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Frontiers in Surgery 2024Chordomas are aggressive tumors that are thought to arise from remnants of the embryological notochord. They can arise along the ventromedial aspect of the sacrum,... (Review)
Review
INTRODUCTION
Chordomas are aggressive tumors that are thought to arise from remnants of the embryological notochord. They can arise along the ventromedial aspect of the sacrum, mobile spine, and clivus-with most cases occurring in the sacrum or skull base. Despite surgery and radiation, chordomas often progress and become refractory to further treatment. The high recurrence rate of chordomas has created an urgent need to develop new systemic treatment options. Recent case reports and clinical trials have highlighted the use of immunotherapy for refractory chordomas. In this review, we summarize the results of these studies and discuss the potential role of immunotherapy for chordomas.
METHODS
The PUBMED database was queried for studies mentioning both "Chordoma" and "Immunotherapy." All case series and case reports that involved administration of an immunotherapy for chordoma were included. Additional studies that were found during literature review were added. ClinicalTrials.Gov was queried for studies mentioning both "Chordoma" and "Immunotherapy." The final cohort consisted of all clinical trials that utilized immunotherapy for chordomas of any location.
RESULTS
Eight case reports and series detailing the use of immunotherapy for treatment refractory chordoma were identified. Most patients received immunotherapy targeting the PD-1/PD-L1 interaction, and two patients received therapy targeting this interaction along with the tyrosine kinase inhibitor pazopanib. One patient received a vaccine derived from autologous tumor cells, and one patient received a viral vector that downregulated the effect of TGF-beta. One clinical trial utilized a brachyury vaccine in conjunction with standard of care radiotherapy.
CONCLUSIONS
Immunotherapy for chordoma is a promising area of investigation with increasing, but small, numbers of case series and clinical trials. Despite challenges in patient accrual, future directions in chordoma immunotherapy may lie in vaccine-based therapies and immune checkpoint inhibitors. Understanding chordoma heterogeneity and microenvironment will likely elucidate important chordoma features that will inform future clinical trial design.
PubMed: 38881706
DOI: 10.3389/fsurg.2024.1375567 -
Diagnostic Pathology Aug 2023Clear cell renal cell carcinoma (ccRCC) is the dominant subtype of kidney cancer. Dysregulation of long-chain acyl-CoA synthetase 1 (ACSL1) is strongly implicated in...
BACKGROUND
Clear cell renal cell carcinoma (ccRCC) is the dominant subtype of kidney cancer. Dysregulation of long-chain acyl-CoA synthetase 1 (ACSL1) is strongly implicated in undesirable results in varieties of cancers. Nevertheless, the dysregulation and associated multi-omics characteristics of ACSL1 in ccRCC remain elusive.
METHODS
We probed the mRNA and protein profiles of ACSL1 in RCC using data from the Cancer Genome Atlas, Gene Expression Omnibus, the Human Protein Atlas (HPA), and Clinical Proteomic Tumor Analysis Consortium (CPTAC) and verified them in our patient cohort and RCC cell lines. Correlations between ACSL1 expression and clinicopathological features, epigenetic modification and immune microenvironment characteristics were analyzed to reveal the multi-omics profile associated with ACSL1.
RESULTS
ACSL1 was down-regulated in ccRCC tissues compared to adjacent normal tissues. Lower expression of ACSL1 was linked to unfavorable pathological parameters and prognosis. The dysregulation of ACSL1 was greatly ascribed to CpG island-associated methylation modification. The ACSL1 high-expression subgroup had enriched fatty acid metabolism-related pathways and high expression of ferroptosis-related genes. In contrast, the ACSL1 low-expression subgroup exhibited higher immune and microenvironment scores, elevated expression of immune checkpoints PDCD1, CTLA4, LAG3, and TIGIT, and higher TIDE scores. Using data from the GDSC database, we corroborated that down-regulation of ACSL1 was associated with higher sensitivity towards Erlotinib, Pazopanib, and PI3K-Akt-mTOR-targeted therapeutic strategies.
CONCLUSION
Taken together, our findings point to ACSL1 as a biomarker for prognostic prediction of ccRCC, identifying the tumor microenvironment (TME) phenotype, and even contributing to treatment decision-making in ccRCC patients.
Topics: Humans; Carcinoma, Renal Cell; Tumor Microenvironment; Prognosis; Multiomics; Phosphatidylinositol 3-Kinases; Proteomics; Carcinoma; Kidney Neoplasms
PubMed: 37608295
DOI: 10.1186/s13000-023-01384-y -
Clinical Pharmacokinetics Aug 2023A genetic variant explaining a part of the exposure of many kinase inhibitors (KIs) is the single nucleotide polymorphism (SNP) CYP3A4*22, resulting in less CYP3A4... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
A genetic variant explaining a part of the exposure of many kinase inhibitors (KIs) is the single nucleotide polymorphism (SNP) CYP3A4*22, resulting in less CYP3A4 enzyme activity. The primary aim of this study was to investigate if the systemic exposure is non-inferior after a dose reduction of KIs metabolized by CYP3A4 in CYP3A4*22 carriers compared to patients without this SNP (i.e., wildtype patients) receiving the standard dose.
METHODS
In this multicenter, prospective, non-inferiority study, patients were screened for the presence of CYP3A4*22. Patients with the CYP3A4*22 SNP received a 20-33% dose reduction. At steady state, a pharmacokinetic (PK) analysis was performed and compared to the PK results from wildtype patients treated with the registered dose using a two-stage individual patient data meta-analysis approach.
RESULTS
In total, 207 patients were included in the final analysis. The CYP3A4*22 SNP was found in 16% of the patients in the final analysis (n = 34). Most of the included patients received imatinib (37%) or pazopanib (22%) treatment. The overall geometric mean ratio (GMR) comparing the exposure of the CYP3A4*22 carriers to the exposure of the wildtype CYP3A4 patients was 0.89 (90% confidence interval: 0.77-1.03).
CONCLUSION
Non-inferiority could not be proven for dose reduction of KIs metabolized by CYP3A4 in CYP3A4*22 carriers compared to the registered dose in wildtype patients. Therefore, an up-front dose reduction based upon the CYP3A4*22 SNP for all KIs does not seem an eligible new way of personalized therapy.
TRIAL REGISTRATION
International Clinical Trials Registry Platform Search Portal; number NL7514; registered 11/02/2019.
Topics: Humans; Cytochrome P-450 CYP3A; Prospective Studies; Genotype; Heterozygote; Neoplasms; Multicenter Studies as Topic
PubMed: 37310647
DOI: 10.1007/s40262-023-01260-4 -
Journal of Mass Spectrometry and... Aug 2023Tyrosine kinase inhibitors (TKIs) are widely used in tumor treatment. The detection of these medicines by liquid chromatography-tandem mass spectrometry (LC-MS/MS) can...
INTRODUCTION
Tyrosine kinase inhibitors (TKIs) are widely used in tumor treatment. The detection of these medicines by liquid chromatography-tandem mass spectrometry (LC-MS/MS) can avoid the interference of structurally similar compounds.
OBJECTIVES
This study aimed to develop and validate a new LC-MS/MS assay for the quantification of eight tyrosine kinase inhibitors in human plasma and to preliminarily evaluate the clinical utility of the therapeutic drug monitoring method.
METHODS
Plasma samples were prepared by simple protein precipitation and separated using an ultra-high-performance reversed phase column. Detection was achieved using a triple quadrupole mass spectrometer in the positive ionization mode. The assay was validated against standard guidelines. We reviewed and analyzed the results of 268 plasma samples obtained from patients administered imatinib and other TKIs collected from January 2020 to November 2021 at Zhongshan Hospital. The analytes were separated and quantified within 3.5 min.
RESULTS
The newly developed method demonstrated linearity for the detected drug concentration in the range of 20 to 2000 ng/ml for gefitinib (r = 0.991) and crizotinib (r = 0.992), 50 to 5000 ng/ml for nilotinib (r = 0.991) and imatinib (r = 0.995), 1500-150,000 ng/ml for vemurafenib (r = 0.998), 1000-100,000 ng/ml for pazopanib (r = 0.993), 0.5-100 ng/ml for axitinib (r = 0.992) and 5-500 ng/ml for sunitinib (r = 0.991) and N-desethyl sunitinib (r = 0.998). The lower limit of quantification (LLOQ) was 20 ng/ml for gefitinib and crizotinib, 50 ng/ml for nilotinib and imatinib, 1500 ng/ml for vemurafenib, 1000 ng/ml for pazopanib, 0.5, and 5 ng/ml for sunitinib and N-desethyl sunitinib, respectively. Specificity, precision, accuracy, and stability were tested, and met the requirements of the guidelines. At the same dose, there was no significant difference in plasma drug concentration between the original imatinib medicine and the generic medicine after patent expiration.
CONCLUSION
We developed a sensitive and reliable method for the quantification of eight TKIs.
PubMed: 37234251
DOI: 10.1016/j.jmsacl.2023.05.001 -
Cancer Cell International Jan 2024Patients with recurrent or metastatic cervical cancer are in urgent need of novel prognosis assessment or treatment approaches. In this study, a novel prognostic gene...
Patients with recurrent or metastatic cervical cancer are in urgent need of novel prognosis assessment or treatment approaches. In this study, a novel prognostic gene signature was discovered by utilizing cuproptosis-related angiogenesis (CuRA) gene scores obtained through weighted gene co-expression network analysis (WGCNA) of The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. To enhance its reliability, the gene signature was refined by integrating supplementary clinical variables and subjected to cross-validation. Meanwhile, the activation of the VEGF pathway was inferred from an analysis of cell-to-cell communication, based on the expression of ligands and receptors in cell transcriptomic datasets. High-CuRA patients had less infiltration of CD8 + T cells and reduced expression of most of immune checkpoint genes, which indicated greater difficulty in immunotherapy. Lower IC50 values of imatinib, pazopanib, and sorafenib in the high-CuRA group revealed the potential value of these drugs. Finally, we verified an independent prognostic gene SFT2D1 was highly expressed in cervical cancer and positively correlated with the microvascular density. Knockdown of SFT2D1 significantly inhibited ability of the proliferation, migration, and invasive in cervical cancer cells. CuRA gene signature provided valuable insights into the prediction of prognosis and immune microenvironment of cervical cancer, which could help develop new strategies for individualized precision therapy for cervical cancer patients.
PubMed: 38200479
DOI: 10.1186/s12935-023-03189-x -
Cancer Chemotherapy and Pharmacology Feb 2024Data on the effects of obesity on drug exposure of oral targeted oncolytics is scarce. Therefore, the aim of this study was to investigate the influence of body weight...
PURPOSE
Data on the effects of obesity on drug exposure of oral targeted oncolytics is scarce. Therefore, the aim of this study was to investigate the influence of body weight and body mass index (BMI) on trough levels of oral oncolytics with an exposure-response relationship. The oral oncolytics of interest were abiraterone, alectinib, cabozantinib, crizotinib, imatinib, pazopanib, sunitinib and trametinib.
METHODS
This retrospective cohort study included patients treated with the selected oral oncolytics at the standard dose, with a measured trough level at steady state and with available body weight. The Spearman's correlation test was used to determine the correlation between body weight and trough levels. The Fisher's exact text was used to compare the frequency of inadequate trough levels between BMI categories.
RESULTS
1265 patients were included across the different oral oncolytics. A negative correlation coefficient was observed between weight and trough levels for crizotinib (n = 75), imatinib (n = 201) and trametinib (n = 310), respectively, ρ = - 0.41, ρ = - 0.24 and ρ = - 0.23, all with a p-value < 0.001. For crizotinib, a higher percentage of patients with a body weight > 100 kg had inadequate trough levels. No statistically significant differences were observed in the frequency of inadequate trough levels between BMI categories.
CONCLUSION
Higher body weight was only correlated with lower plasma trough levels for crizotinib, imatinib, and trametinib. Therefore, patients with a high body weight may require dose escalation to obtain adequate target levels when treated with these oral oncolytics.
Topics: Humans; Imatinib Mesylate; Crizotinib; Retrospective Studies; Sunitinib; Obesity
PubMed: 37906253
DOI: 10.1007/s00280-023-04601-z -
Indian Journal of Cancer Sep 2023Data on occurrence of pneumothorax after the use of oral pazopanib in advanced soft tissue sarcoma (STS) with lung metastases are scarce in literature. We aimed to...
AIM
Data on occurrence of pneumothorax after the use of oral pazopanib in advanced soft tissue sarcoma (STS) with lung metastases are scarce in literature. We aimed to evaluate those in our patients.
METHODS
This was a single center retrospective study of incidence of pneumothorax in patients with lung metastases in advanced STS treated with oral pazopanib between July, 2016 and December, 2020. Patients were treated with pazopanib usually from 2nd line onwards with a dose ranging from 400 mg to 800 mg once daily.
RESULTS
Total of 34 patients with lung metastasis in a setting of advanced STS were treated with oral pazopanib during the study period. The setting of pazopanib use was 2nd line in four and 1st line in one of them. The starting dose was 600 mg once daily in three patients, 400 mg OD in one patient, and 800 mg OD in one patient. Five patients developed pneumothorax with duration on pazopanib of 6, 7, 24, 6, and 2.5 months, respectively. Three patients had symptoms and required chest tube drainage. None of them were smokers or had any other underlying lung disease. The disease response of those patients was stable disease in four and partial response in one during treatment with pazopanib. One patient had a rechallenge with further pazopanib course without any recurrence of pneumothorax.
CONCLUSIONS
Pneumothorax is a rare pulmonary complication after pazopanib use in patients with lung metastasis. Clinicians should be aware of this rare complication as literature is scarce. Rechallenge with pazopanib is feasible after pneumothorax.
PubMed: 38090966
DOI: 10.4103/ijc.IJC_95_21 -
Bioactive Materials Jan 2024Atypical teratoid/rhabdoid tumor (ATRT) is a rare childhood malignancy that originates in the central nervous system. Over ninety-five percent of ATRT patients have...
Atypical teratoid/rhabdoid tumor (ATRT) is a rare childhood malignancy that originates in the central nervous system. Over ninety-five percent of ATRT patients have biallelic inactivation of the tumor suppressor gene . ATRT has no standard treatment, and a major limiting factor in therapeutic development is the lack of reliable ATRT models. We employed CRISPR/Cas9 gene-editing technology to knock out and genes in human episomal induced pluripotent stem cells (Epi-iPSCs), followed by brief neural induction, to generate an ATRT-like model. The dual knockout Epi-iPSCs retained their stemness with the capacity to differentiate into three germ layers. High expression of and in neurally induced knockout spheroids was comparable to that in two ATRT cell lines. Beta-catenin protein expression was higher in SMARCB1-deficient cells and spheroids than in normal Epi-iPSC-derived spheroids. Nucleophosmin, Osteopontin, and Ki-67 proteins were also expressed by the SMARCB1-deficient spheroids. In summary, the tumor model resembled embryonal features of ATRT and expressed ATRT biomarkers at mRNA and protein levels. Ribociclib, PTC-209, and the combination of clofilium tosylate and pazopanib decreased the viability of the ATRT-like cells. This disease modeling scheme may enable the establishment of individualized tumor models with patient-specific mutations and facilitate high-throughput drug testing.
PubMed: 37637078
DOI: 10.1016/j.bioactmat.2023.08.009 -
Frontiers in Pharmacology 2023Lung adenocarcinoma is a common cause of mortality in patients with cancer. Recent studies have indicated that copper-related cell death may not occur in the same way...
Lung adenocarcinoma is a common cause of mortality in patients with cancer. Recent studies have indicated that copper-related cell death may not occur in the same way as previously described. Long non-coding RNAs (lncRNAs) play a key role in the occurrence and development of tumors; however, the relationship between cuproptosis and lncRNAs in tumorigenesis and lung adenocarcinoma (LUAD) treatment has not been well established. Our study aimed to construct a model to analyze the prognosis of lung adenocarcinoma in patients using a carcinogenesis-related lncRNA (CR) signature. The transcriptional profiles of 507 samples from The Cancer Genome Atlas were assessed. Cox regression and co-expression analyses, and the least absolute shrinkage and selection operator (LASSO) were used to filter the CR and develop the model. The expression status of the six prognostic CRs was used to classify all samples into high- and low-risk groups. The overall disease-free survival rate was compared between the two groups. The Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes were used to identify the pathways and mechanisms involved in this model. Subsequently, immunotherapy response, sensitivity, and correlation analyses for several anti-tumor medications were performed. experiments, including qPCR, were conducted in nine lung adenocarcinoma cell lines and 16 pairs of lung adenocarcinoma and para-carcinoma tissues. After confirmation using the ROC curve, patients in the low-risk category benefited from both overall and disease-free survival. Gene Ontology analysis highlighted cell movement in the model. In the experiments, qPCR results showed the expression levels of six CRs in 16 pairs of carcinoma and para-carcinoma tissues, which were in accordance with the results of the model. AL138778.1 is a protective factor that can weaken the invasion and migration of A549 cells, and AL360270.1 is a hazardous factor that promotes the invasion and migration of A549 cells. According to this model, targeted treatments such as axitinib, gefitinib, linsitinib, pazopanib, and sorafenib may be more appropriate for low-risk patients. Six CR profiles (AL360270.1, AL138778.1, CDKN2A-DT, AP003778.1, LINC02718, and AC034102.8) with predictive values may be used to evaluate the prognosis of patients with lung adenocarcinoma undergoing therapy.
PubMed: 37745054
DOI: 10.3389/fphar.2023.1236655 -
Cancer Science Feb 2024Of the drugs used in second-line chemotherapy for soft tissue sarcoma (STS), trabectedin is effective for liposarcoma and leiomyosarcoma (L-sarcoma), eribulin for...
Of the drugs used in second-line chemotherapy for soft tissue sarcoma (STS), trabectedin is effective for liposarcoma and leiomyosarcoma (L-sarcoma), eribulin for liposarcoma, and pazopanib for non-liposarcoma. The indications for these drugs in STS other than L-sarcoma have not been established. Here we explored the prognosis, mutation profiles, and drug-response factors in STS using real-world big data. Clinicogenomic data on 1761 patients with sarcoma who underwent FoundationOne CDx were obtained from a national database in Japan. Patients with TP53 and KDM2D mutations had a significantly shorter survival period of 253 (95% CI, 99-404) and 330 (95% CI, 20-552) days, respectively, than those without mutations. Non-supervised clustering based on mutation profiles generated 13 tumor clusters. The response rate (RR) to trabectedin was highest in an MDM2-amplification cluster (odds ratio [OR]: 2.2; p = 0.2). The RR was lowest for eribulin in an MDM2-amplification cluster (OR: 0.4; p = 0.03) and highest in a TERT-mutation cluster (OR: 3.0; p = 0.03). The RR was highest for pazopanib in a PIK3CA/PTEN-wild type cluster (OR: 2.1; p = 0.03). In particular, patients harboring mutations in genes regulating the PI3K/Akt/mTOR pathway had a lower RR than patients without mutations (OR: 0.3; p = 0.04). In STS, mutation profiles were more useful in predicting the drug response than histology. The present study demonstrated the potential of tailored therapy guided by mutation profiles established by comprehensive genomic profiling testing in optimizing second-line chemotherapy for STS. The findings of this study will hopefully contribute some valuable insights into enhancing STS treatment strategies and outcomes.
Topics: Humans; Trabectedin; Phosphatidylinositol 3-Kinases; Sarcoma; Liposarcoma; Genomics; Pyrimidines; Polyether Polyketides; Ketones; Indazoles; Sulfonamides; Furans
PubMed: 38115234
DOI: 10.1111/cas.16050