Non-small Cell Lung Carcinoma Research Articles

Time to treatment discontinuation in first-line non-small cell lung carcinoma: an overview

Objective Time To Discontinuation (TTD) is defined as the time from the start of treatment to the end of treatment, usually occurring due to loss of efficacy or occurrence of adverse events. It has become an important surrogate efficacy endpoint especially in real-world studies due to its correlation with endpoints such as Progression Free Survival (PFS). The aim of the study is to conduct a literature review of all studies reporting TTD in first-line therapy of Non-Small Cell Lung Cancer (NSCLC). Methods All articles that reported TTD for any first-line treatment of NSCLC as of 30 June 2022 were extracted from the PubMed search engine. From these articles, the drugs, study type, and TTD values were extracted. A descriptive analysis of the studies was made, dividing the TTD by subgroup according to the type of treatment (traditional chemotherapy, target therapy, immunotherapy) and study design (clinical trials, real world studies). Results Fifty-five studies were considered for the analysis, of which 12 were published in 2021; 28 were clinical trials and 27 were real-world studies. Thirty of the studies considered involved conventional chemotherapy and expressed TTD values from 1.4 to 4.5 months, 5 of the studies considered involved immunotherapy with TTD values from 2.1 to 7.4 months and 18 of the studies considered target therapy, with TTD values from 4 to 31 months. The clinical trials reported TTD values from 1.4 to 16 months and the real-world studies from 2 to 31 months. Conclusion Studies reporting TTD are increasing, most notably real-world studies. Given the increasing importance of TTD as an efficacy endpoint, it becomes critical to measure and monitor it in various therapeutic settings such as NSCLC. This is the first study to review all TTD values of drugs used in first-line NSCLC.

EGFR: an Overview and Mutation on Lung Cancer

Cancer is a popular and well-known disease all over the world. It is a genetic disease that mutations occur on patients’ genome and cause cells to proliferate uncontrollably and start to invade surrounding tissues which is not commonly seen on normal cells and tissues. It is a common cause of death in the world. In 2020, the number of people died because of cancer is 10 million. Among these deaths, lung cancer account for 2.21 million cases which is the second largest group of all cancer types. Among all lung cancer types, non-small cell lung carcinoma (NSCLC) constitutes around 80 percent lung cancer. EGFR is a gene that mutation on it is often found within the genome of NSCLC patients. According to a report, 30466 patients among 115815 NSCLC patients are found to have EGFR mutation in order to provide suggestion for patients with mutation on EGFR to have a better therapeutic effect, learning the function of a gene and its impact on metastasis is necessary. This review intended to give an overview on the EGFR (epidermal growth factor receptor) which mutation on it is often seen on lung Cancer.

Battling Non-Small Cell Lung Carcinoma: Applying Biomarkers Testing to Pick the Best Immune Checkpoint Inhibitors Therapy

Immune checkpoint inhibitors is a new treatment for Non-Small Cell Lung Carcinoma. Benefit from such ICI therapy, however, have been enjoyed by a minority of NSCLC patients, and durable clinical outcomes are scarce. Thus, identifying reliable biomarkers to predict patients’ possible response, and to indicate the progression status of tumors to further refine ICIs’ application in treating NSCLCs is of decisive importance. However, as ICIs are novel therapies applied for only a decade, long-term post-treatment follow-ups are scant, and the probing or detection methods for biomarkers may not be as reliable as believed. Thus, many of the biomarkers require further investigations to elucidate their exact role in varying NSCLC microenvironments. Based on previously established results and integrating updated clinical data, this review lists the 2 currently accepted ICI therapeutic regimens, presents their respective mechanisms of action and their corresponding predictive or prognostic biomarkers currently available. This systematic categorization of biomarkers to respective therapies may inform clinicians about the use of ICI therapies and raise their attention to emerging and established biomarkers in new treatment strategies.

Phenotyping the Histopathological Subtypes of Non-Small-Cell Lung Carcinoma: How Beneficial Is Radiomics?

The aim of this study was to investigate the usefulness of radiomics in the absence of well-defined standard guidelines. Specifically, we extracted radiomics features from multicenter computed tomography (CT) images to differentiate between the four histopathological subtypes of non-small-cell lung carcinoma (NSCLC). In addition, the results that varied with the radiomics model were compared. We investigated the presence of the batch effects and the impact of feature harmonization on the models' performance. Moreover, the question on how the training dataset composition influenced the selected feature subsets and, consequently, the model's performance was also investigated. Therefore, through combining data from the two publicly available datasets, this study involves a total of 152 squamous cell carcinoma (SCC), 106 large cell carcinoma (LCC), 150 adenocarcinoma (ADC), and 58 no other specified (NOS). Through the matRadiomics tool, which is an example of Image Biomarker Standardization Initiative (IBSI) compliant software, 1781 radiomics features were extracted from each of the malignant lesions that were identified in CT images. After batch analysis and feature harmonization, which were based on the ComBat tool and were integrated in matRadiomics, the datasets (the harmonized and the non-harmonized) were given as an input to a machine learning modeling pipeline. The following steps were articulated: (i) training-set/test-set splitting (80/20); (ii) a Kruskal-Wallis analysis and LASSO linear regression for the feature selection; (iii) model training; (iv) a model validation and hyperparameter optimization; and (v) model testing. Model optimization consisted of a 5-fold cross-validated Bayesian optimization, repeated ten times (inner loop). The whole pipeline was repeated 10 times (outer loop) with six different machine learning classification algorithms. Moreover, the stability of the feature selection was evaluated. Results showed that the batch effects were present even if the voxels were resampled to an isotropic form and whether feature harmonization correctly removed them, even though the models' performances decreased. Moreover, the results showed that a low accuracy (61.41%) was reached when differentiating between the four subtypes, even though a high average area under curve (AUC) was reached (0.831). Further, a NOS subtype was classified as almost completely correct (true positive rate ~90%). The accuracy increased (77.25%) when only the SCC and ADC subtypes were considered, as well as when a high AUC (0.821) was obtained-although harmonization decreased the accuracy to 58%. Moreover, the features that contributed the most to models' performance were those extracted from wavelet decomposed and Laplacian of Gaussian (LoG) filtered images and they belonged to the texture feature class.. In conclusion, we showed that our multicenter data were affected by batch effects, that they could significantly alter the models' performance, and that feature harmonization correctly removed them. Although wavelet features seemed to be the most informative features, an absolute subset could not be identified since it changed depending on the training/testing splitting. Moreover, performance was influenced by the chosen dataset and by the machine learning methods, which could reach a high accuracy in binary classification tasks, but could underperform in multiclass problems. It is, therefore, essential that the scientific community propose a more systematic radiomics approach, focusing on multicenter studies, with clear and solid guidelines to facilitate the translation of radiomics to clinical practice.

The cytotoxic activity of carfilzomib together with nelfinavir is superior to the bortezomib/nelfinavir combination in non-small cell lung carcinoma

Chemotherapy resistance is still a major problem in the treatment of patients with non-small-cell-lung carcinoma (NSCLC), and novel concepts for the induction of cytotoxicity in NSCLC are highly warranted. Proteotoxicity, the induction of cytotoxicity by targeting the ubiquitin proteasome system, represents an appealing innovative strategy. The combination of the proteasome inhibitor bortezomib (BTZ) and the proteotoxic stress-inducing HIV drug nelfinavir (NFV) synergistically induces proteotoxicity and shows encouraging preclinical efficacy in NSCLC. The second-generation proteasome inhibitor carfilzomib (CFZ) is superior to BTZ and overcomes BTZ resistance in multiple myeloma patients. Here, we show that CFZ together with NFV is superior to the BTZ + NFV combination in inducing endoplasmic reticulum stress and proteotoxicity through the accumulation of excess proteasomal substrate protein in NSCLC in vitro and ex vivo. Interestingly, NFV increases the intracellular availability of CFZ through inhibition of CFZ export from NSCLC cells that express multidrug resistance (MDR) protein. Combining CFZ with NFV may therefore represent a future treatment option for NSCLC, which warrants further investigation.

Loss of EPS8 sensitizes non-small-cell lung carcinoma to chemotherapy-induced DNA damage.

Epidermal growth factor receptor pathway substrate number 8 (EPS8) has been reported to be critical in mediating tumor progression. However, the molecular and biological consequences of EPS8 overexpression remain unclear. Here we evaluated whether EPS8 increased DNA damage repair in non-small-cell lung carcinoma (NSCLC) cells and the mechanism of EPS8-mediated DNA damage repair which influenced chemosensitivity. Serial studies of functional experiments revealed that EPS8 knockdown inhibited cell growth, induced cell-cycle arrest and increased cisplatin therapeutic effects on NSCLC. EPS8 was found to induce DNA damage repair via upregulation of phosphorylated-ATM and downregulation of the tumor suppressor p53 and G1 cell kinase inhibitor p21. Moreover, in conjunction with cisplatin, decreasing EPS8 protein levels further increased p53 protein level and inhibited ATM signaling. Transplanted tumor studies were also performed to demonstrate that EPS8 knockdown inhibited tumor growth and sensitized tumors to cisplatin treatment. In conclusion, we have described a novel molecular mechanism through which EPS8 is likely to be involved in cancer progression and chemoresistance via DNA damage repair, indicating that EPS8 expression may influence the response to chemotherapy. Therefore, targeting EPS8 may be a potential therapeutic approach for patients with NSCLC.

Targeting Inflammation in Non-Small Cell Lung Cancer through Drug Repurposing

Lung cancer is the most common cause of cancer-related deaths. Lung cancers can be classified as small-cell (SCLC) or non-small cell (NSCLC). About 84% of all lung cancers are NSCLC and about 16% are SCLC. For the past few years, there have been a lot of new advances in the management of NSCLC in terms of screening, diagnosis and treatment. Unfortunately, most of the NSCLCs are resistant to current treatments and eventually progress to advanced stages. In this perspective, we discuss some of the drugs that can be repurposed to specifically target the inflammatory pathway of NSCLC utilizing its well-defined inflammatory tumor microenvironment. Continuous inflammatory conditions are responsible to induce DNA damage and enhance cell division rate in lung tissues. There are existing anti-inflammatory drugs which were found suitable for repurposing in non-small cell lung carcinoma (NSCLC) treatment and drug modification for delivery via inhalation. Repurposing anti-inflammatory drugs and their delivery through the airway is a promising strategy to treat NSCLC. In this review, suitable drug candidates that can be repurposed to treat inflammation-mediated NSCLC will be comprehensively discussed together with their administration via inhalation from physico-chemical and nanocarrier perspectives.

Robot-assisted thoracic surgery for stages IIB–IVA non-small cell lung cancer: retrospective study of feasibility and outcome

Robot-assisted thoracic surgery (RATS) for higher stages non-small cell lung carcinoma (NSCLC) remains controversial. This study reports the feasibility of RATS in patients with stages IIB–IVA NSCLC. A single-institute, retrospective study was conducted with patients undergoing RATS for stages IIB–IVA NSCLC, from January 2015 until January 2020. Unforeseen N2 disease was excluded. Data were collected from the Dutch Lung Cancer Audit database. Conversion rate, radical (R0) resection rate, local recurrence rate and complications were analyzed, as were risk factors for conversion. RATS was performed in 95 patients with NSCLC clinical or pathological stages IIB (N = 51), IIIA (N = 39), IIIB (N = 2) and IVA (N = 3). 10.5% had received neoadjuvant chemoradiotherapy. Pathological staging was T3 in 33.7% and T4 in 34.7%. RATS was completed in 77.9% with a radical resection rate of 94.8%. Lobectomy was performed in 67.4% of the total resections. Conversion was for strategic (18.9%) and emergency (3.2%) reasons. Pneumonectomy (p = 0.001), squamous cell carcinoma (p < 0.001), additional resection of adjacent structures (p = 0.025) and neoadjuvant chemoradiation (p = 0.017) were independent risk factors for conversion. Major post-operative complications occurred in ten patients (10.5%) including an in-hospital mortality of 2.1% (n = 2). Median recurrence-free survival was estimated at 39.4 months (CI 16.4–62.5). Two- and 5-year recurrence-free survival rates were 53.8% and 36.7%, respectively. This study concludes that RATS is safe and feasible in higher staged NSCLC tumors after exclusion of unforeseen N2 disease. It brings new perspective on the potential of RATS in higher stages, dealing with larger and more invasive tumors.

Cytological, cell block and immunohistochemical analysis of spectrum of malignant pleural effusion with special reference to non-small cell lung carcinoma: A hospital based study of North East India

Malignant pleural effusions (MPE) can result from primary malignancies of the pleura or from underlying intrathoracic or extrathoracic malignancies that reach the pleural space by hematogenous, lymphatic, or contiguous spread. Conventional smear and cell block (CB) technique is one of the oldest methods for the evaluation of body cavity fluids. The principal advantage of cell block over conventional smears are an additional yield of malignant cells and obtaining multiple sections for ancillary tests such as immunohistochemistry (IHC). This study is a hospital-based cross-sectional study which was conducted for a period of 14 months from June 2021 to July 2022 in a tertiary care centre of North East India. Among 277 pleural effusion specimens 11.91% cases were positive for malignancy.Lung carcinoma was the most common cause of malignant pleural effusion. Non-small cell lung carcinoma comprised majority of lung carcinoma cases. Adenocarcinoma was the most common subtype of NSCLC with female preponderance. Cytological diagnosis had a Sensitivity of 76.19%, specificity of 100% andAccuracy of 96.5%. Immunohistochemistry of lung carcinoma in cell block preparation revealed 77.77% cases of adenocarcinoma of lung were positive for TTF-1(P&amp;#60;0.018). Immuno-expression of P63 and P40 showed positive expression in both the cases of squamous cell carcinoma. Conventional smear and cell block method with application of immunohistochemistry will help us in accurate diagnosis of primary site of the tumour aiding early treatment especially in resources restricted hospitals.

Inflammasomes driven inflammation in lung cancer revisited: a short review

Lung cancer is the leading cause of cancer-related deaths worldwide. The main risk factor for lung cancer is exposure to chemicals present in cigarettes and atmospheric pollutants, which, among other mechanisms, can increase the risk of cancer by inducing pulmonary inflammation. Among the complex features of inflammatory processes, the role of inflammasomes has attracted increasing attention due to their role in different stages of carcinogenesis. Inflammasomes are intracellular multiprotein complexes that when activated promote the maturation of interleukin-1beta (IL-1β) and IL-18, pro-inflammatory cytokines involved in the promotion, progression, epithelial-mesenchymal transition, metastasis, and resistance to therapy of lung cancer. In this way, this review summarizes the recent findings of inflammasome research in different stages of lung cancer, with a focus on non-small cell lung carcinoma (NSCLC), and highlights these multiprotein complexes as promising targets for cancer therapy.

Loss of function SMAD4 nonstop mutations in human cancer.

SMAD4 is a tumour suppressor gene that is mutated in a variety of cancers. SMAD4 nonstop mutations, which convert stop codons to sense codons that extend transcription, have been identified in genomic databases but have not been characterised in human pathology samples. The frequency of SMAD4 nonstop mutations and the consequences of nonstop mutations on SMAD4 protein expression are unknown. We retrospectively analysed our cancer sequencing database of 38,002 tumour specimens and evaluated the spectrum of SMAD4 mutations. SMAD4 protein expression was evaluated by immunohistochemistry in tumours with SMAD4 nonstop mutations. In total, 1956 SMAD4 mutations were identified in 1822 tumours. SMAD4 mutations were most common in tumours of the gastrointestinal tract and included nonsense variants (n=344), frameshift indels (n=258), splice site variants (n=104), and missense variants at codon R361 (n=245). In a subset of cases with immunohistochemistry, SMAD4 expression was lost in 23 of 25 tumours (92%) with protein truncating variants and in 7 of 27 tumours (26%) with missense variants. Four cases harboured SMAD4 nonstop mutations. SMAD4 nonstop mutations were identified in two pancreatic adenocarcinomas, one colonic adenocarcinoma, and one non-small cell lung carcinoma. Immunohistochemistry demonstrated loss of SMAD4 protein expression in each of the four tumours with SMAD4 nonstop mutations. SMAD4 nonstop mutations are associated with loss of SMAD4 protein expression in multiple tumour types. SMAD4 nonstop mutations should be clinically interpreted as pathogenic loss of function alterations when identified in cancer sequencing panels.

Myo1e overexpression in lung adenocarcinoma is associated with increased risk of mortality

This study aims to perform a comprehensive genomic analysis to assess the influence of overexpression of MYO1E in non-small cell lung carcinoma (NSCLC) and whether there are differences in survival and mortality risk in NSCLC patients depending on both DNA methylation and RNA expression of MYO1E. The DNA methylation probe cg13887966 was inversely correlated with MYO1E RNA expression in both LUAD and LUSC subpopulations showing that lower MYO1E RNA expression was associated with higher MYO1E DNA methylation. Late stages of lung cancer showed significantly lower MYO1E DNA methylation and significantly higher MYO1E RNA expression for LUAD but not for LUSC. Low DNA methylation as well as high RNA expression of MYO1E are associated with a shorter median survival time and an increased risk of mortality for LUAD, but not for LUSC. This study suggests that changes in MYO1E methylation and expression in LUAD patients may have an essential role in lung cancer’s pathogenesis. It shows the utility of MYO1E DNA methylation and RNA expression in predicting survival for LUAD patients. Also, given the low normal expression of MYO1E in blood cells MYO1E DNA methylation has the potential to be used as circulating tumor marker in liquid biopsies.

Chemokine Receptors CCR6 and PD1 Blocking scFv E27 Enhances Anti-EGFR CAR-T Therapeutic Efficacy in a Preclinical Model of Human Non-Small Cell Lung Carcinoma.

Chimeric antigen receptor (CAR)-T cells, a therapeutic agent for solid tumors, are not completely effective due to a lack of infiltration of T cells into the tumor site and immunity caused by Programmed Death Receptor 1(PD1). Here, an epidermal growth factor receptor (EGFR) CAR-T cell was engineered to express the chemokine receptor CCR6 and secrete PD1 blocking Single-chain antibody fragment (scFv) E27 to enhance their anti-tumor effects. The findings showed that CCR6 enhanced the migration of EGFR CAR-E27-CCR6 T cells in vitro by the Transwell migration assay. When incubated with tumor cells, EGFR CAR-E27-CCR6 T cells specifically exerted potent cytotoxicity and produced high levels of pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin-2 (IL-2), and interferon-γ (IFN-γ). A non-small cell lung carcinoma (NSCLC) cell line-derived xenograft model was constructed by implanting modified A549 cell lines into immunodeficient NOD.PrkdcscidIl2rgem1/Smoc (NSG) mice. In comparison with traditional EGFR CAR-T cells, live imaging indicated that EGFR CAR-E27-CCR6 T cells displayed superior anti-tumor function. In addition, the histopathological examination of mouse organs showed no obvious organic damage. Our findings confirmed that PD1 blocking and CCR6 can enhance the anti-tumor function of EGFR CAR-T cells in an NSCLC xenograft model, providing an effective treatment strategy to improve the efficacy of CAR-T in NSCLC.

Therapeutic drug monitoring guided dosing versus standard dosing of alectinib in advanced ALK positive non-small cell lung cancer patients: Study protocol for an international, multicenter phase IV randomized controlled trial (ADAPT ALEC).

Alectinib is first-line therapy in patients with stage IV non-small cell lung carcinoma (NSCLC) and an anaplastic lymphoma kinase (ALK) fusion. A shorter median progression-free survival (mPFS) was observed when alectinib minimum plasma concentrations during steady state (Cmin,SS) were below 435 ng/mL. This may suggest that patients should have an alectinib Cmin,SS ≥ 435 ng/mL for a more favorable outcome. This potential target could be attained by using therapeutic drug monitoring (TDM), i.e. adjusting the dose based on measured plasma trough concentrations. Hypothetically, this will increase mPFS, but this has not yet been evaluated in a randomized controlled trial (RCT). Therefore, the ADAPT ALEC trial is designed, with the primary objective to prolong mPFS in NSCLC patients treated with alectinib by using TDM. ADAPT ALEC is a multicenter, phase IV RCT, in which patients aged ≥ 18 years with advanced ALK positive (+) NSCLC eligible for alectinib in daily care are enrolled. Participants will be randomized (1:1 ratio) into intervention arm A (TDM) or B (control), stratified by brain metastases and prior ALK treatments. Starting dose in both arms is the approved flat fixed dose of alectinib 600 mg taken twice daily with food. In case of alectinib Cmin,SS < 435 ng/mL, arm A will receive increased doses of alectinib till Cmin,SS ≥ 435 ng/mL when considered tolerable. The primary outcome is mPFS, where progressive disease is defined according to RECIST v1.1 or all-cause death and assessed by CT-scans and MRI brain. Secondary endpoints are feasibility and tolerability of TDM, patient and physician adherence, overall response rate, median overall survival, intracranial PFS, quality of life, toxicity, alectinib-M4 concentrations and cost-effectiveness of TDM. Exploratory endpoints are circulating tumor DNA and body composition. The ADAPT ALEC will show whether treatment outcomes of patients with advanced ALK+ NSCLC improve when using TDM-guided dosing of alectinib instead of fixed dosing. The results will provide high quality evidence for deciding whether TDM should be implemented as standard of care and this will have important consequences for the prescribing of alectinib. ClinicalTrials.gov, identifier NCT05525338.

Immune checkpoint inhibitor-related haemophagocytic lymphohistiocytosis in a patient with non-small cell lung carcinoma.

Hemophagocytic lymphohistiocytosis (HLH) has been reported as a rare complication of immune checkpoint inhibitors (ICI); however, ICI-related HLH is a life-threatening and comparatively late adverse event. Early diagnosis is critical, and it should be included in the differential diagnosis especially in patients with cytopenia with fever and hyperferritinaemia.

Relationship between Systemic Inflammatory Markers, GLUT1 Expression, and Maximum 18F-Fluorodeoxyglucose Uptake in Non-Small Cell Lung Carcinoma and Their Prognostic Significance

Factors involved in inflammation and cancer interact in various ways with each other, and biomarkers of systemic inflammation may have a prognostic value in cancer. Glucose transporter 1 (GLUT1) plays a pivotal role in glucose transport and metabolism and it is aberrantly expressed in various cancer types. We evaluated the differential expression of GLUT1, along with 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) in non-small-cell lung cancer (NSCLC), and then analyzed their prognostic significance. A total of 163 patients with resectable NSCLC were included in this study. Tumor sections were immunohistochemically stained for GLUT1 and GLUT3. Maximum standardized uptake value (SUVmax) was measured by preoperative FDG-PET, and neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and lymphocyte-monocyte ratio (LMR) were derived from pretreatment blood count. GLUT1 and GLUT3 was positively expressed in 74.8% and 6.1% of the NSCLC tissues, respectively. GLUT1 expression was significantly correlated with squamous cell carcinoma histology, poor differentiation, high pathologic stage, old age, male, smoking, and high SUVmax (>7) (all p < 0.05). The squamous cell carcinoma and smoker group also showed significantly higher SUVmax (both p < 0.001). Systemic inflammation markers, including NLR, PLR, and LMR, were positively correlated with high SUVmax (all p < 0.05). High GLUT1 expression, high SUVmax, high NLR, and low LMR, were significantly associated with poor overall survival in patients with NSCLC. However, in the multivariate survival analysis, LMR was an independent prognostic factor overall (HR 1.86, 95% CI 1.05-3.3) and for the stage I/II cohort (HR 2.3, 95% CI 1.24-4.3) (all p < 0.05). Systemic inflammatory markers-NLR, PLR, and LMR are strongly correlated with the SUVmax and are indicators of aggressive tumor behavior. Specifically, LMR is a promising prognostic biomarker in NSCLC patients.

Glycomic, Glycoproteomic, and Proteomic Profiling of Philippine Lung Cancer and Peritumoral Tissues: Case Series Study of Patients Stages I-III.

Lung cancer is the leading cause of cancer death and non-small cell lung carcinoma (NSCLC) accounting for majority of lung cancers. Thus, it is important to find potential biomarkers, such as glycans and glycoproteins, which can be used as diagnostic tools against NSCLC. Here, the N-glycome, proteome, and N-glycosylation distribution maps of tumor and peritumoral tissues of Filipino lung cancer patients (n = 5) were characterized. We present several case studies with varying stages of cancer development (I-III), mutation status (EGFR, ALK), and biomarker expression based on a three-gene panel (CD133, KRT19, and MUC1). Although the profiles of each patient were unique, specific trends arose that correlated with the role of aberrant glycosylation in cancer progression. Specifically, we observed a general increase in the relative abundance of high-mannose and sialofucosylated N-glycans in tumor samples. Analysis of the glycan distribution per glycosite revealed that these sialofucosylated N-glycans were specifically attached to glycoproteins involved in key cellular processes, including metabolism, cell adhesion, and regulatory pathways. Protein expression profiles showed significant enrichment of dysregulated proteins involved in metabolism, adhesion, cell-ECM interactions, and N-linked glycosylation, supporting the protein glycosylation results. The present case series study provides the first demonstration of a multi-platform mass-spectrometric analysis specifically for Filipino lung cancer patients.

Toxicity evaluation of choline ionic liquid-based nanocarriers of pharmaceutical agents for lung treatment.

In vitro cytotoxicity evaluation of linear copolymer (LC) containing choline ionic liquid units and its conjugates with an antibacterial drug in anionic form, that is, p-aminosalicylate (LC_PAS), clavulanate (LC_CLV), or piperacillin (LC_PIP) was carried out. These systems were tested against normal: human bronchial epithelial cells (BEAS-2B), and cancers: adenocarcinoma human alveolar basal epithelial cells (A549), and human non-small cell lung carcinoma cell line (H1299). Cells viability, after linear copolymer LC and their conjugates addition for 72 h, was measured at concentration range of 3.125-100 μg/mL. The MTT test allowed the designation of IC50 index, which was higher for BEAS-2B, and significantly lower in the case of cancer cell lines. The cytometric analyzes, that is, Annexin-V FITC apoptosis assay and cell cycle analysis as well as gene expression measurements for interleukins IL6 and IL8 were carried out, and showed pro-inflammatory activity of tested compounds toward cancer cells, while it was not observed against normal cell line.

Abstract OT3-13-01: First in Human Study of AG01 a chimerized monoclonal antibody to Progranulin/Glycoprotein 88 (GP88)

Abstract Progranulin (PGRN/GP88) is an 88 kDa glycoprotein characterized by seven and a half double cysteine rich repeats in the granulin-epithelin family. PGRN/GP88 is an autocrine biological driver of tumorigenesis, survival &amp; drug resistance in several cancers including breast, ovarian, multiple myeloma, prostate cancers, non-small cell lung carcinoma (NSCLCA) &amp; digestive cancers. PGRN/GP88 tissue expression is an independent prognostic factor of recurrence while elevated serum PGRN/GP88 level in metastatic breast, lung &amp; prostate cancer patients is associated with poor outcomes such as progression &amp; shortened survival. An anti-human PGRN/GP88 monoclonal antibody inhibiting PGRN/GP88 action has been developed &amp; expressed as recombinant antibody in CHO cells. Activities including pharmacology, manufacturing, formulation &amp; GLP toxicology studies have been carried out. The IND application has been cleared by the Food and Drug Administration to proceed with the first-in-human AG01 clinical study in adult patients ((pts) with advanced solid tumors. We present an ongoing First in Human Phase 1A (dose escalation,1+(3+3) &amp; IB (expansion cohorts) study of AG01 in pts advanced solid tumor malignancies (1A) with 4 expansion cohorts (1B) in pts with advanced Triple Negative Breast Cancer (TNBC), Hormone Resistant ER+/Her2- BC, advanced NSCLC &amp; mesothelioma. Study Design: This is an open-label, dose escalation study of AG01 antibody administered intravenously (IV) over 90 minutes every 14 days +/- 1 day (1A), followed by 4 predefined expansion cohorts, which will be treated at the RP2D determined in the phase 1A of this study. In the 1A part, initially accelerated titration design will be utilized to guide dose progression &amp; estimation of the maximum tolerated dose (MTD and/or maximum administered dose (MAD). In the 1A portion of the study pts with advanced relapsed/refractory solid tumor malignancies who failed 1 or more standard of care (SOC) therapies (tx) or for whom no SOC tx exists will be accrued. The primary objective of the 1A part is to determine the MTD and/or MAD of AG01. Secondary objectives are to determine the RP2D, assess the safety/tolerability, the pharmacokinetics (PKs) &amp; immunogenicity of AG01 &amp; the preliminary anti-tumor activity of AG01 via RECIST 1.1. The exploratory objectives are to determine PGRN/GP88 expression in tumor tissue and PGRN/GP88 blood levels using A&amp;G’s ELISA test. In the 1B Cohort Expansion phase, 4 separate cohorts of pts with PGRN/GP88 tissue expression of 1+, 2+, 3+ by IHC will be enrolled. Cohort 1- TNBC: ER and/or PR &amp;lt; 1% by IHC, HER2 &amp;lt; 3+ by IHC and/or FISH negative, pts must have failed 1 or more SOC tx for metastatic BC. Cohort 2- Hormone-resistant BC: ER and/or PR &amp;gt;1%, HER2 &amp;lt; 3+ by IHC and/or FISH negative, failed 1 or more prior hormonal tx (HT) or HT/CD4/6 kinase inhibitor tx or other targeted tx. Cohort 3- NSCLCA: metastatic/recurrent NSCLCA failed 2 or more SOC tx. Cohort 4 -Mesothelioma- failed 1 or more SOC tx for metastatic/recurrent mesothelioma or not a candidate for SOC tx. The primary objective of 1B part is to evaluate the antitumor efficacy of AG01 by overall response rate (ORR) defined as completed response (CR), partial response (PR), stable disease &amp;gt;=24 weeks (SD) (CR+PR+ SD) based on RECIST v1.1 in the 4 cohorts with each cohort assessed separately for response. Secondary objectives are to evaluate progression free survival (PFS), duration of response (DOR) &amp; overall survival (OS) of pts in cohorts 1-4, &amp; to evaluate the ORR, DOR &amp; PFS based on GP88 tissue expression, to further characterize the PKs &amp; the safety/tolerability of AG01. Exploratory objectives in 1B part will assess AG01 effect on circulating PGRN/GP88 levels in plasma or other potential biomarkers in the 4 cohorts. The estimated study sample is approximately 77 pts; 17 pts for the 1A part &amp; 60 pts for 1B part. The study is open to accrual at the UMGCCC. Supported by NCI grants R44CA224718 and R44CA162629 Citation Format: KATHERINE TKACZUK, Paula Rosenblatt, Ranee Mehra, Katherine Scilla, Nancy Tait, Binbin Yue, Ginette Serrero. First in Human Study of AG01 a chimerized monoclonal antibody to Progranulin/Glycoprotein 88 (GP88) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT3-13-01.

Role of adjuvant treatment in stage IB non-small cell lung carcinoma.

Role of adjuvant treatment in stage IB non-small cell lung carcinoma.