Molecular profiling-guided therapy in gastroesophageal carcinoma: A single-institution experience.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e15582-e15582
Author(s):  
Lionel Aurelien Kankeu Fonkoua ◽  
Jason Liao ◽  
Nelson S. Yee
Keyword(s):  
Targeted Therapy ◽  
Tyrosine Kinases ◽  
Clonal Evolution ◽  
Gastroesophageal Junction ◽  
Resistance Mechanism ◽  
Molecular Profiling ◽  
Molecular Profile ◽  
Limited Efficacy ◽  
The Impact ◽  
Guided Therapy

e15582 Background: Gastroesophageal carcinoma (GEC) including carcinoma of stomach (GC), gastroesophageal junction (GEJ), and esophagus (EC) is the 2nd leading cause of cancer death worldwide. Chemotherapy and HER2-targeted therapy (trastuzumab) have shown limited efficacy. We aim to assess the impact of molecular profile (MP)-guided therapy (MPgt) by correlating expression of select biomarkers in GEC patients (pts) with survival. Methods: 27 GEC (11 GC, 9 GEJ, 7 EC) submitted to Caris Life Sciences for molecular profiling between 2011 and 2016 were analyzed and correlated with pt survival. The impact of MPgt was assessed by calculating the ratio of progression-free survival (PFS) on MPgt to PFS on the preceding empiric therapy. MPgt was deemed beneficial if PFS ratio ≥1.3. Results: In-situ hybridization indicated amplification of HER2 (15.4%) and c-MET (7.4%). Immunohistochemistry revealed increased expression of TOPO1 (57.7%), TOP2A (38.5%), HER2 (15.4%) and c-MET (6.9%), as well as decreased expression of TS (69.2%), ERCC1 (42.3%), and PGP (15.4%). These data suggest sensitivity to topoisomerase inhibitors, anthracyclines, trastuzumab, MET-targeted therapy, fluoropyrimidine, platinums, and taxanes, respectively. Expression of these markers was heterogeneous among pts, and a trend toward improved PFS was noted in pts with low/absent ERCC1 expression on platinum-based therapy ( P= 0.06). Of the 13 pts who had sufficient data to assess the benefit of MPgt, 5 (38%) achieved a PFS ratio ≥1.3. One pt with metastatic HER2-amplified EC who had initially demonstrated clinical benefit from trastuzumab-containing chemotherapy, developed a new HER2 and c-MET co-amplified lung metastasis. Conclusions: While MPgt was beneficial in 38% of pts, tumor-associated plasticity, clonal evolution, and adaptive resistance may have limited efficacy. The emergence of HER2 and c-MET co-amplified clones is a potential resistance mechanism in HER2-amplified GEC, and highlights combined inhibition of receptor tyrosine kinases as a therapeutic strategy. Further studies with expanded data sets will be needed to test the hypothesis that actionable targets can be used independently to predict treatment response in GEC pts.

scholarly journals Profiling of circulating tumor DNA and tumor tissue for treatment selection in patients with advanced and refractory carcinoma: a prospective, two-stage phase II Individualized Cancer Treatment trial

2021 ◽  
Vol 13 ◽  
pp. 175883592098765
Author(s):  
Jakob M. Riedl ◽  
Samantha O. Hasenleithner ◽  
Gudrun Pregartner ◽  
Lukas Scheipner ◽  
Florian Posch ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Tumor Tissue ◽  
Progression Free Survival ◽  
Metastatic Tumor ◽  
Molecular Profiling ◽  
Molecular Profile ◽  
Evidence Based ◽  
Blood Draw ◽  
The Impact ◽  
Matched Treatment

Background: Molecular profiling (MP) represents an opportunity to match patients to a targeted therapy and when tumor tissue is unavailable, circulating tumor deoxyribonucleic acid (ctDNA) can be harnessed as a non-invasive analyte for this purpose. We evaluated the success of a targeted therapy selected by profiling of ctDNA and tissue in patients with advanced and refractory carcinoma. Patients and methods: A blood draw as well as an optional tissue biopsy were obtained for MP. Whole-genome sequencing and a cancer hotspot panel were performed, and publicly available databases were used to match the molecular profile to targeted treatments. The primary endpoint was the progression-free survival (PFS) ratio (PFS on MP-guided therapy/PFS on the last evidence-based therapy), whereas the success of the targeted therapy was defined as a PFS ratio ⩾1.2. To test the impact of molecular profile-treatment matching strategies, we retrospectively analyzed selected cases via the CureMatch PreciGENE™ decision support algorithm. Results: Interim analysis of 24 patients yielded informative results from 20 patients (83%). A potential tumor-specific drug could be matched in 11 patients (46%) and eight (33%) received a matched treatment. Median PFS in the matched treatment group was 61.5 days [interquartile range (IQR) 49.8–71.0] compared with 81.5 days (IQR 68.5–117.8) for the last evidence-based treatment, resulting in a median PFS ratio of 0.7 (IQR 0.6–0.9). Hence, as no patient experienced a PFS ratio ⩾1.2, the study was terminated. Except for one case, the CureMatch analysis identified either a two-drug or three-drug combination option. Conclusions: Our study employed a histotype–agnostic approach to harness molecular profiling data from both ctDNA and metastatic tumor tissue. The outcome results indicate that more innovative approaches to study design and matching algorithms are necessary to achieve improved patient outcomes. EU Clinical Trials Registry ( https://www.clinicaltrialsregister.eu ): EudraCT: 2014-005341-44

scholarly journals Playing the Whack-A-Mole Game: ERK5 Activation Emerges Among the Resistance Mechanisms to RAF-MEK1/2-ERK1/2- Targeted Therapy

2021 ◽  
Vol 9 ◽  
Author(s):  
Alessandro Tubita ◽  
Ignazia Tusa ◽  
Elisabetta Rovida
Keyword(s):  
Tyrosine Kinases ◽  
Resistance Mechanism ◽  
Resistance Mechanisms ◽  
Mitogen Activated Protein Kinase ◽  
Cancer Therapies ◽  
New Era ◽  
Mitogen Activated Protein ◽  
The Impact ◽  
The Ideal

Molecularly tailored therapies have opened a new era, chronic myeloid leukemia being the ideal example, in the treatment of cancer. However, available therapeutic options are still unsatisfactory in many types of cancer, and often fail due to the occurrence of resistance mechanisms. With regard to small-molecule compounds targeting the components of the Mitogen-Activated Protein Kinase (MAPK) cascade RAF-MEK1/2-ERK1/2, these drugs may result ineffective as a consequence of the activation of compensatory pro-survival/proliferative signals, including receptor tyrosine kinases, PI3K, as well as other components of the MAPK family such as TPL2/COT. The MAPK ERK5 has been identified as a key signaling molecule in the biology of several types of cancer. In this review, we report pieces of evidence regarding the activation of the MEK5-ERK5 pathway as a resistance mechanism to RAF-MEK1/2-ERK1/2 inhibitors. We also highlight the known and possible mechanisms underlying the cross-talks between the ERK1/2 and the ERK5 pathways, the characterization of which is of great importance to maximize, in the future, the impact of RAF-MEK1/2-ERK1/2 targeting. Finally, we emphasize the need of developing additional therapeutically relevant MEK5-ERK5 inhibitors to be used for combined treatments, thus preventing the onset of resistance to cancer therapies relying on RAF-MEK1/2-ERK1/2 inhibitors.

Multiplatform molecular analysis of biomarkers in renal cell carcinoma.

2015 ◽  
Vol 33 (7_suppl) ◽  
pp. 501-501 ◽  
Author(s):  
Thai Huu Ho ◽  
Sherri Z. Millis ◽  
Nancy Doll ◽  
Zoran Gatalica ◽  
Sandeep K. Reddy ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Targeted Therapy ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Collecting Duct ◽  
Predictive Biomarkers ◽  
Molecular Profiling ◽  
Aberrant Expression ◽  
Duct Carcinoma ◽  
The Impact

501 Background: Predictive biomarkers of response to targeted therapy are lacking in renal cell carcinoma (RCC). We evaluated a cohort of RCC patients referred for molecular profiling to identify potentially actionable recurrent molecular aberrations. Methods: 166 consecutive renal cases referred to Caris Life Sciences over 2 yrs were evaluated with central pathology review. Cases were subtyped into clear cell (ccRCC), n=100, papillary (PRCC), n=20, sarcomatoid, n=10, translocation, n=6, medullary, n=4 or unclassified, n=26. 63% of cases were metastatic. Testing included a combination of sequencing (Sanger or next generation sequencing [NGS]), protein expression (immunohistochemistry [IHC]), and/or gene amplification (CISH or FISH). Results: ccRCC had a 52% loss of PTEN, while PRCC had a 21% loss (p value=0.02). 100% of ccRCC with sarcomatoid features (4) showed aberrant expression of PD-L1 and were infiltrated with PD-1+ tumor infiltrating lymphocytes; 100% of 10 non-ccRCC sarcomatoids also had aberrant expression of PD-L1. Loss of PBRM1 expression was observed in 60% of ccRCC. Loss of histone 3 lysine 36 trimethylation (H3K36me3), which is associated with SETD2 mutations, was observed in 30% of ccRCC. TOP2A was overexpressed in ccRCC at 30% and in non-ccRCC at 50%. 100% of ccRCC and PRCC overexpressed EGFR; a single unclassified renal cell carcinoma did not overexpress EGFR. 50% of cases had cMET overexpression, amplification, or mutation. HER2 was not amplified or overexpressed in any RCC; a single rare HER2 mutation (R816H) was found in a collecting duct carcinoma. VHL mutations were identified in 50% of ccRCC tumors. We observed lower rates of TP53 (14%), ATM (6%), and PIK3CA(4% ccRCC, 7% PRCC) mutations compared to other cancers. Conclusions: Multiplatform molecular profiling of renal cell carcinoma identifies potential predictive biomarkers in ccRCC. The documented activity of everolimus in ccRCC (RECORD-1 trial) may be attributable to PIK3CA pathway alterations. RCC with sarcomatoid features may respond to PD1/PD-L1 targeted immunotherapies. The impact of molecular profiling in ccRCC to predict responses to currently available targeted therapy has important implications for trial design and patient selection.

scholarly journals Molecular Profiling-Selected Therapy for Treatment of Advanced Pancreaticobiliary Cancer: A Retrospective Multicenter Study

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Ron Epelbaum ◽  
Einat Shacham-Shmueli ◽  
Baruch Klein ◽  
Abed Agbarya ◽  
Baruch Brenner ◽  
...  
Keyword(s):  
Null Hypothesis ◽  
Impact Analysis ◽  
Treatment Decision ◽  
Treatment Decisions ◽  
Molecular Profiling ◽  
Outcome Analysis ◽  
Multicenter Cohort Study ◽  
Pancreaticobiliary Cancer ◽  
The Impact ◽  
Guided Therapy

This multicenter cohort study assessed the impact of molecular profiling (MP) on advanced pancreaticobiliary cancer (PBC). The study included 30 patients treated with MP-guided therapy after failing ≥1 therapy for advanced PBC. Treatment was considered as having benefit for the patient if the ratio between the longest progression-free survival (PFS) on MP-guided therapy and the PFS on the last therapy before MP was ≥1.3. The null hypothesis was that ≤15% of patients gain such benefit. Overall, ≥1 actionable (i.e., predictive of response to specific therapies) biomarker was identified/patient. Immunohistochemistry (the most commonly used method for guiding treatment decisions) identified 1–6 (median: 4) actionable biomarkers per patient. After MP, patients received 1–4 (median: 1) regimens/patient (most commonly, FOLFIRI/XELIRI). In a decision-impact analysis, of the 27 patients for whom treatment decisions before MP were available, 74.1% experienced a treatment decision change in the first line after MP. Twenty-four patients were evaluable for clinical outcome analysis; in 37.5%, the PFS ratio was ≥1.3. In one-sided exact binomial test versus the null hypothesis,P= 0.0015; therefore, the null hypothesis was rejected. In conclusion, our analysis demonstrated the feasibility, clinical decision impact, and potential clinical benefits of MP-guided therapy in advanced PBC.

Clinical Utility of Molecular Profiling in Higher Risk MDS Treated with Azacitidine: Can We Tailor Therapy Accordingly?

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1984-1984 ◽  
Author(s):  
David Sallman ◽  
Eric Padron ◽  
Jinming Song ◽  
Mohammad Omar Hussaini ◽  
Christine Vaupel ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Research Funding ◽  
Somatic Mutations ◽  
Multivariable Analysis ◽  
Molecular Profiling ◽  
Molecular Profile ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Myeloid Malignancies ◽  
The Impact

Abstract Background Hypomethylating agent (HMA) therapy represents the standard of care for patients with higher risk myelodysplastic syndromes although only 50% of patients respond to treatment. Recent evidence from molecular profiling through next-generation sequencing (NGS) in myeloid diseases has been conflicting as to the value of somatic mutations as a biomarker for response to HMA. TET2 mutations, predominantly in the absence of ASXL1 mutations (or variant allele frequency (VAF) < 10%), have been shown to predict HMA response in MDS and chronic myelomonocytic leukemia (CMML) (Itzykson et al., 2011; Bejar et al., 2014 (80% decitabine)) while DNMT3A mutations predict response to frontline HMA treatment in acute myeloid leukemia (AML) (Coombs et al., 2016). Therefore, our goal was to identify molecular predictors of response and outcomes to azacitidine in myeloid malignancies. Patients and Methods Genetically profiled higher-risk MDS, CMML and oligoblastic AML (20-30% blasts) cases were retrospectively identified from the Moffitt Cancer Center MDS database. We evaluated gene mutations associated with DNA methylation (TET2, DNMT3A, IDH1, IDH2, and WT1) and up to 19 additional genes. NGS was performed prior to the initiation of HMA in all patients. The lower limit of VAF detection was set at 5% and the minimum depth of coverage at each position was 500X. Clinical variables and outcomes of MDS patients were characterized at the time of sample procurement. Fisher's exact and t-tests were used for comparative analyses. Kaplan-Meier curves were used to estimate overall survival and analyzed from the date of mutation identification. Multivariate Cox regression models were created to adjust for clinical characteristics. Results From May 2013 to February 2016, a total of 77 patients with NGS for somatic mutations prior to HMA therapy were identified with a median age of 70 years and male predominance (66%). Of the cohort, 97% of patients (n=75) were treated with azacitidine with 17% of patients (n=13) proceeding to allogeneic hematopoietic stem cell transplant (AHSCT). A total of 86% of patients (n=66) had at least one pathogenic mutation. Mutations in DNA methylation occurred in 43% of patients (n=33) while TET2 mutation without clonal ASXL1 mutations occurred in 13% of patients (n=10). At a median follow up 17 months, the median OS of the entire cohort was 12.5 months. Patients with a DNA methylation mutation had a median OS that was not reached (NR) vs a median OS of 11.5 months in wildtype (WT) patients (HR 0.38, 95% CI 0.21 to 0.75; P = 0.005), which remained significant when censoring patients at time of AHSCT (P = 0.002). TP53 mutant (MT) patients (n=14, 18% of cohort) had a median OS of 7.9 months vs 15.4 months in WT patients (HR 3.69, 95% CI 3.04 to 28.8; P = 0.0001). The presence of DNA methylation or TP53 mutation in comparison to wildtype patients significantly stratified prognosis in azacitidine treated patients (Figure 1A, P = 0.0001). In multivariable analysis incorporating age and revised international prognostic scoring system (IPSS-R) category, DNA methylation (HR 0.45, 95% CI 0.21 to 0.96; P = 0.04) and TP53 (HR 2.34, 95% CI 1.04 to 5.26; P = 0.04) mutation status remained predictive for survival. Notably, response rates in DNA methylation mutant patients were similar to WT patients (40% versus 42%) with no difference in treatment duration. However, the overall response rate of TET2 MT/ASXL1 WT patients was 70% versus 36% in the rest of the cohort (P =0.08) and 0% in TET2 MT/ASXL1 MT patients (0/6, P =0.01) with a significantly longer duration of treatment in the TET2 MT/ASXL1 WT cohort (median number of cycles 7.5 versus 4; P = 0.002). Additionally, TET2 MT/ASXL1 WT patients had longer survival (median OS NR vs 12.2 months; P = 0.047). When censoring for transplant, the impact of TET2 MT/ASXL1 WT genoptype was significantly strengthened with 70% of patients alive past 15 months (median OS NR vs 9.9 months; HR 0.24, 95% CI 0.19 to 0.75; P = 0.007; Figure 1B). Conclusion In patients with myeloid malignancies, molecular profiling via NGS can predict outcomes to azacitidine therapy. Patients with mutations of DNA methylation have improved OS whereas OS is poor in TP53 MT patients. Most importantly, TET2 MT/ASXL1 WT identifies a genotypic subgroup with particularly good outcomes when treated with HMA without AHSCT and potentially challenges the early timing of AHSCT for higher risk patients and this molecular profile. Figure 1 Figure 1. Disclosures Padron: Novartis: Honoraria; Incyte: Research Funding; CTI: Honoraria, Research Funding; KALOBIOS: Research Funding. Vaupel:Genoptix, a Novartis Company: Employment. Hall:Genoptix, a Novartis Company: Employment. Komrokji:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Speakers Bureau; Boehringer-Ingelheim: Research Funding; Incyte: Consultancy.

scholarly journals Interim analysis of a real-world precision medicine platform for molecular profiling of metastatic or advanced cancers: MONDTI

ESMO Open ◽  
2019 ◽  
Vol 4 (4) ◽  
pp. e000538 ◽  
Author(s):  
Markus Kieler ◽  
Matthias Unseld ◽  
Daniela Bianconi ◽  
Fredrik Waneck ◽  
Robert Mader ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Growth Factor ◽  
Precision Medicine ◽  
Molecular Profiling ◽  
Solid Tumours ◽  
High Rate ◽  
Molecular Profile ◽  
Individual Treatment ◽  
Tumour Board ◽  
Hodgkin's Lymphomas

BackgroundHigh-throughput genomic profiling of tumour specimens facilitates the identification of individual actionable mutations which could be used for individualised targeted therapy. This approach is becoming increasingly more common in the clinic; however, the interpretation of results from molecular profiling tests and efficient guiding of molecular therapies to patients with advanced cancer offer a significant challenge to the oncology community.Experimental designMONDTI is a precision medicine platform for molecular characterisation of metastatic solid tumours to identify actionable genomic alterations. From 2013 to 2016, comprehensive molecular profiles derived from real-time biopsy specimens and archived tumour tissue samples of 295 patients were performed. Results and treatment suggestions were discussed within multidisciplinary tumour board meetings.ResultsThe mutational profile was obtained from 293 (99%) patients and a complete immunohistochemical (IHC) and cytogenetic profile was obtained in 181 (61%) and 188 (64%) patients. The most frequent cancer types were colorectal cancer (12%), non-Hodgkin’s lymphomas (9.8%) and head and neck cancers (7.8%). The most commonly detected mutations were TP53 (39%), KRAS (19%) and PIK3CA (9.5%), whereas ≥1 mutation were identified in 217 (74%) samples. Regarding the results for IHC testing, samples were positive for phospho-mammalian target of rapamycin (phospho-mTOR) (71%), epidermal growth factor receptor (EGFR) (68%), mesenchymal epithelial transition (MET) (56%) and/or platelet-derived growth factor alpha (PDGFRα)-expression (48%). Of the 288 tumour samples with one or more genetic alteration detected, 160 (55.6%) targeted therapy recommendations through 67 multidisciplinary tumour board meetings were made; in 69 (24%) cases, an individual treatment concept was initiated.ConclusionsThe results reveal that the open concept for all solid tumours characterised for molecular profile and immunotherapy could not only match individualised treatment concepts at a high rate but also underscores the challenges encountered when offering molecularly matched therapies to a patient population with an advanced stage cancer.

scholarly journals Mammary analogue secretory carcinoma of the salivary gland with NTRK fusions: new approaches for diagnostics and targeted therapy (review)

2020 ◽  
Vol 10 (2) ◽  
pp. 69-78
Author(s):  
A. V. Ignatova ◽  
A. M. Mudunov ◽  
S. О. Podvyaznikov ◽  
Yu. V. Alymov
Keyword(s):  
Salivary Gland ◽  
Targeted Therapy ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Acquired Resistance ◽  
Molecular Profiling ◽  
Molecular Profile ◽  
Secretory Carcinoma ◽  
Generation Sequencing

Mammary analogue secretory carcinoma (MASC) of the salivary gland is a rare salivary cancer, histologically resembling to secretory carcinoma of the breast. In 2017 World Health Organization reported MASC is a new salivary cancer subtype. The aim of this article is to collect and analyze data about MASC, particularly clinical, histological and molecular profile, to evaluate targeted therapy effects. We discuss a case report of dramatic and durable response with entrectinib and the development of acquired resistance in an NTRK3-fusion positive salivary cancer, detected by next-generation sequencing. Next-generation sequencing as a comprehensive molecular profiling, that helps to investigate molecular profile of rare tumors and gives an opportunity to use an effective therapeutic options. Identifying ETV6-NTRK3 positive MASC provides a better prognosis for metastatic disease by using a novel effective targeted therapy with tyrosine kinase inhibitors (entrectinib, larotrectinib). Despite a durable and dramatic response, we showed an interesting case of the development of acquired resistance to tyrosine kinase inhibitors mediated by the appearance of a novel NTRK3 G623R mutation. Finally, we believe in great perspectives of comprehensive molecular profiling and targeted therapy for rare malignancies with NTRK gene fusions, including second-generation tyrosine kinase inhibitors.

Characterization of genomic alterations and biomarker expression patterns of gastrointestinal cancers using a multiplatform molecular profiling tool.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 594-594
Author(s):  
Giselle Alexandra Suero-Abreu ◽  
Miguel Gonzalez Velez ◽  
Marshall McKenna ◽  
Narjust Duma ◽  
Shalini R Krishnasamy ◽  
...  
Keyword(s):  
Decision Making ◽  
Clinical Decision Making ◽  
Expression Patterns ◽  
Clinical Decision ◽  
Median Number ◽  
Molecular Profiling ◽  
Molecular Profile ◽  
Gastrointestinal Cancers ◽  
Genomic Alterations ◽  
The Impact

594 Background: Given the heterogeneity of gastrointestinal cancers (GICs), molecular profiling is becoming part of the standard of care for many solid tumors. The aim of this study was to evaluate the molecular profile of patients (pts) with GICs using a multiplatform profiling tool and to assess how the pattern of detected molecular alterations could guide clinical decision-making in these tumors. Methods: We retrospectively analyzed samples of 85 pts with GICs via a multiplatform profiling service (Caris Life Sciences, Phoenix, AZ) in order to evaluate clinically relevant genomic alterations (CRGAs) and clinically relevant biomarker expression (CRBs) in GICs. Results: A total of 85 pts with GICs were analyzed. 45 (53 %) were males and 40 (47%) were females. Tumors were colorectal 43 (51%), pancreatic 11 (13%) esophageal 11 (13%) gastric 8 (9%), hepatobiliary 8 (11%), anal canal 3 (4%), and small intestine 1 (1%). 80 cases (94%) had adequate sample for profiling. CRGAs were identified in 71 cases (89%) with a median of 3 CRGAs in the cohort. The most commonly detected CRGAs were TP53 45 (56%), APC 35 (44%), KRAS 32 (40%), ATM 14 (18%) and PTEN 5 (6%). The median number of CRBs was 9 and high expression levels were seen of mismatch repair biomarkers (MLH1, MSH2, MSH6, PMS2) in 45 (56%), TOPO1 in 44 (55%), PTEN in 27 (34%), TOP2A in 20 (25%), ERCC1 in 19 (24%), and both TS and TUBB3 in 17 (21%). Based on actionable CRGAs and CRBs, 94% of pts matched at least one FDA approved treatment with proven clinical benefit, with a median of 4 available therapies per pt. In addition, there was a median of 189 chemotherapy and 64 targeted therapy clinical trial opportunities available for these pts given the molecular blueprint of their GICs. Conclusions: Multiplatform molecular profiling identified a high frequency of actionable CRGAs and CRBs in GIC pts. This approach has the potential to aid in clinical decision-making by providing a stratification of beneficial therapeutic alternatives individualized to the molecular framework of tumor. Larger prospective studies are warranted to further investigate the impact of profiling guided treatment decisions on patient outcomes.

scholarly journals Protein Tyrosine Kinases: Their Roles and Their Targeting in Leukemia

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 184
Author(s):  
Kalpana K. Bhanumathy ◽  
Amrutha Balagopal ◽  
Frederick S. Vizeacoumar ◽  
Franco J. Vizeacoumar ◽  
Andrew Freywald ◽  
...  
Keyword(s):  
Growth Factor ◽  
Protein Kinase ◽  
Tyrosine Kinase ◽  
Protein Kinases ◽  
Tyrosine Kinases ◽  
Treatment Options ◽  
Growth Factor Receptor ◽  
Tyrosine Protein Kinase ◽  
Mesenchymal Epithelial Transition Factor ◽  
The Impact

Protein kinases constitute a large group of enzymes catalysing protein phosphorylation and controlling multiple signalling events. The human protein kinase superfamily consists of 518 members and represents a complicated system with intricate internal and external interactions. Protein kinases are classified into two main families based on the ability to phosphorylate either tyrosine or serine and threonine residues. Among the 90 tyrosine kinase genes, 58 are receptor types classified into 20 groups and 32 are of the nonreceptor types distributed into 10 groups. Tyrosine kinases execute their biological functions by controlling a variety of cellular responses, such as cell division, metabolism, migration, cell–cell and cell matrix adhesion, cell survival and apoptosis. Over the last 30 years, a major focus of research has been directed towards cancer-associated tyrosine kinases owing to their critical contributions to the development and aggressiveness of human malignancies through the pathological effects on cell behaviour. Leukaemia represents a heterogeneous group of haematological malignancies, characterised by an uncontrolled proliferation of undifferentiated hematopoietic cells or leukaemia blasts, mostly derived from bone marrow. They are usually classified as chronic or acute, depending on the rates of their progression, as well as myeloid or lymphoblastic, according to the type of blood cells involved. Overall, these malignancies are relatively common amongst both children and adults. In malignant haematopoiesis, multiple tyrosine kinases of both receptor and nonreceptor types, including AXL receptor tyrosine kinase (AXL), Discoidin domain receptor 1 (DDR1), Vascular endothelial growth factor receptor (VEGFR), Fibroblast growth factor receptor (FGFR), Mesenchymal–epithelial transition factor (MET), proto-oncogene c-Src (SRC), Spleen tyrosine kinase (SYK) and pro-oncogenic Abelson tyrosine-protein kinase 1 (ABL1) mutants, are implicated in the pathogenesis and drug resistance of practically all types of leukaemia. The role of ABL1 kinase mutants and their therapeutic inhibitors have been extensively analysed in scientific literature, and therefore, in this review, we provide insights into the impact and mechanism of action of other tyrosine kinases involved in the development and progression of human leukaemia and discuss the currently available and emerging treatment options based on targeting these molecules.

scholarly journals Solid-Phase Extraction Embedded Dialysis (SPEED), an Innovative Procedure for the Investigation of Microbial Specialized Metabolites

Marine Drugs ◽  
2021 ◽  
Vol 19 (7) ◽  
pp. 371
Author(s):  
Phuong-Y Mai ◽  
Géraldine Le Goff ◽  
Erwan Poupon ◽  
Philippe Lopes ◽  
Xavier Moppert ◽  
...  
Keyword(s):  
Solid Phase Extraction ◽  
Solid Phase ◽  
Chemical Space ◽  
Molecular Profile ◽  
Phase Extraction ◽  
Specialized Metabolites ◽  
Streptomyces Albidoflavus ◽  
Cultivation Process ◽  
The Impact

Solid-phase extraction embedded dialysis (SPEED technology) is an innovative procedure developed to physically separate in-situ, during the cultivation, the mycelium of filament forming microorganisms, such as actinomycetes and fungi, and the XAD-16 resin used to trap the secreted specialized metabolites. SPEED consists of an external nylon cloth and an internal dialysis tube containing the XAD resin. The dialysis barrier selects the molecular weight of the trapped compounds, and prevents the aggregation of biomass or macromolecules on the XAD beads. The external nylon promotes the formation of a microbial biofilm, making SPEED a biofilm supported cultivation process. SPEED technology was applied to the marine Streptomyces albidoflavus 19-S21, isolated from a core of a submerged Kopara sampled at 20 m from the border of a saltwater pond. The chemical space of this strain was investigated effectively using a dereplication strategy based on molecular networking and in-depth chemical analysis. The results highlight the impact of culture support on the molecular profile of Streptomyces albidoflavus 19-S21 secondary metabolites.

Sign in / Sign up

Export Citation Format

Share Document