferred lymphoid infiltration into melanoma. Gene set analysis of high KDM6A showed strong associations with immune responses and downregulation of genes associated with Myc and other oncogenic pathways. The LMC analysis confirmed the prognostic significance of KDM6A and its interaction with EZH2 but also revealed the expression of KDM5C and DDX3X to be prognostically significant. The analysis also confirmed a partial correlation of KDM6A with immune tumor infiltrates. Conclusion: When considered together, the results from these two series are consistent with the involvement of X-linked epigenetic regulators in the improved survival of females from melanoma. The identification of gene signatures associated with their expression presents insights into the development of new treatment initiatives but provides a basis for exploration in future studies.

Abstract LB-227: Receptor tyrosine kinase phosphorylation: Simultaneous detection of 10 kinases upon inhibitor treatment

2010 ◽  
Author(s):  
Tanja Henzler ◽  
Stefanie Pohl ◽  
Nicole Schneiderhan-Mara ◽  
Stefanie Rimmele ◽  
April Livengood ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Simultaneous Detection ◽  
Kinase Phosphorylation ◽  
Inhibitor Treatment

scholarly journals Tracking the Evolution of Resistance to ALK Tyrosine Kinase Inhibitors Through Longitudinal Analysis of Circulating Tumor DNA

2018 ◽  
pp. 1-14 ◽  
Author(s):  
Ibiayi Dagogo-Jack ◽  
A. Rose Brannon ◽  
Lorin A. Ferris ◽  
Catarina D. Campbell ◽  
Jessica J. Lin ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Longitudinal Analysis ◽  
Kinase Inhibitors ◽  
Circulating Tumor Dna ◽  
Evolution Of Resistance ◽  
Alk Positive ◽  
Tumor Dna ◽  
Generation Sequencing

Purpose ALK (anaplastic lymphoma kinase) rearrangements predict for sensitivity to ALK tyrosine kinase inhibitors (TKIs); however, responses to ALK TKIs are generally short lived. Serial molecular analysis is an informative strategy used to identify genetic mediators of resistance. Although multiple studies support the clinical benefits of repeat tissue sampling, the clinical utility of longitudinal circulating tumor DNA analysis has not been established in ALK-positive lung cancer. Patients and Methods We used a 566-gene hybrid-capture next-generation sequencing assay to perform a longitudinal analysis of plasma specimens from 22 ALK-positive patients with acquired resistance to ALK TKIs to track the evolution of resistance during treatment. To determine tissue–plasma concordance, we compared plasma findings with the results of repeat biopsies. Results At disease progression, we detected an ALK fusion in plasma from 19 (86%) of 22 patients and identified ALK resistance mutations in plasma specimens from 11 patients (50%). There was 100% agreement between tissue- and plasma-detected ALK fusions. Among 16 patients for which contemporaneous plasma and tissue specimens were available, we observed 100% concordance between ALK mutation calls. ALK mutations emerged and disappeared during treatment with sequential ALK TKIs, which suggests that plasma mutation profiles were dependent on the specific TKI administered. ALK G1202R—the most frequent plasma mutation detected after progression on a second-generation TKI—was consistently suppressed during treatment with lorlatinib. Conclusion Plasma genotyping by next-generation sequencing is an effective method for detecting ALK fusions and ALK mutations in patients who experience disease progression on ALK TKIs. The correlation between plasma ALK mutations and the response to distinct ALK TKIs highlights the potential for plasma analysis to guide the selection of ALK-directed therapies.

scholarly journals BRCA1 Gene Mutations in Sporadic Ovarian Carcinomas: Detection by PCR and Reverse Allele-specific Oligonucleotide Hybridization

1999 ◽  
Vol 45 (7) ◽  
pp. 976-981 ◽  
Author(s):  
Dan Tong ◽  
Margit Stimpfl ◽  
Alexander Reinthaller ◽  
Norbert Vavra ◽  
Silvia Müllauer-Ertl ◽  
...  
Keyword(s):  
Somatic Mutations ◽  
Detection System ◽  
Brca1 Mutation ◽  
Simultaneous Detection ◽  
Brca1 Gene ◽  
Germline Mutations ◽  
Ovarian Carcinomas ◽  
Primary Fallopian Tube Carcinoma ◽  
Oligonucleotide Hybridization ◽  
Allele Specific

Abstract Background: Although germline mutations in BRCA1 play a central role in familial breast and ovarian cancers, to date, no somatic mutations in BRCA1 have been reported in sporadic breast cancer, and only five somatic mutations have been identified in the sporadic ovarian carcinomas. Because loss of heterozygosity appears frequently at the BRCA1 locus in nonfamilial breast and ovarian carcinomas, we searched for mutations in the BRCA1 gene in sporadic ovarian tumors. Methods: We developed a detection system based on PCR and reverse allele-specific oligonucleotide hybridization on membrane strips for the simultaneous detection of 17 frequently occurring mutations in the BRCA1 gene. Results: As little as 2% mutant DNA in a sample could be detected. Two of 122 DNA samples isolated from sporadic ovarian tumor biopsies contained the Cys61Gly mutation. Both mutations were germline mutations. One of these was an ovarian metastasis of a primary fallopian tube carcinoma. The tubal carcinoma was also confirmed to contain the Cys61Gly mutation. Conclusions: This is the first report that a germline BRCA1 mutation is associated with primary tubal carcinoma. The 17 specific mutations in the BRCA1 gene do not play a major role in the tumorigenesis and progression of sporadic ovarian cancer.

Sign in / Sign up

Export Citation Format

Share Document