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Frontiers in Immunology 2023Neuroblastoma (NB) is a childhood tumor that originates in the peripheral sympathetic nervous system and is responsible for 15% of cancer-related deaths in the pediatric... (Review)
Review
Neuroblastoma (NB) is a childhood tumor that originates in the peripheral sympathetic nervous system and is responsible for 15% of cancer-related deaths in the pediatric population. Despite intensive multimodal treatment, many patients with high-risk NB relapse and develop a therapy-resistant tumor. One of the phenomena related to therapeutic resistance is intratumor heterogeneity resulting from the adaptation of tumor cells in response to different selective environmental pressures. The transcriptional and epigenetic profiling of NB tissue has recently revealed the existence of two distinct cellular identities in the NB, termed adrenergic (ADRN) and mesenchymal (MES), which can spontaneously interconvert through epigenetic regulation. This phenomenon, known as tumor plasticity, has a major impact on cancer pathogenesis. The aim of this review is to describe the peculiarities of these two cell states, and how their plasticity affects the response to current therapeutic treatments, with special focus on the immunogenic potential of MES cells. Furthermore, we will discuss the opportunity to combine immunotherapy with chemotherapy to counteract NB phenotypic interconversion.
Topics: Child; Humans; Epigenesis, Genetic; Neoplasm Recurrence, Local; Neuroblastoma; Immunotherapy
PubMed: 37849756
DOI: 10.3389/fimmu.2023.1268645 -
Cancer Letters Nov 2023Chemotherapeutic agents have profound effects on cancer, stroma and immune cells that - in most cases - depend upon the dosage and schedule of administration.... (Review)
Review
Metronomic chemotherapy, dampening of immunosuppressive cells, antigen presenting cell activation, and T cells. A quartet against refractoriness and resistance to checkpoint inhibitors.
Chemotherapeutic agents have profound effects on cancer, stroma and immune cells that - in most cases - depend upon the dosage and schedule of administration. Preclinical and clinical studies summarized and discussed in the present review have demonstrated that maximum tolerable dosage (MTD) vs low-dosage, continuous (metronomic) administration of most chemotherapeutics have polarized effects on immune cells. In particular, metronomic schedules might be associated - among others effects - with activation of antigen presenting cells and generation of new T cell clones to enhance the activity of several types of immunotherapies. Ongoing and planned clinical trials in different types of cancer will confirm or dismiss this hypothesis and provide candidate biomarker data for the selection of patients who are likely to benefit from these combinatorial strategies.
Topics: Humans; Antineoplastic Combined Chemotherapy Protocols; T-Lymphocytes; Neoplasms; Administration, Metronomic; Antigen-Presenting Cells
PubMed: 37806515
DOI: 10.1016/j.canlet.2023.216441 -
Cureus Sep 2023Leptomeningeal carcinomatosis (LC) is an uncommon sequelae of metastatic cancer affecting the pia and arachnoid mater. It has been postulated that recent improvements...
Leptomeningeal carcinomatosis (LC) is an uncommon sequelae of metastatic cancer affecting the pia and arachnoid mater. It has been postulated that recent improvements in cancer patient survival time have increased the frequency of LC and other rare metastatic conditions that patients previously would not have lived long enough to experience. LC carries a universally poor prognosis with a mean survival of between two to four months if treated; however, the recent increase in incidence has allowed for further research into the condition and potential treatments. Options for administering chemotherapy have been limited in the past, but recent developments in surgical chemotherapeutic ports have allowed for intrathecal delivery of drugs like methotrexate without systemic exposure. In fact, innovative delivery systems undergoing clinical trials can deliver these drugs in a metronomic fashion to limit the leukoencephalopathy complications of methotrexate. Primary breast cancer is the most common source of metastatic leptomeningeal lesions, and such a lesion was observed by the authors in the cadaver of a 70-year-old Caucasian female with unspecified breast cancer in a medical school anatomic laboratory. The cause of death was listed as "complication of malignant neoplasm of unspecified site of unspecified female breast." Through this case report, we seek to develop our understanding of this rare metastatic phenomenon and highlight the importance of student cadaveric dissection.
PubMed: 37790014
DOI: 10.7759/cureus.44533 -
Breast (Edinburgh, Scotland) Dec 2023To analyze the safety and efficacy of orally administered metronomic capecitabine plus pyrotinib in HER2 positive metastatic breast cancer (MBC) patients, we conducted a...
PURPOSE
To analyze the safety and efficacy of orally administered metronomic capecitabine plus pyrotinib in HER2 positive metastatic breast cancer (MBC) patients, we conducted a prospective phase II study with a single-arm design.
METHODS
HER2 positive patients received oral metronomic capecitabine 500 mg three times a day and pyrotinib 400 mg per day. The primary endpoint was progression-free survival (PFS). Other endpoints included objective response rate (ORR), overall survival (OS), clinical benefit rate (CBR) and safety.
RESULTS
The study included 50 patients with MBC that was HER2-positive, while 1 patient was excluded due to nonstandard medication. The median PFS and OS was 11.9 months (95%CI 8.8-14.6) and 29.3 months (95%CI 24.4-34.8) respectively. ORR was 34.7%, and CBR was 81.6% with 2 CR (4.1%), 15 PR (30.6%) and 23 SD (46.9%). The mPFS in first- or second-line treatment was 12.2 months. The most frequent treatment-related adverse events included hand-foot syndrome, diarrhea, vomiting and nausea. Grade 3 adverse events occurred in 15(30.6%) patients, including hand-foot syndrome (12.2%), diarrhea (12.2%), vomiting (4.1%), and nausea (2.0%). 1 grade 4 adverse event of diarrhea (2.0%) was observed.
CONCLUSION
The combination of metronomic capecitabine and pyrotinib is a promising regimen with competitive efficacy and improved tolerability in HER2 positive metastatic breast cancer patients.
Topics: Female; Humans; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Capecitabine; Diarrhea; Hand-Foot Syndrome; Nausea; Prospective Studies; Receptor, ErbB-2; Vomiting
PubMed: 37742492
DOI: 10.1016/j.breast.2023.103581 -
BioImpacts : BI 2023Gastric cancer is one of the most commonly known malignancies and is the fifth cancer-related death globally. Whereas natural killer (NK) cells play a critical role in...
INTRODUCTION
Gastric cancer is one of the most commonly known malignancies and is the fifth cancer-related death globally. Whereas natural killer (NK) cells play a critical role in tumor elimination; therefore, adoptive NK cell therapy has become a promising approach in cancer cytotherapy. Hence, this study investigated the chemo-immune cell therapy in MKN-45 derived xenograft gastric cancer model.
METHODS
Three groups of animals have received the following treatments separately: activated NK cells, capecitabine, the combination of capecitabine and activated NK cells, and one was considered as the control group. Morphometric properties of tumor samples were evaluated at the end of the study. NK cells infiltration was evaluated by immunohistochemistry (IHC) of hCD56. Mitotic count and treatment response was assessed by hematoxylin and eosin (H&E) staining. The proliferation ratio to apoptosis was determined by IHC assessment of Ki67 and caspase 3.
RESULTS
The results indicated that the NK cell therapy could effectively decrease the mitotic count in pathology assessment, but the tumor was not completely eradicated. In combination with metronomic chemotherapy (MC) of capecitabine, NK cell therapy demonstrated a significant difference in tumor morphometric properties compared to the control group. The proliferation ratio to apoptosis was also in line with pathology data.
CONCLUSION
Although NK cell therapy could effectively decrease the mitotic count , the obtained findings indicated lesser potency than MC despite activation. In order to enhance NK cell therapy effectiveness, suppressive features of the tumor microenvironment and inhibitory immune checkpoints blockade should be considered.
PubMed: 37736341
DOI: 10.34172/bi.2022.26386 -
International Immunopharmacology Nov 2023Liver transplantation is one of the most effective treatments for hepatocellular carcinoma (HCC). The balance between inhibiting immune rejection and preventing tumor...
Liver transplantation is one of the most effective treatments for hepatocellular carcinoma (HCC). The balance between inhibiting immune rejection and preventing tumor recurrence after liver transplantation is the key to determining the long-term prognosis of patients with HCC after liver transplantation. In our previous study, we found that capecitabine (CAP), an effective drug for the treatment of HCC, could exert an immunosuppressive effect after liver transplantation by inducing T cell ferroptosis. Recent studies have shown that ferroptosis is highly associated with autophagy. In this study, we confirmed that the autophagy inducer rapamycin (RAPA) combined with metronomic capecitabine (mCAP) inhibits glutathione peroxidase 4 (GPX4) and promotes ferroptosis in CD4 T cells to exert immunosuppressive effects after rat liver transplantation. Compared with RAPA or mCAP alone, the combination of RAPA and mCAP could adequately reduce liver injury in rats with acute rejection after transplantation. The CD4 T cell counts in peripheral blood, spleen, and transplanted liver of recipient rats significantly decreased, and the oxidative stress level and ferrous ion concentration of CD4 T cells significantly increased in the combination group. In vitro, the combination of drugs significantly promoted autophagy, decreased GPX4 protein expression, and induced ferroptosis in CD4 T cells. In conclusion, the autophagy inducer RAPA improved the mCAP-induced ferroptosis in CD4 T cells. Our results support the concept of ferroptosis as an autophagy-dependent cell death and suggest that the combination of ferroptosis inducers and autophagy inducers is a new research direction for improving immunosuppressive regimens after liver transplantation.
Topics: Humans; Rats; Animals; Sirolimus; T-Lymphocytes; Capecitabine; Liver Transplantation; Ferroptosis; Carcinoma, Hepatocellular; Liver Neoplasms; Neoplasm Recurrence, Local; CD4-Positive T-Lymphocytes
PubMed: 37625370
DOI: 10.1016/j.intimp.2023.110810 -
Metabolites Aug 2023Neuroblastoma (NB) is a childhood cancer in which amplification of the MYCN gene is the most acknowledged marker of poor prognosis. MYCN-amplified NB cells rely on both...
Neuroblastoma (NB) is a childhood cancer in which amplification of the MYCN gene is the most acknowledged marker of poor prognosis. MYCN-amplified NB cells rely on both glycolysis and mitochondrial oxidative phosphorylation (OXPHOS) for energy production. Previously, we demonstrated that a ketogenic diet (KD) combined with metronomic cyclophosphamide (CP) delayed tumor growth in MYCN-amplified NB xenografts. The anti-diabetic drug metformin (MET) also targets complex I of the OXPHOS system. Therefore, MET-induced disruptions of mitochondrial respiration may enhance the anti-tumor effect of CP when combined with a KD. In this study, we found that MET decreased cell proliferation and mitochondrial respiration in MYCN-amplified NB cell lines, while the combination of KD, MET, and low-dose CP (triple therapy) also reduced tumor growth and improved survival in vivo in MYCN-amplified NB xenografts. Gene ontology enrichment analysis revealed that this triple therapy had the greatest effect on the transcription of genes involved in fatty acid ß-oxidation, which was supported by the increased protein expression of CPT1A, a key mitochondrial fatty acid transporter. We suspect that alterations to ß-oxidation alongside the inhibition of complex I may hamper mitochondrial energy production, thus explaining these augmented anti-tumor effects, suggesting that the combination of MET and KD is an effective adjuvant therapy to CP in MYCN-amplified NB xenografts.
PubMed: 37623854
DOI: 10.3390/metabo13080910 -
EBioMedicine Sep 2023Pharmacological synergisms are an attractive anticancer strategy. However, with more than 5000 approved-drugs and compounds in clinical development, identifying...
BACKGROUND
Pharmacological synergisms are an attractive anticancer strategy. However, with more than 5000 approved-drugs and compounds in clinical development, identifying synergistic treatments represents a major challenge.
METHODS
High-throughput screening was combined with target deconvolution and functional genomics to reveal targetable vulnerabilities in glioblastoma. The role of the top gene hit was investigated by RNA interference, transcriptomics and immunohistochemistry in glioblastoma patient samples. Drug combination screen using a custom-made library of 88 compounds in association with six inhibitors of the identified glioblastoma vulnerabilities was performed to unveil pharmacological synergisms. Glioblastoma 3D spheroid, organotypic ex vivo and syngeneic orthotopic mouse models were used to validate synergistic treatments.
FINDINGS
Nine targetable vulnerabilities were identified in glioblastoma and the top gene hit RRM1 was validated as an independent prognostic factor. The associations of CHK1/MEK and AURKA/BET inhibitors were identified as the most potent amongst 528 tested pairwise drug combinations and their efficacy was validated in 3D spheroid models. The high synergism of AURKA/BET dual inhibition was confirmed in ex vivo and in vivo glioblastoma models, without detectable toxicity.
INTERPRETATION
Our work provides strong pre-clinical evidence of the efficacy of AURKA/BET inhibitor combination in glioblastoma and opens new therapeutic avenues for this unmet medical need. Besides, we established the proof-of-concept of a stepwise approach aiming at exploiting drug poly-pharmacology to unveil druggable cancer vulnerabilities and to fast-track the identification of synergistic combinations against refractory cancers.
FUNDING
This study was funded by institutional grants and charities.
Topics: Animals; Mice; Glioblastoma; Aurora Kinase A; Drug Synergism; Cell Line, Tumor; Antineoplastic Agents; Drug Combinations
PubMed: 37572644
DOI: 10.1016/j.ebiom.2023.104752 -
Cancers Aug 2023Maintenance chemotherapy (MC) defines the administration of prolonged relatively low-intensity chemotherapy with the aim of "maintaining" tumor complete remission. This... (Review)
Review
Maintenance chemotherapy (MC) defines the administration of prolonged relatively low-intensity chemotherapy with the aim of "maintaining" tumor complete remission. This paper aims to report an update of the RMS2005 trial, which demonstrated better survival for patients with high-risk localized rhabdomyosarcoma (RMS) when MC with vinorelbine and low-dose cyclophosphamide was added to standard chemotherapy, and to discuss the published experience on MC in RMS. In the RMS2005 study, the outcome for patients receiving MC vs. those who stopped the treatment remains superior, with a 5-year disease-free survival of 78.1% vs. 70.1% ( = 0.056) and overall survival of 85.0% vs. 72.4% ( = 0.008), respectively. We found seven papers describing MC in RMS, but only one randomized trial that did not demonstrate any advantage when MC with eight courses of trofosfamide/idarubicine alternating with trofosfamide/etoposide has been employed in high-risk RMS. The use of MC showed better results in comparison to high-dose chemotherapy in non-randomized studies, including metastatic patients, and demonstrated feasibility and tolerability in relapsed RMS. Many aspects of MC in RMS need to be investigated, including the best drug combination and the optimal duration. The ongoing EpSSG trial will try to answer some of these questions.
PubMed: 37568826
DOI: 10.3390/cancers15154012 -
Journal of Oral Biology and... 2023The PTGS2 gene codes for the cyclooxygenase-2 (COX-2) enzyme that catalyzes the committed step in prostaglandin (PG) synthesis. Various and data suggest that...
Prostaglandin-endoperoxide synthase 2 (PTGS2) gene expression and its association with genes regulating the VEGF signaling pathway in head and neck squamous cell carcinoma.
INTRODUCTION
The PTGS2 gene codes for the cyclooxygenase-2 (COX-2) enzyme that catalyzes the committed step in prostaglandin (PG) synthesis. Various and data suggest that prostaglandin E2 mediates as a signaling molecule for activating the VEGF signaling pathway (VSP), forming an association between COX-2 and VSP. Several chemotherapy regimens increasingly rely on preventing the synthesis of PGs. The targeted and metronomic chemotherapy agents, which suppress the COX-2 enzymes, have a major role in suppressing the oral cancer cascade. Hence, this study was designed to understand the pattern of PTGS2 expression and genes regulating VSP in head and neck cancers.
METHODS
PTGS2 expression was analyzed in the TCGA database computationally with the help of the UALCAN web-server. The expression of VEGF signaling pathway genes was mined, and their expression pattern was determined. Co-expression analysis was done to elucidate the association between VEGF signaling genes and PTGS2. The ShineyGo web server was used for gene set enrichment.
RESULTS
Significantly high PTGS2 expression was observed in tumor samples. Further genes regulating VEGF signaling were significantly overexpressed in tumor samples. Co-expression analysis results showed a significant positive correlation between PTGS2 and angiogenesis-regulating genes. The majority of the genes were enriched for angiogenesis pathways.
CONCLUSION
PTGS2 was significantly expressed in head and neck cancer, and its expression was associated with genes regulating angiogenesis.
PubMed: 37559688
DOI: 10.1016/j.jobcr.2023.07.002