Description of PTPRG genetic variants identified in a cohort of Chronic Myeloid Leukemia patients and their ability to influence response to Tyrosine kinase Inhibitors.

Tyrosine kinase inhibitors (TKIs) have remarkably transformed Ph+ chronic myeloid leukemia (CML) management; however, TKI resistance remains a major clinical challenge. Mutations in BCR-ABL1 are well studied but fail to explain 20-40% of resistant cases, suggesting the activation of alternative, BCR-ABL1-independent pathways. Protein Tyrosine Phosphatase Receptor Gamma (PTPRG), a tumor suppressor, was found to be well expressed in CML patients responsive to TKIs and remained at low level in resistant patients. In this study, we aimed to identify genetic variants in PTPRG that could potentially modulate TKIs response in CML patients. DNA was extracted from peripheral blood samples collected from two CML cohorts (Qatar and Italy) and targeted exome sequencing was performed. Among 31 CML patients, six were TKI-responders and 25 were TKI-non-responsive. Sequencing identified ten variants, seven were annotated and three were novel SNPs (c.1602_1603insC, c.85+14412delC, and c.2289-129delA). Among them, five variants were identified in 15 resistant cases. Of these, one novel exon variant (c.1602_1603insC), c.841-29C>T (rs199917960) and c.1378-224A>G (rs2063204) were found to be significantly different between the resistant cases compared to responders. Our findings suggest that PTPRG variants may act as an indirect resistance mechanism of BCR-ABL1 to affect TKI treatment.

Phase I clinical trial of HC-1119 soft capsule in Chinese healthy adult male subjects: Pharmacokinetics and safety of single-dose proportionality and effects of food.

BACKGROUND: Preclinical studies showed that HC-1119, a deuterated version of enzalutamide, could competitively inhibit androgen binding to androgen receptor by blocking the transmission of androgen receptor signaling pathway as enzalutamide, inducing apoptosis of prostate cancer cells and reducing the proliferation of prostate cancer cells. Animal pharmacokinetic studies also show that deuterization of enzalutamide as HC-1119 could retain the basic properties of mother drug, increases the stability of compounds to metabolic enzymes and the drug exposure in vivo, prolong the half-life and reduce the production of metabolites, which may lead to a better efficacy and safety of HC-1119 compared with enzalutamide. METHODS: To evaluate the pharmacokinetics and safety of HC-1119 and the effects of food on pharmacokinetics in healthy adult Chinese men after single-dose administration of HC-1119. A total of 47 Chinese healthy adult male subjects received HC-1119 soft capsule at a single oral dose of 40, 80, or 160 mg followed on fasting or 160 mg after high-fat meal respectively. HC-1119 prototype and its metabolites M1 and M2 in plasma were collected individually in a total 23 time points. Pharmacokinetics were determined by sensitive LC/MS/MS for dose-proportionality study. RESULTS: In subjects taking HC-1119 soft capsules on fasting, Cmax of HC-1119 prototype increased dose-dependently. Either Cmax and AUC0-∞ of M1 or Cmax of M2 showed statistically significant difference. Dose-proportionality evaluation showed linear pharmacokinetic characteristics in Cmax of HC-1119 prototype, Cmax and AUC0-∞ of M2 in dose range of 40-160 mg. Cmax of HC-1119 was significantly different between the two groups as 160 mg HC-1119 on fasting or after a high-fat diet respectively, while the other parameter were not. HC-1119 and its metabolites M1 and M2 showed a linear dynamic trend. CONCLUSIONS: HC-1119 is expected to have lower clinical dose than the similar drug enzalutamide. The absorption of HC-1119 and the main pharmacokinetic parameters of HC-1119 and its metabolites M1 and M2 were not affected by high-fat diet. The clinical application of HC-1119 soft capsule in the later stage can be recommended for both fasting and postprandial. The safety and tolerance were good in this population.

Expression dynamics of the immune mediators ARG1, TBET, CIITA, IL10 and TGFB1 in chronic myeloid leukaemia patients during the first year of imatinib therapy.

The use of tyrosine kinase inhibitors seems to restore the broadly compromised immune system described in chronic myeloid leukaemia (CML) patients at diagnosis leading to a re-activation of the effector-mediated immune surveillance. Here, we describe the expression dynamics of immune factors during the first year on imatinib therapy. Gene expression was evaluated in 132 peripheral blood samples from 79 CML patients, including 34 who were serially followed. An aliquot of the stored sample used to monitor BCR-ABL1 levels was retro-transcribed to cDNA and gene expression was quantified by real-time PCR. An elevated expression of ARG1 was observed at diagnosis, while TBET, CIITA, IL10 and TGFB1 were significantly decreased. Once on therapy, each gene displayed a particular behaviour. ARG1 normalized to control levels at 3 months only in optimal molecular responders and was identified as the major contributor to the difference among patients. TBET reached normal levels after 12 months in optimal responders and non-responders, regardless the Th1-response previously associated, and CIITA continued downregulated. IL10 and TGFB1 achieved normal levels early at 3 months in both groups, afterwards IL10 was sustained while TGFB1 was slightly increased after 1 year in responders. Our findings are in agreement with an immune re-activation after imatinib initiation; however, some immune mediators may require a longer exposition. The follow-up of novel and reliable biomarkers, such as ARG1, one of the principal mechanisms of myeloid-derived-suppressor cells to inhibit immune system, may be useful to deepen the characterization of early responder patients.

Effects of dexmedetomidine on hemodynamic, oxygenation, microcirculation, and inflammatory markers in a porcine model of sepsis

Purpose: To determine whether dexmedetomidine aggravates hemodynamic, metabolic variables, inflammatory markers, and microcirculation in experimental septic shock. Methods: Twenty-four pigs randomized into: Sham group (n = 8), received saline; Shock group (n = 8), received an intravenous infusion of Escherichia coli O55 (3 × 109 cells/mL, 0.75 mL/kg, 1 hour); Dex-Shock group (n = 8), received bacteria and intravenous dexmedetomidine (bolus 0.5 mcg/kg followed by 0.7 mcg/kg/h). Fluid therapy and/ornorepinephrine were administered to maintain a mean arterial pressure > 65 mmHg. Hemodynamic, metabolic, oxygenation, inflammatory markers, and microcirculation were assessed at baseline, at the end of bacterial infusion, and after 60, 120, 180, and 240 minutes. Results: Compared to Shock group, Dex-Shock group presented a significantly increased oxygen extraction ratio at T180 (23.1 ± 9.7 vs. 32.5 ± 9.2%, P = 0.0220), decreased central venous pressure at T120 (11.6 ± 1 vs. 9.61 ± 1.2 mmHg, P = 0.0214), mixed-venous oxygen saturation at T180 (72.9 ± 9.6 vs. 63.5 ± 9.2%, P = 0.026), and increased plasma lactate (3.7 ± 0.5 vs. 5.5 ± 1 mmol/L, P = 0.003). Despite the Dex-Shock group having a better sublingual vessel density at T240 (12.5 ± 0.4 vs. 14.4 ± 0.3 mL/m2; P = 0.0003), sublingual blood flow was not different from that in the Shock group (2.4 ± 0.2 vs. 2.4 ± 0.1 mL/kg, P = 0.4418). Conclusions: Dexmedetomidine did not worsen the hemodynamic, metabolic, inflammatory, or sublingual blood flow disorders resulting from septic shock. Despite inducing a better sublingual vessel density, dexmedetomidine initially and transitorily increased the mismatch between oxygen supply and demand.

Identification of DNA methylation biomarkers with potential to predict response to neoadjuvant chemotherapy in triple-negative breast cancer.

Neoadjuvant chemotherapy (NAC) is used to treat triple-negative breast cancer (TNBC) prior to resection. Biomarkers that accurately predict a patient's response to NAC are needed to individualise therapy and avoid chemotoxicity from unnecessary chemotherapy. We performed whole-genome DNA methylation profiling on diagnostic TNBC biopsy samples from the Sequential Evaluation of Tumours Undergoing Preoperative (SETUP) NAC study. We found 9 significantly differentially methylated regions (DMRs) at diagnosis which were associated with response to NAC. We show that 4 of these DMRs are associated with TNBC overall survival (P < 0.05). Our results highlight the potential of DNA methylation biomarkers for predicting NAC response in TNBC.

The mRNA Expression and Regulation of Glucocorticoid Receptor Isoforms Associated with Response of Multiple Myeloma Treated with a Glucocorticoids-Dependent Regimen of Dexamethasone, Bortezomib and Thalidomide.

OBJECTIVE: Glucocorticoids (GCs) are the effective first-line drugs and indispensable in chemotherapy regimens to treat patients with multiple myeloma (MM). Previous studies in a variety of hematologic malignancies have shown that the biological action of GC is mediated through the expression and activation and of glucocorticoids receptor (GR) isoforms in vitro. GR and its regulation are crucial determinants of the efficacy of GC independent therapy. There is currently lack of research on patients with MM. METHODS: 132 patients with MM were divided into responders (78 cases) and nonresponders (54 cases) according to the efficacy evaluated after four cycles of GC-dependent regimen. 66 patients with iron-deficiency anemia were served as controls. Preparation of mononuclear bone marrow cells (MBMCs) was purified by Ficoll-Hypaque gradient centrifugation. The mRNA expression of GR α, ß, γ, P, SRp30, SRp40, HSP90, NF-κB and AP-1 were detected by real time RT-PCR. TRIAL REGISTRATION: CHiCTR-RCH-12002872. RESULTS: The expression of four GR isoforms exhibited the following trend in MM patients and controls: GRα>GR-P>GRγ>GRß. GRα and HSP90 expression in responders was significantly higher than that of the nonresponders (P<0.050). HSP90/GRα expression in MM patients exhibited significantly higher than that in controls (P<0.001). SRp30c and SRp40 mRNA expression both showed significant positive correlation with GRα transcript (P<0.001). Compared with controls, NF-kB and AP -1 expression in MM patients was higher. NF-kB and AP-1 expression of nonresponders were significantly higher than that of responders. The difference was not obvious statistically (P>0.050). CONCLUSION: Our findings raise the possibility that low expression of GRα and HSP90 plays important roles in nonresponders. Lack of HSP90 might affect GR structure and further take part in nonresponse. SRp30c and SRp40 mRNA expression both showed significant positive correlation with GRα. That might become new targets for treatment of nonresponders in MM patients, although further studies are needed for clarification.

What Are the Biomarkers for Immunotherapy in SCLC?

Small-cell lung cancer (SCLC) is an aggressive malignancy that exhibits a rapid doubling time, a high growth fraction, and the early development of widespread metastases. The addition of immune checkpoint inhibitors to first-line chemotherapy represents the first significant improvement of systemic therapy in several decades. However, in contrast to its effects on non-SCLC, the advantageous effects of immunotherapy addition are modest in SCLC. In particular, only a small number of SCLC patients benefit from immune checkpoint inhibitors. Additionally, biomarkers selection is lacking for SCLC, with clinical trials largely focusing on unselected populations. Here, we review the data concerning the major biomarkers for immunotherapy, namely, programmed death ligand 1 expression and tumour mutational burden. Furthermore, we explore other potential biomarkers, including the role of the immune microenvironment in SCLC, the role of genetic alterations, and the potential links between neurological paraneoplastic syndromes, serum anti-neuronal nuclear antibodies, and outcomes in SCLC patients treated with immunotherapy.

Benefits of functional assays in personalized cancer medicine: more than just a proof-of-concept.

As complex and heterogeneous diseases, cancers require a more tailored therapeutic management than most pathologies. Recent advances in anticancer drug development, including the immuno-oncology revolution, have been too often plagued by unsatisfying patient response rates and survivals. In reaction to this, cancer care has fully transitioned to the "personalized medicine" concept. Numerous tools are now available tools to better adapt treatments to the profile of each patient. They encompass a large array of diagnostic assays, based on biomarkers relevant to targetable molecular pathways. As a subfamily of such so-called companion diagnostics, chemosensitivity and resistance assays represent an attractive, yet insufficiently understood, approach to individualize treatments. They rely on the assessment of a composite biomarker, the ex vivo functional response of cancer cells to drugs, to predict a patient's outcome. Systemic treatments, such as chemotherapies, as well as targeted treatments, whose efficacy cannot be fully predicted yet by other diagnostic tests, may be assessed through these means. The results can provide helpful information to assist clinicians in their decision-making process. We explore here the most advanced functional assays across oncology indications, with an emphasis on tests already displaying a convincing clinical demonstration. We then recapitulate the main technical obstacles faced by researchers and clinicians to produce more accurate, and thus more predictive, models and the recent advances that have been developed to circumvent them. Finally, we summarize the regulatory and quality frameworks surrounding functional assays to ensure their safe and performant clinical implementation. Functional assays are valuable in vitro diagnostic tools that already stand beyond the "proof-of-concept" stage. Clinical studies show they have a major role to play by themselves but also in conjunction with molecular diagnostics. They now need a final lift to fully integrate the common armament used against cancers, and thus make their way into the clinical routine.

Identification and Prognostic Value Exploration of Cyclophosphamide (Cytoxan)-Centered Chemotherapy Response-Associated Genes in Breast Cancer.

In this study, we aimed to explore cyclophosphamide (Cytoxan) response-associated genes and constructed a model to predict the prognosis of breast cancer (BRCA) patients. Samples obtained from TCGA and GEO databases were subjected to Weighted Gene Coexpression Network Analysis (WGCNA) and univariate Cox and LASSO Cox regression analysis to identify and validate the Cytoxan response-related prognostic signature. Moreover, multivariate Cox regression analysis was performed to analyze the independence of factors, and the nomogram model was constructed by including all the independent factors. WGCNA revealed that 159 genes are significantly correlated with Cytoxan response in BRCA samples, and the samples with a different prognosis could be effectively distinguished based on the expression of those 159 genes. Ten genes were further selected to be related to the prognosis of BRCA patients, including PCDHB2, GRIK2, FRMD7, CCSER1, PCDHGA1, PCDHA1, LRRC37A6P, PCDHGA12, ZNF486, and PCDHGB5, based on the Risk Score model. Among them, PCDHA1 expression was validated in cells and patient samples. Multivariate Cox regression analysis confirmed that the Risk Score is an independent factor. Furthermore, the nomogram model showed that the predicted survival probability is closely related to the actual survival probability. In conclusion, we identified 159 genes potentially correlated with the Cytoxan response of BRCA patients, which had prognostic value in BRCA.

Glutamine Antagonist GA-607 Causes a Dramatic Accumulation of FGAR which can be used to Monitor Target Engagement.

BACKGROUND: Metabolomic analyses from our group and others have shown that tumors treated with glutamine antagonists (GA) exhibit robust accumulation of formylglycinamide ribonucleotide (FGAR), an intermediate in the de novo purine synthesis pathway. The increase in FGAR is attributed to the inhibition of the enzyme FGAR amidotransferase (FGAR-AT) that catalyzes the ATP-dependent amidation of FGAR to formylglycinamidine ribonucleotide (FGAM). While perturbation of this pathway resulting from GA therapy has long been recognized, no study has reported systematic quantitation and analyses of FGAR in plasma and tumors. OBJECTIVE: Herein, we aimed to evaluate the efficacy of our recently discovered tumor-targeted GA prodrug, GA-607 (isopropyl 2-(6-acetamido-2-(adamantane-1-carboxamido)hexanamido)-6-diazo-5-oxohexanoate), and demonstrate its target engagement by quantification of FGAR in plasma and tumors. METHODS: Efficacy and pharmacokinetics of GA-607 were evaluated in a murine EL4 lymphoma model followed by global tumor metabolomic analysis. Liquid chromatography-mass spectrometry (LC-MS) based methods employing the ion-pair chromatography approach were developed and utilized for quantitative FGAR analyses in plasma and tumors. RESULTS: GA-607 showed preferential tumor distribution and robust single-agent efficacy in a murine EL4 lymphoma model. While several metabolic pathways were perturbed by GA-607 treatment, FGAR showed the highest increase qualitatively. Using our newly developed sensitive and selective LC-MS method, we showed a robust >80- and >10- fold increase in tumor and plasma FGAR levels, respectively, with GA-607 treatment. CONCLUSION: These studies describe the importance of FGAR quantification following GA therapy in cancer and underscore its importance as a valuable pharmacodynamic marker in the preclinical and clinical development of GA therapies.

Wild-Type KRAS Allele Effects on Druggable Targets in KRAS Mutant Lung Adenocarcinomas.

KRAS mutations are one of the most common oncogenic drivers in non-small cell lung cancer (NSCLC) and in lung adenocarcinomas in particular. Development of therapeutics targeting KRAS has been incredibly challenging, prompting indirect inhibition of downstream targets such as MEK and ERK. Such inhibitors, unfortunately, come with limited clinical efficacy, and therefore the demand for developing novel therapeutic strategies remains an urgent need for these patients. Exploring the influence of wild-type (WT) KRAS on druggable targets can uncover new vulnerabilities for the treatment of KRAS mutant lung adenocarcinomas. Using commercially available KRAS mutant lung adenocarcinoma cell lines, we explored the influence of WT KRAS on signaling networks and druggable targets. Expression and/or activation of 183 signaling proteins, most of which are targets of FDA-approved drugs, were captured by reverse-phase protein microarray (RPPA). Selected findings were validated on a cohort of 23 surgical biospecimens using the RPPA. Kinase-driven signatures associated with the presence of the KRAS WT allele were detected along the MAPK and AKT/mTOR signaling pathway and alterations of cell cycle regulators. FoxM1 emerged as a potential vulnerability of tumors retaining the KRAS WT allele both in cell lines and in the clinical samples. Our findings suggest that loss of WT KRAS impacts on signaling events and druggable targets in KRAS mutant lung adenocarcinomas.

Emerging role of circulating tumor cells in immunotherapy.

Over the last few years, immunotherapy, in particular, immune checkpoint inhibitor therapy, has revolutionized the treatment of several types of cancer. At the same time, the uptake in clinical oncology has been slow owing to the high cost of treatment, associated toxicity profiles and variability of the response to treatment between patients. In response, personalized approaches based on predictive biomarkers have emerged as new tools for patient stratification to achieve effective immunotherapy. Recently, the enumeration and molecular analysis of circulating tumor cells (CTCs) have been highlighted as prognostic biomarkers for the management of cancer patients during chemotherapy and for targeted therapy in a personalized manner. The expression of immune checkpoints on CTCs has been reported in a number of solid tumor types and has provided new insight into cancer immunotherapy management. In this review, we discuss recent advances in the identification of immune checkpoints using CTCs and shed light on the potential applications of CTCs towards the identification of predictive biomarkers for immunotherapy.

High-throughput screening and genome-wide analyses of 44 anticancer drugs in the 1000 Genomes cell lines reveals an association of the NQO1 gene with the response of multiple anticancer drugs.

Cancer patients exhibit a broad range of inter-individual variability in response and toxicity to widely used anticancer drugs, and genetic variation is a major contributor to this variability. To identify new genes that influence the response of 44 FDA-approved anticancer drug treatments widely used to treat various types of cancer, we conducted high-throughput screening and genome-wide association mapping using 680 lymphoblastoid cell lines from the 1000 Genomes Project. The drug treatments considered in this study represent nine drug classes widely used in the treatment of cancer in addition to the paclitaxel + epirubicin combination therapy commonly used for breast cancer patients. Our genome-wide association study (GWAS) found several significant and suggestive associations. We prioritized consistent associations for functional follow-up using gene-expression analyses. The NAD(P)H quinone dehydrogenase 1 (NQO1) gene was found to be associated with the dose-response of arsenic trioxide, erlotinib, trametinib, and a combination treatment of paclitaxel + epirubicin. NQO1 has previously been shown as a biomarker of epirubicin response, but our results reveal novel associations with these additional treatments. Baseline gene expression of NQO1 was positively correlated with response for 43 of the 44 treatments surveyed. By interrogating the functional mechanisms of this association, the results demonstrate differences in both baseline and drug-exposed induction.

Transient deterioration of albumin-bilirubin scores in early post-dose period of molecular targeted therapies in advanced hepatocellular carcinoma with 50% or higher liver occupation: A STROBE-compliant retrospective observational study.

ABSTRACT: Real-world clinical cases of molecularly targeted agent (MTA) administration to patients with advanced hepatocellular carcinoma (HCC) with ≥50% liver occupation have been reported, but treatment outcomes have rarely been described. We have encountered several cases in which albumin-bilirubin (ALBI) scores deteriorated markedly and C-reactive protein (CRP) levels elevated in the early post-dose period. The present study therefore investigated early clinical changes in ALBI score and CRP levels after initiating MTA in advanced HCC patients with ≥50% liver occupation, focusing on antitumor response at 6 weeks.This retrospective study included 46 HCC patients with liver occupation ≥50% and 191 patients with <50%, Child-Pugh score ≤7, and Eastern Cooperative Oncology Group Performance Status scores of 0 or 1, who were treated with sorafenib or lenvatinib as first-line systemic therapy at our hospital between June 2011 and January 2020. We analyzed their medical records up to March 2020 and investigated the outcomes and changes in CRP and ALBI scores classified according to antitumor response at 6 weeks.Overall survival was significantly longer in patients with partial response (PR) + stable disease (SD) (13.7 months) than in patients with progressive disease (PD) (1.7 months, P < .001) in the ≥50% group. Patients with antitumor response of PR + SD at 6 weeks in the ≥50% group showed more marked deterioration of ALBI score at 2 weeks than those in the <50% group. These significant differences between groups had again disappeared at 4 and 6 weeks. Focusing on patients with PD at 6 weeks, ALBI score deteriorated over time in both groups. Regarding CRP, on 6-week PR + SD patients, a significant increase in CRP levels at 1 and 2 weeks was evident in the >50% group compared to the <50% group. These significant differences between groups had again disappeared at 4 and 6 weeks. In PD patients, no difference between groups in CRP elevation occurred at 1 and 2 weeks.In MTA treatment for patients with ≥50% liver occupation, to obtain an antitumor response of PR + SD, adequate management might be important considering transient deteriorated ALBI scores and elevated CRP levels.

Neurological Immunotoxicity from Cancer Treatment.

The emergence of immune-based treatments for cancer has led to a growing field dedicated to understanding and managing iatrogenic immunotoxicities that arise from these agents. Immune-related adverse events (irAEs) can develop as isolated events or as toxicities affecting multiple body systems. In particular, this review details the neurological irAEs from immune checkpoint inhibitors (ICI) and chimeric antigen receptor (CAR) T cell immunotherapies. The recognition and treatment of neurological irAEs has variable success, depending on the severity and nature of the neurological involvement. Understanding the involved mechanisms, predicting those at higher risk for irAEs, and establishing safety parameters for resuming cancer immunotherapies after irAEs are all important fields of ongoing research.

Performance Comparisons of AlexNet and GoogLeNet in Cell Growth Inhibition IC50 Prediction.

Drug responses in cancer are diverse due to heterogenous genomic profiles. Drug responsiveness prediction is important in clinical response to specific cancer treatments. Recently, multi-class drug responsiveness models based on deep learning (DL) models using molecular fingerprints and mutation statuses have emerged. However, for multi-class models for drug responsiveness prediction, comparisons between convolution neural network (CNN) models (e.g., AlexNet and GoogLeNet) have not been performed. Therefore, in this study, we compared the two CNN models, GoogLeNet and AlexNet, along with the least absolute shrinkage and selection operator (LASSO) model as a baseline model. We constructed the models by taking drug molecular fingerprints of drugs and cell line mutation statuses, as input, to predict high-, intermediate-, and low-class for half-maximal inhibitory concentration (IC50) values of the drugs in the cancer cell lines. Additionally, we compared the models in breast cancer patients as well as in an independent gastric cancer cell line drug responsiveness data. We measured the model performance based on the area under receiver operating characteristic (ROC) curves (AUROC) value. In this study, we compared CNN models for multi-class drug responsiveness prediction. The AlexNet and GoogLeNet showed better performances in comparison to LASSO. Thus, DL models will be useful tools for precision oncology in terms of drug responsiveness prediction.

Development of fluorescent-labeled trapping reagents based on cysteine to detect soft and hard electrophilic reactive metabolites.

Trapping assays are conducted at lead optimization stages to detect reactive metabolites (RMs) that can contribute to drug toxicity. The commonly used dansyl glutathione (dGSH) provides a sensitive analysis owing to the fluorescent label, however, it captures only soft electrophilic RMs. TRs for hard electrophilic RMs, few of which are labeled fluorescently, can detect hard electrophilic aldehydes only by forming unstable imine derivatives. In this study, we aimed to develop novel fluorescently labeled TRs that detect both soft and hard electrophilic RMs and form stable ring structures with aldehydes. We designed four dansylated TRs based on cysteine, which has both soft and hard nucleophilic groups. To evaluate the reactivity of the TRs, we incubated them with several substrates and found that one of the TRs (CysGlu-Dan) detected all the soft and hard electrophilic RMs. We also examined the inhibition potential of each TR for seven major CYPs involved in drug metabolism and found that CysGlu-Dan showed an inhibitory profile similar to that of dGSH. In conclusion, CysGlu-Dan can be used to evaluate the risk of RMs in drug discovery.

Prognostic Role for CYFRA 21-1 in Patients With Advanced-stage NSCLC Treated With Bevacizumab Plus Chemotherapy.

AIM: To investigate potential associations between selected oncomarkers [carcinoembryonic antigen (CEA), C-terminus of cytokeratin 19 (CYFRA 21-1, CYFRA), and squamous cell carcinoma antigen (SCC)] and outcomes in patients with NSCLC treated with bevacizumab plus chemotherapy. PATIENTS AND METHODS: We retrospectively analysed 105 patients with NSCLC from the Czech TULUNG registry treated at University Hospital in Pilsen with bevacizumab plus chemotherapy. Response to therapy was tested by Fisher's exact test. Survival statistics were evaluated using the Kaplan-Meier method and Cox analysis. RESULTS: Only normal values of CYFRA (not CEA or SCC) were associated with significantly better overall and progression-free survival in univariate analysis. We also observed a trend for a better disease control rate in patients with normal levels of CYFRA. In a multivariate Cox model, only CYFRA was associated with significantly better overall but not progression-free survival. CONCLUSION: In our retrospective study, we point out the possibility of using CYFRA as a prognostic marker in patients with NSCLC treated with chemotherapy plus bevacizumab.

Molecular Characteristics of Lymphocyte-predominant Triple-negative Breast Cancer.

BACKGROUND/AIM: Tumor-infiltrating lymphocytes (TILs) are considered a prognostic marker for triple-negative breast cancer (TNBC). Immune checkpoint inhibitor (ICI)-based treatments are more effective for tumors with PD-L1-positive TILs, suggesting crucial roles of TILs in the local tumor immunity. However, factors attracting TILs are still largely unknown. Focusing on tumor antigenicity, we examined TNBC samples to identify the characteristics of TIL-high tumors. PATIENTS AND METHODS: Nine treatment-naïve TNBCs (TIL-high: five, TIL-low: four) were subjected to next-generation sequencing (NGS). Loss of heterozygosity (LOH) of PTEN was also analyzed. RESULTS: A variety of copy number variations were observed, and no genes differed significantly between TIL-high and -low groups. However, PTEN loss was more frequently observed in the TIL-high group: 60% compared to 25% in TIL-low tumors. NGS correlated well with LOH analysis in identifying PTEN loss. All three tumors with PTEN loss in the TIL-high group showed high PD-L1. All nine samples were microsatellite-stable. CONCLUSION: Frequent PTEN loss and high expression of PD-L1 in TIL-high TNBC suggest that PTEN mutation may be a biomarker for ICIs.

Biomarker-targeted therapies for advanced-stage gastric and gastro-oesophageal junction cancers: an emerging paradigm.

Advances in cancer biology and sequencing technology have enabled the selection of targeted and more effective treatments for individual patients with various types of solid tumour. However, only three molecular biomarkers have thus far been demonstrated to predict a response to targeted therapies in patients with gastric and/or gastro-oesophageal junction (G/GEJ) cancers: HER2 positivity for trastuzumab and trastuzumab deruxtecan, and microsatellite instability (MSI) status and PD-L1 expression for pembrolizumab. Despite this lack of clinically relevant biomarkers, distinct molecular subtypes of G/GEJ cancers have been identified and have informed the development of novel agents, including receptor tyrosine kinase inhibitors and monoclonal antibodies, several of which are currently being tested in ongoing trials. Many of these trials include biomarker stratification, and some include analysis of circulating tumour DNA (ctDNA), which both enables the noninvasive assessment of biomarker expression and provides an indication of the contributions of intratumoural heterogeneity to response and resistance. The results of these studies might help to optimize the selection of patients to receive targeted therapies, thus facilitating precision medicine approaches for patients with G/GEJ cancers. In this Review, we describe the current evidence supporting the use of targeted therapies in patients with G/GEJ cancers and provide guidance on future research directions.