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PLoS Biology Sep 2023A major cause of cancer recurrence following chemotherapy is cancer dormancy escape. Taxane-based chemotherapy is standard of care in breast cancer treatment aimed at...
A major cause of cancer recurrence following chemotherapy is cancer dormancy escape. Taxane-based chemotherapy is standard of care in breast cancer treatment aimed at killing proliferating cancer cells. Here, we demonstrate that docetaxel injures stromal cells, which release protumor cytokines, IL-6 and granulocyte colony stimulating factor (G-CSF), that in turn invoke dormant cancer outgrowth both in vitro and in vivo. Single-cell transcriptomics shows a reprogramming of awakened cancer cells including several survival cues such as stemness, chemoresistance in a tumor stromal organoid (TSO) model, as well as an altered tumor microenvironment (TME) with augmented protumor immune signaling in a syngeneic mouse breast cancer model. IL-6 plays a role in cancer cell proliferation, whereas G-CSF mediates tumor immunosuppression. Pathways and differential expression analyses confirmed MEK as the key regulatory molecule in cancer cell outgrowth and survival. Antibody targeting of protumor cytokines (IL-6, G-CSF) or inhibition of cytokine signaling via MEK/ERK pathway using selumetinib prior to docetaxel treatment prevented cancer dormancy outgrowth suggesting a novel therapeutic strategy to prevent cancer recurrence.
Topics: Animals; Mice; Docetaxel; Interleukin-6; Taxoids; Cytokines; Granulocyte Colony-Stimulating Factor; Mitogen-Activated Protein Kinase Kinases; Neoplasms
PubMed: 37699010
DOI: 10.1371/journal.pbio.3002275 -
Lung Cancer (Amsterdam, Netherlands) May 2023Data to guide treatment selection in metastatic nonsquamous (mNSq) non-small cell lung cancer (NSCLC) after progression on current standard-of-care (SoC) treatment are...
Real-world treatment patterns and outcomes of patients with metastatic nonsquamous non-small cell lung cancer after progression on standard-of-care therapy in the United States.
OBJECTIVES
Data to guide treatment selection in metastatic nonsquamous (mNSq) non-small cell lung cancer (NSCLC) after progression on current standard-of-care (SoC) treatment are limited. We investigated patterns of treatment and clinical outcomes following one or more disease progressions on SoC.
MATERIALS AND METHODS
Electronic medical records in the ConcertAI Patient360 NSCLC database were analyzed for US adults with mNSq NSCLC who initiated treatment between 2016 and 2021. Analyses were conducted separately for patients who had ≥1 prior lines of therapy and progression(s) without (Cohort 1) or with (Cohort 2) evidence of targetable genetic alterations (EGFR, ALK, or ROS1). Outcomes included real-world progression-free survival (rwPFS) and overall survival (rwOS).
RESULTS
Cohorts 1 and 2 included 281 and 109 patients, respectively. In Cohort 1, subsequent treatment was most often with docetaxel monotherapy (18.5%) or docetaxel + ramucirumab (32.4%). Most patients in Cohort 2 received platinum-based doublet chemotherapy with (22.9%) or without (34.9%) immunotherapy. Median rwPFS and rwOS were 2.9 and 7.2 months, respectively, in Cohort 1, and 3.2 and 10.4 months in Cohort 2. Neither the addition of ramucirumab to docetaxel in Cohort 1 nor the addition of immunotherapy to chemotherapy in Cohort 2 was associated with a marked improvement in additional survival.
CONCLUSION
Patients with progressive mNSq NSCLC most commonly received later-line docetaxel for cancer without driver mutations, or platinum-based chemotherapy (following one or more lines of tyrosine kinase inhibitor therapy) for cancer with driver mutations, consistent with guideline recommendations. Median survival was poor regardless of subsequent treatment, highlighting the need for more effective options.
Topics: Adult; Humans; United States; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Docetaxel; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37003208
DOI: 10.1016/j.lungcan.2023.107177 -
PloS One 2023Despite an increase in the use of targeted anticancer drugs and immunotherapy, cytotoxic anticancer drugs such as docetaxel continue to play a clinically important role....
Despite an increase in the use of targeted anticancer drugs and immunotherapy, cytotoxic anticancer drugs such as docetaxel continue to play a clinically important role. The aim of this study was to evaluate drug-drug interactions between docetaxel and coadministered medicines in patients with breast cancer a claims database. The Health Insurance Review and Assessment Service (HIRA) database (2017 to 2019) was used in this study. We evaluated the risk of neutropenia (defined using receipt of granulocyte colony-stimulating factor (G-CSF) prescriptions) under docetaxel administration or the coadministration of docetaxel and an interacting anticancer drug (predefined based on approval information obtained from the Korean Ministry of Food and Drug Safety and the Lexicomp electronic database). The propensity score matching method was applied to balance covariates in the case (patients with G-CSF prescriptions) and control (patients without G-CSF prescriptions) groups. We identified 947 female patients with breast cancer prescribed with docetaxel and excluded 321 patients based on inclusion criteria. Of the remaining 626 patients, 280 were assigned to the case group and 346 to the control group. Predefined drugs were coadministered to 71 (11.3%) patients during the 7-day period before and after the administration of docetaxel. Adjusted odds ratios (ORs) calculated using the logistic regression model applied to the propensity score matching showed no significant difference between the administration of docetaxel alone and docetaxel coadministration (adjusted OR, 2.010; 95% confidence interval, 0.906, 4.459). In conclusion, we suggest that coadministration of docetaxel and a predefined interacting drug are not associated with G-CSF prescription.
Topics: Humans; Female; Docetaxel; Breast Neoplasms; Taxoids; Antineoplastic Combined Chemotherapy Protocols; Neutropenia; Antineoplastic Agents; Granulocyte Colony-Stimulating Factor; Insurance; Drug Interactions
PubMed: 37327237
DOI: 10.1371/journal.pone.0287382 -
Pharmacology Research & Perspectives Aug 2020Oral administration of docetaxel in combination with the CYP3A4 inhibitor ritonavir is used in clinical trials to improve oral bioavailability of docetaxel. Diarrhea was... (Comparative Study)
Comparative Study
Oral administration of docetaxel in combination with the CYP3A4 inhibitor ritonavir is used in clinical trials to improve oral bioavailability of docetaxel. Diarrhea was the most commonly observed and dose-limiting toxicity. This study combined preclinical and clinical data and investigated incidence, severity and cause of oral docetaxel-induced diarrhea. In this study, incidence and severity of diarrhea in patients were compared to exposure to orally administered docetaxel. Intestinal toxicity after oral or intraperitoneal administration of docetaxel was further explored in mice lacking Cyp3a and mice lacking both Cyp3a and P-glycoprotein. In patients, severity of diarrhea increased significantly with an increase in AUC and C (P = .035 and P = .025, respectively), but not with an increase in the orally administered dose (P = .11). Furthermore, incidence of grade 3/4 diarrhea after oral docetaxel administration was similar as reported after intravenous docetaxel administration. Intestinal toxicity in mice was only observed at high systemic exposure to docetaxel and was similar after oral and intraperitoneal administration of docetaxel. In conclusion, our data show that the onset of severe diarrhea after oral administration of docetaxel in humans is similar after oral and intravenous administration of docetaxel and is caused by the concentration of docetaxel in the systemic blood circulation. Mouse experiments confirmed that intestinal toxicity is caused by a high systemic exposure and not by local intestinal exposure. Severe diarrhea in patients after oral docetaxel is reversible and is not related to the route of administration of docetaxel.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Administration, Intravenous; Administration, Oral; Adult; Aged; Animals; Antineoplastic Agents; Area Under Curve; Cytochrome P-450 CYP3A; Diarrhea; Docetaxel; Female; Humans; Incidence; Injections, Intraperitoneal; Male; Mice; Mice, Knockout; Middle Aged; Severity of Illness Index
PubMed: 32725720
DOI: 10.1002/prp2.633 -
Iranian Journal of Medical Sciences Sep 2023Autophagy is a conservative mechanism for cell survival as the main response of cells to stress conditions. The present study aimed to assess the effect of docetaxel on...
BACKGROUND
Autophagy is a conservative mechanism for cell survival as the main response of cells to stress conditions. The present study aimed to assess the effect of docetaxel on the survival, fertilization, and expression of autophagy-related genes in vitrified oocytes.
METHODS
The study was conducted in 2018 at the Stem Cells Technology Research Center, Shiraz University of Medical Sciences (Shiraz, Iran). Denuded oocytes were randomly selected and assigned to five groups, namely control (n=133), docetaxel (n=136), docetaxel+cryoprotectants (n=146), docetaxel+vitrification (n=138), and vitrification (n=145). The effect of vitrification on the expression of autophagy-related gene 5 () and was determined using a real-time polymerase chain reaction. Data were analyzed using SPSS software (version 26.0) and GraphPad Prism 9.
RESULTS
Survival and fertilization rates in each experimental group were significantly reduced compared to the control group (P=0.001). After fertilization of oocytes, the 2-cell formation rate was significantly reduced in the docetaxel+vitrification and vitrification groups compared to the control and docetaxel groups (P=0.001 and P=0.001, respectively). Pre-incubation of oocytes with docetaxel reduced gene expression levels of and in the docetaxel+cryoprotectants and docetaxel+vitrification groups (P=0.001 and P=0.019, respectively). The expression level of these genes was also reduced in the docetaxel group compared to the control group (P=0.001).
CONCLUSION
Incubation of mouse metaphase II oocytes with docetaxel prior to vitrification reduced the expression of autophagy-related genes and increased survival and fertilization rates compared to untreated oocytes.
Topics: Mice; Animals; Vitrification; Docetaxel; Cryopreservation; Metaphase; Beclin-1; Oocytes; Cryoprotective Agents; Autophagy
PubMed: 37786462
DOI: 10.30476/IJMS.2023.88390.2811 -
Clinical Cancer Research : An Official... Jan 2023A phase II study was conducted to evaluate the safety and efficacy of the combination of HER2 bispecific antibody (HER2Bi)-armed activated T cells (HER2 BAT) and...
PURPOSE
A phase II study was conducted to evaluate the safety and efficacy of the combination of HER2 bispecific antibody (HER2Bi)-armed activated T cells (HER2 BAT) and programmed death 1 inhibitor, pembrolizumab.
PATIENTS AND METHODS
Patients with metastatic castration-resistant prostate cancer (mCRPC) with 0 to 1 performance status and normal liver, kidney, and marrow function, pre- or post-docetaxel chemotherapy were eligible. Primary endpoint was 6-month progression-free survival (PFS). Peripheral blood mononuclear cells were obtained by a single apheresis, shipped to University of Virginia, activated with OKT3 and expanded for 14 days in IL2, harvested, and armed with HER2Bi and cryopreserved. HER2 BATs were infused twice weekly for 4 weeks and pembrolizumab was administered every 21 days for a maximum duration of 6 months starting 1 to 3 weeks prior to HER2 BATs infusion.
RESULTS
Fourteen patients were enrolled with a median age of 69 (range 57-82 years) and median PSA of 143.4 (range 8.2-4210 ng/dL). Two patients had peritoneal metastases, 1 had lymph node (LN) only metastases and 11 had bone metastases of which 7 had bone and LN metastases. All were pretreated with androgen receptor axis targeted agents and 7 (50%) had prior docetaxel chemotherapy. The toxicities were grade1-2 infusion reactions with fever, chills, headaches, nausea and/or myalgias. Primary endpoint of 6 month PFS was achieved in 5 of 14 patients (38.5%; 95% confidence interval, 19.5%-76.5%). Median PFS was 5 months and median survival was 31.6 months.
CONCLUSIONS
The safety and promising efficacy makes this combination worthy of future investigation in mCRPC.
Topics: Male; Humans; Middle Aged; Aged; Aged, 80 and over; Docetaxel; Prostatic Neoplasms, Castration-Resistant; Leukocytes, Mononuclear; T-Lymphocytes; Antineoplastic Combined Chemotherapy Protocols
PubMed: 36255393
DOI: 10.1158/1078-0432.CCR-22-1601 -
Oncology Research and Treatment 2020
Review
Topics: Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Humans; Male; Neoplasm Metastasis; Prostatic Neoplasms; Thiohydantoins
PubMed: 32434198
DOI: 10.1159/000507054 -
Urologie (Heidelberg, Germany) Dec 2023In advanced prostate cancer, disease progression during ongoing androgen deprivation therapy (ADT) is referred to as castration-resistant prostate cancer (CRPC). Various... (Review)
Review
BACKGROUND
In advanced prostate cancer, disease progression during ongoing androgen deprivation therapy (ADT) is referred to as castration-resistant prostate cancer (CRPC). Various therapeutic modalities are available for its treatment, including endocrine therapy, chemotherapy, poly (ADP-ribose) polymerase [PARP] inhibition, radionuclide therapy, and radioligand therapy.
OBJECTIVES
This review outlines practical aspects and considerations regarding treatment sequencing in mCRPC.
MATERIALS AND METHODS
The findings are based on existing prospective phase 3 studies that have demonstrated clinically relevant and statistically significant benefits in radiographically progression-free and/or overall survival.
RESULTS
Sequential therapy, aside from numerous patient-specific factors, depends on the treatment patients received in the hormone-sensitive prostate cancer (mHSPC) setting. Following pretreatment with ADT alone or ADT plus docetaxel in the mHSPC context, additional endocrine therapy is the standard approach. In the event of progression under combined endocrine therapy initiated in the mHSPC setting, docetaxel currently serves as the standard for the majority of patients. Patients who received triplet therapy as a pretreatment in the mHSPC scenario can be treated with radioligand therapy or second-line chemotherapy.
CONCLUSION
Various active and well-tolerated treatment options are available for patients with metastatic castration-resistant prostate cancer (mCRPC). The choice of therapy is primarily determined by previous treatments, but many other individual factors are also taken into consideration.
Topics: Male; Humans; Docetaxel; Prostatic Neoplasms, Castration-Resistant; Androgen Antagonists; Prospective Studies
PubMed: 37847397
DOI: 10.1007/s00120-023-02212-3 -
International Journal of Molecular... Sep 2023Docetaxel is a first-line chemotherapy drug used to treat advanced prostate cancer, but patients who have used it often face the challenges of drug resistance and side...
Docetaxel is a first-line chemotherapy drug used to treat advanced prostate cancer, but patients who have used it often face the challenges of drug resistance and side effects. Kaempferol is a naturally occurring flavonol; our previous studies have confirmed that it has excellent anti-prostate activity. To investigate the anti-prostate cancer effects of docetaxel in combination with kaempferol, we conducted experiments at the cellular and whole-animal level. Plate cloning assays showed that the combination of docetaxel and kaempferol had a synergistic effect in inhibiting the proliferation of prostate cancer cells. The combination of these two compounds was found to induce autophagy in prostate cancer cells via transmission electron microscopy, and changes in the expression of autophagy-related proteins via Western blot assays also confirmed the occurrence of autophagy at the molecular level. We also confirmed the anti-prostate cancer effect of docetaxel in combination with kaempferol in vivo by establishing a mouse xenograft prostate cancer model. Autophagy-related proteins were also examined in mouse tumor tissues and verified the presence of autophagy in mouse tumor tissues. The above cellular and animal data suggest that docetaxel in combination with kaempferol has significant anti-prostate cancer effects and that it works by inducing autophagy in cells.
Topics: Male; Humans; Animals; Mice; Docetaxel; Kaempferols; Taxoids; Prostatic Neoplasms; Autophagy; Autophagy-Related Proteins; Cell Line, Tumor; Xenograft Model Antitumor Assays; Apoptosis
PubMed: 37833967
DOI: 10.3390/ijms241914519 -
Acta Pharmacologica Sinica Oct 2018Apatinib, a small-molecule inhibitor of VEGFR-2, has attracted much attention due to its encouraging anticancer activity in third-line clinical treatment for many...
Apatinib, a small-molecule inhibitor of VEGFR-2, has attracted much attention due to its encouraging anticancer activity in third-line clinical treatment for many malignancies, including non-small cell lung cancer (NSCLC). Its usage in second-line therapy with chemotherapeutic drugs is still under exploration. In this study we investigated the antitumor effect of apatinib combined with docetaxel against NSCLC and its cellular pharmacokinetic basis. A549 xenograft nude mice were treated with apatinib (100 mg/kg every day for 20 days) combined with docetaxel (8 mg/kg, ip, every four days for 5 times). Apatinib significantly enhanced the antitumor effect of docetaxel and alleviated docetaxel-induced liver damage as well as decreased serum transaminases (ALT and AST). LC-MS/MS analysis revealed that apatinib treatment significantly increased the docetaxel concentration in tumors (up to 1.77 times) without enhancing the docetaxel concentration in the serum, heart, liver, lung and kidney. Furthermore, apatinib decreased docetaxel-induced upregulation of P-glycoprotein in tumors. The effects of apatinib on the uptake, efflux and subcellular distribution of docetaxel were investigated in A549 and A549/DTX (docetaxel-resistant) cells in vitro. A cellular pharmacokinetic study revealed that apatinib significantly increased cellular/subcellular accumulation (especially in the cytosol) and decreased the efflux of docetaxel in A549/DTX cells through P-gp, while apatinib exerted no significant effect on the cellular pharmacokinetics of docetaxel in A549 cells. Consequently, the IC value of docetaxel in A549/DTX cells was more significantly decreased by apatinib than that in A549 cells. These results demonstrate that apatinib has potential for application in second-line therapy combined with docetaxel for NSCLC patients, especially for docetaxel-resistant or multidrug-resistant patients.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Docetaxel; Drug Synergism; Humans; Liver; Male; Mice, Nude; Protective Agents; Pyridines; Up-Regulation; Xenograft Model Antitumor Assays
PubMed: 29770798
DOI: 10.1038/aps.2018.16