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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 -
Frontiers in Veterinary Science 2024Veterinary oncology has experienced significant evolution over the last few decades, with chemotherapy being currently applied to several neoplasms with therapeutic... (Review)
Review
Veterinary oncology has experienced significant evolution over the last few decades, with chemotherapy being currently applied to several neoplasms with therapeutic success. Traditionally, chemotherapy protocols are based on classic cytostatic drugs under the concept of maximum tolerated dose (MTD), which has been associated with a greater risk of toxicity and resistance. Thus, new therapeutic alternatives have emerged, such as metronomic chemotherapy (MC), introducing a new paradigm in cancer treatment. MC consists of administering low doses of chemotherapy drugs continuously over a long period of time, modulating the tumour microenvironment (TME) due to the combination of cytotoxic, antiangiogenic and immunomodulatory effects. This multi-targeted therapy has been described as a treatment option in several canine and feline cancers since 2007, with positive results already published in the literature, particularly in mammary carcinomas and soft tissue sarcomas in dogs. The aim of this review article is to describe the current knowledge about the use of MC in small animal oncology, with emphasis on its mechanisms of action, the most commonly used drugs and clinical outcome.
PubMed: 38903691
DOI: 10.3389/fvets.2024.1397376 -
Frontiers in Oncology 2024
PubMed: 38482207
DOI: 10.3389/fonc.2024.1385766 -
Cancers Jun 2022Cytotoxic chemotherapy remains the mainstay of treatment for advanced pancreatic adenocarcinoma (PDAC). Emerging studies support metronomic chemotherapy (MCT) as...
Cytotoxic chemotherapy remains the mainstay of treatment for advanced pancreatic adenocarcinoma (PDAC). Emerging studies support metronomic chemotherapy (MCT) as effective, challenging established paradigms of dosing and schedules. The blood-based ChemoSensitivity Assay has been shown to predict response and survival in advanced PDAC patients treated with standard chemotherapy. The current study combines these concepts for a highly personalized treatment approach. This was a retrospective analysis; a pilot ( = 50) and validation cohort ( = 45) were studied. The ChemoSensitivity Assay was performed at baseline and during therapy; results were correlated to drugs administered and patient outcomes. MCT was administered based on the assay results at the treating physician's discretion. Patients in the pilot cohort experienced favorable survival compared with historical controls (median overall survival (mOS) 16.8 mo). Patients whose treatment closely matched the ChemoSensitivity Assay predictions experienced longer median time on lines of therapy (5.3 vs. 3.3 mo, = 0.02) and showed a trend for longer mOS (20.9 vs. 12.5 mo, = 0.055) compared with those not closely matched. These findings were confirmed in the validation cohort. Overall, patients treated with MCT closely matching Assay results experienced a remarkable mOS of 27.7 mo. ChemoSensitivity profiling-guided MCT is a promising approach for personalized therapy in advanced PDAC.
PubMed: 35740571
DOI: 10.3390/cancers14122906 -
Journal of Neuroendocrinology Oct 2022Neuroendocrine tumors (NETs) are more commonly slow-growing, therefore patients often receive chronic systemic therapies for tumor growth control and preservation of...
Neuroendocrine tumors (NETs) are more commonly slow-growing, therefore patients often receive chronic systemic therapies for tumor growth control and preservation of quality of life. Metronomic chemotherapy (mCT) is in line with this goal as it leads to stabilization of tumor growth over time without severe systemic toxicity. This is a retrospective analysis of patients with metastatic NETs receiving metronomic capecitabine (mCAP) or temozolomide (mTEM), at a NET-referral center. The aims of the study were to explore activity and safety of mCT and relationships between some characteristics of the patient population and clinical outcomes. Among a total of 67 patients with metastatic well or moderately differentiated (W/M-D) NETs, mostly gastroenteropancreatic (GEP) and nonfunctioning, 1.2 years (95% CI: 0.8-1.8) median progression-free survival (mPFS), and 3.0 years (95% CI: 2.3-4.9) median overall survival (mOS) were observed. Disease control rate was 85%. Grade 3 adverse events occurred in 15% of patients in mCAP and 13% in mTEM, and were mostly hematological and gastrointestinal. At univariate and multivariate analysis none of the variables analyzed (treatment regimen, sex, age at diagnosis, site of primary tumor and metastases, number of previous mCT lines, baseline tumor status before mCT, Ki67 value) were significantly correlated to OS and PFS. Our retrospective study suggested that mCAP and mTEM can be active and well tolerated in patients with metastatic W/M-D NETs, irrespective of the primary site, site of metastases, line of treatment and baseline tumor status.
Topics: Humans; Neuroendocrine Tumors; Retrospective Studies; Quality of Life; Antineoplastic Combined Chemotherapy Protocols; Treatment Outcome; Capecitabine
PubMed: 36306196
DOI: 10.1111/jne.13189 -
Cancers Feb 2023Patients with advanced ovarian cancer (OC) have a detrimental prognosis. The options for systemic treatment of advanced OC in later lines of treatment are limited by the...
Patients with advanced ovarian cancer (OC) have a detrimental prognosis. The options for systemic treatment of advanced OC in later lines of treatment are limited by the availability of active therapies and their applicability to often fragile, exhausted patients with poor performance status. Metronomic chemotherapy (MC) is a concept of a continuous administration of cytotoxic drugs, which is characterized by multidirectional activity (anti-proliferative, anti-angiogenic, and anti-immunosuppressive) and low toxicity. We have performed a retrospective analysis of consecutive, advanced, chemo-refractory OC patients treated with MC based on single-agent topotecan (1 mg p.o. q2d) or on a topotecan (1 mg q2d) and cyclophosphamide (50 mg p.o. qd) combination (CyTo). Metronomic chemotherapy demonstrated promising activity, with 72% and 86% of patients achieving biochemical or objective disease control and 18% and 27% of patients achieving a biochemical or objective response, respectively. The median PFS in the whole population was 3.65 months, but the median PFS in patients with a biochemical response to MC (18.2% of patients) reached 10.7 months. The study also suggested that overweight or obese patients had significantly better outcomes on MC than patients with BMI <25 kg/m. This article is the first report in the literature on metronomic chemotherapy based on a topotecan + cyclophosphamide combination (CyTo). The CyTo regimen demonstrated safety, clinical activity, and potential broad clinical applicability in advanced OC patients and will be evaluated in a forthcoming clinical trial.
PubMed: 36831410
DOI: 10.3390/cancers15041067 -
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 -
Thoracic Cancer Aug 2023This single-arm prospective phase II trial was performed to assess the efficacy and safety of the dual oral metronomic vinorelbine and capecitabine (mNC) regimen in...
A phase II study of a doublet metronomic chemotherapy regimen consisting of oral vinorelbine and capecitabine in Chinese women with HER2-negative metastatic breast cancer.
BACKGROUND
This single-arm prospective phase II trial was performed to assess the efficacy and safety of the dual oral metronomic vinorelbine and capecitabine (mNC) regimen in women with HER2-negative metastatic breast cancer (MBC) in China.
METHODS
The mNC regimen was administered to the enrolled cases, including oral vinorelbine (VNR) 40 mg three times weekly (on days 1, 3 and 5 every week) and capecitabine (CAP) 500 mg three times a day, until disease progression or intolerable toxicity. The primary endpoint was the 1-year progression-free survival (PFS) rate. Secondary endpoints included objective response rate (ORR), disease control rate (DCR), clinical benefit rate (CBR) and treatment-related adverse events (TRAEs). Stratified factors included treatment lines and hormone receptor (HR) status.
RESULTS
Between June 2018 and March 2023, 29 patients were enrolled into the study. The median follow-up time was 25.4 months (range, 2.0-53.8). In the entire group, the 1-year PFS rate was 54.1%. ORR, DCR and CBR were 31.0%, 96.6% and 62.1%, respectively. The mPFS was 12.5 months (range, 1.1-28.1). Subgroup analysis revealed that ORRs were 29.4% and 33.3% in first- and ≥second-line chemotherapy, respectively. ORRs were 29.2% (7/24) and 40.0% (2/5) for HR-positive MBC and metastatic triple-negative breast cancer (mTNBC), respectively. Grade 3/4 TRAEs were neutropenia (10.3%) and nausea/vomiting (6.9%).
CONCLUSIONS
The dual oral mNC regimen showed very good safety features and improved compliance without loss of efficacy in both first- and second-line treatments. The regimen also reached an excellent ORR in the mTNBC subgroup.
Topics: Humans; Female; Breast Neoplasms; Capecitabine; Vinorelbine; East Asian People; Prospective Studies; Vinblastine; Antineoplastic Combined Chemotherapy Protocols; Receptor, ErbB-2; Triple Negative Breast Neoplasms; Neoplasm Metastasis; Treatment Outcome
PubMed: 37402471
DOI: 10.1111/1759-7714.15011 -
Indian Journal of Surgical Oncology Jun 2023To evaluate the feasibility, tolerance, and efficacy of OMCT (oral metronomic chemotherapy) after CRS + HIPEC for peritoneal mesothelioma in patients with poor...
OBJECTIVE
To evaluate the feasibility, tolerance, and efficacy of OMCT (oral metronomic chemotherapy) after CRS + HIPEC for peritoneal mesothelioma in patients with poor prognostic factors: PCI > 20, incomplete CRS, poor performance status, or progression on systemic chemotherapy.
METHODS
A retrospective analysis of patients undergoing CRS + HIPEC for peritoneal mesothelioma and receiving OMCT for poor risk factors.
RESULTS
Sixteen patients underwent CRS + HIPEC between 2013 and 2017. The median PCI was 31.5. Complete cytoreduction (CC-0/1) was obtained in 8 patients (50%). All 16 received HIPEC except one patient with baseline renal dysfunction.Thirteen patients had PCI > 20 where only 5 had CC-0/1. Of 8 suboptimal cytoreduction (CC-2/3), 7 received OMCT (6 for progression on chemotherapy and one for mixed histology). Three patients had PCI < 20 and all had CC-0/1 clearance. Only one received OMCT for progression on adjuvant chemotherapy. Patients receiving OMCT for progression on adjuvant chemotherapy (ACT) were in poor PS.The median follow-up was 13.4 months. Five are alive with the disease (three are on OMCT). Six are alive without disease (2 are on OMCT). The mean OS was 24.3 months and the mean DFS was 18 months. Outcomes were similar between CC-0/1 and CC-2/3 groups, OMCT vs no OMCT groups.All patients receiving OMCT for progression on neoadjuvant chemotherapy had better survival (alive at 12, 20, 32, 36 months) compared to those receiving OMCT for progression on the ACT ( = 0.012).
CONCLUSION
OMCT is a good alternative in high-volume peritoneal mesothelioma with incomplete cytoreduction and progression on chemotherapy. OMCT may improve outcomes in these scenarios when started early.
PubMed: 37359939
DOI: 10.1007/s13193-022-01691-8 -
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