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Current Oncology (Toronto, Ont.) Apr 2023The treatment paradigm for metastatic castrate-sensitive prostate cancer (mCSPC) has evolved rapidly in the past decade with the approval of several life-prolonging... (Review)
Review
The treatment paradigm for metastatic castrate-sensitive prostate cancer (mCSPC) has evolved rapidly in the past decade with the approval of several life-prolonging therapies including docetaxel chemotherapy and multiple androgen receptor pathway inhibitors (ARPI) in combination with androgen deprivation therapy (ADT). Recently reported phase-three trials have demonstrated a survival benefit of upfront triplet therapy with ADT, docetaxel plus either abiraterone acetate or darolutamide when compared to ADT plus docetaxel alone. However, multiple questions including the incremental benefit of docetaxel to a combination of ADT and ARPI, the timing of ARPI, optimal patient selection for triplet therapy and clinical and genomic biomarkers still remain to be answered. Moreover, real-world data suggest suboptimal treatment intensification with many patients treated with ADT alone highlighting challenges in implementation. In this article, we review the phase-three data associated with triplet therapy in mCSPC. We also discuss the knowledge gaps that exist despite the completion of these studies and how ongoing studies are likely to change the paradigm in the near future. Finally, we provide a simple algorithm based on current data that clinicians can use in daily practice to select patients for appropriate treatment strategies.
Topics: Male; Humans; Prostatic Neoplasms; Docetaxel; Androgen Antagonists; Standard of Care; Abiraterone Acetate
PubMed: 37185445
DOI: 10.3390/curroncol30040332 -
Molecular Oncology Oct 2023Chemotherapy remains the standard treatment for triple-negative breast cancer (TNBC); however, chemoresistance compromises its efficacy. The RNA-binding protein Hu...
Chemotherapy remains the standard treatment for triple-negative breast cancer (TNBC); however, chemoresistance compromises its efficacy. The RNA-binding protein Hu antigen R (HuR) could be a potential therapeutic target to enhance the chemotherapy efficacy. HuR is known to mainly stabilize its target mRNAs, and/or promote the translation of encoded proteins, which are implicated in multiple cancer hallmarks, including chemoresistance. In this study, a docetaxel-resistant cell subline (231-TR) was established from the human TNBC cell line MDA-MB-231. Both the parental and resistant cell lines exhibited similar sensitivity to the small molecule functional inhibitor of HuR, KH-3. Docetaxel and KH-3 combination therapy synergistically inhibited cell proliferation in TNBC cells and tumor growth in three animal models. KH-3 downregulated the expression levels of HuR targets (e.g., β-Catenin and BCL2) in a time- and dose-dependent manner. Moreover, KH-3 restored docetaxel's effects on activating Caspase-3 and cleaving PARP in 231-TR cells, induced apoptotic cell death, and caused S-phase cell cycle arrest. Together, our findings suggest that HuR is a critical mediator of docetaxel resistance and provide a rationale for combining HuR inhibitors and chemotherapeutic agents to enhance chemotherapy efficacy.
Topics: Animals; Humans; Apoptosis; Cell Line, Tumor; Cell Proliferation; Docetaxel; RNA-Binding Proteins; Triple Negative Breast Neoplasms
PubMed: 37357618
DOI: 10.1002/1878-0261.13478 -
JAMA Network Open Nov 2023Patients with high-grade prostate cancer with low levels of prostate-specific antigen (PSA; <4 ng/mL) are at high risk of mortality, necessitating an improved treatment... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
Patients with high-grade prostate cancer with low levels of prostate-specific antigen (PSA; <4 ng/mL) are at high risk of mortality, necessitating an improved treatment paradigm.
OBJECTIVE
To assess for these patients whether adding docetaxel to standard of care (SOC) treatment is associated with decreased prostate cancer-specific mortality (PCSM) and all-cause mortality (ACM).
DATA SOURCES
PubMed search from 2000 to 2022.
STUDY SELECTION
Five prospective randomized clinical trials (RCTs) performed in the US, France, and the United Kingdom evaluating SOC treatment with radiotherapy and androgen deprivation therapy (ADT) or with radical prostatectomy vs SOC plus docetaxel.
DATA EXTRACTION AND SYNTHESIS
Individual data were included from patients with nonmetastatic prostate cancer, a PSA level of less than 4 ng/mL, and a Gleason score of 8 to 10. Patients initiated treatment between February 21, 2006, and December 31, 2015 (median follow-up, 7.1 [IQR, 5.4-9.9] years). Data were analyzed on December 16, 2022.
MAIN OUTCOMES AND MEASURES
Hazard ratio (HR) of ACM and subdistribution HR (sHR) of PCSM adjusted for performance status (1 vs 0 or good health), Gleason score (9 or 10 vs 8), tumor category (T3-T4 vs T1-T2 or TX), and duration of ADT (2 years vs 4-6 months).
RESULTS
From a cohort of 2184 patients, 145 patients (6.6%) in 4 RCTs were eligible (median age, 63 [IQR, 46-67] years). Thirty-one patients died, and of these deaths, 22 were due to prostate cancer. Performance status was 0 for 139 patients (95.9%) and 1 for 6 patients (4.1%). A reduced but nonsignificant risk of ACM (HR, 0.51 [95% CI, 0.24-1.09]) and PCSM (sHR, 0.42 [95% CI, 0.17-1.02]) was associated with patients randomized to SOC plus docetaxel compared with SOC. The risk reduction in ACM (HR, 0.46 [95% CI, 0.21-1.02]) was more pronounced among patients with a performance status of 0 and was significant for PCSM (sHR, 0.30 [95% CI, 0.11-0.86]).
CONCLUSIONS AND RELEVANCE
Adding docetaxel to SOC treatment for patients who are in otherwise good health with a PSA level of less than 4 ng/mL and a Gleason score of 8 to 10 was associated with a significant reduction in PCSM and therefore has the potential to improve prognosis.
Topics: Male; Humans; Middle Aged; Docetaxel; Prostate-Specific Antigen; Prostatic Neoplasms; Prostate; Prostatectomy; Randomized Controlled Trials as Topic
PubMed: 37910103
DOI: 10.1001/jamanetworkopen.2023.40787 -
The Oncologist Mar 2024In the ARASENS trial (NCT02799602), darolutamide in combination with androgen-deprivation therapy (ADT) and docetaxel significantly reduced the risk of death by 32.5%...
BACKGROUND
In the ARASENS trial (NCT02799602), darolutamide in combination with androgen-deprivation therapy (ADT) and docetaxel significantly reduced the risk of death by 32.5% (HR, 0.68; 95% CI, 0.57-0.80; P < .0001) compared with placebo plus ADT with docetaxel in patients with metastatic hormone-sensitive prostate cancer (mHSPC). We present efficacy and safety of darolutamide versus placebo in Black patients from ARASENS.
PATIENTS AND METHODS
Patients with mHSPC were randomized 1:1 to darolutamide 600 mg or placebo twice daily in combination with ADT and docetaxel. The primary endpoint was overall survival. Key secondary endpoints included time to castration-resistant prostate cancer (CRPC) and safety.
RESULTS
In ARASENS, 54 Black patients received darolutamide (n = 26) or placebo (n = 28) plus ADT and docetaxel. In Black patients, overall survival favored darolutamide versus placebo (median, not reached vs. 38.7 months; stratified HR, 0.41; 95% CI, 0.17-1.02), with 4-year survival rates of 62% versus 41%. The darolutamide group also had longer time to CRPC compared with the placebo group (median, not reached vs .12.6 months; HR, 0.09; 95% CI, 0.02-0.30). The safety profile of darolutamide in Black patients was consistent with that observed for the overall ARASENS population (grade 3/4 treatment-emergent adverse events, TEAEs: 61.5% vs. 66.1%; serious TEAEs: 42.3% vs. 44.8%).
CONCLUSION
In this small population of Black patients with mHSPC from the ARASENS trial, darolutamide was associated with an improvement in survival and time to CRPC and was well tolerated. Efficacy and safety findings in Black patients were consistent with the overall ARASENS population.
Topics: Humans; Male; Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Pyrazoles; Randomized Controlled Trials as Topic
PubMed: 37812679
DOI: 10.1093/oncolo/oyad254 -
The Israel Medical Association Journal... Jan 2023
Topics: Humans; Docetaxel; Myositis; Acute Disease
PubMed: 36718745
DOI: No ID Found -
Molecules (Basel, Switzerland) Oct 2020Cancer is one of the greatest challenges of the modern medicine. Although much effort has been made in the development of novel cancer therapeutics, it still remains one... (Review)
Review
Cancer is one of the greatest challenges of the modern medicine. Although much effort has been made in the development of novel cancer therapeutics, it still remains one of the most common causes of human death in the world, mainly in low and middle-income countries. According to the World Health Organization (WHO), cancer treatment services are not available in more then 70% of low-income countries (90% of high-income countries have them available), and also approximately 70% of cancer deaths are reported in low-income countries. Various approaches on how to combat cancer diseases have since been described, targeting cell division being among them. The so-called mitotic poisons are one of the cornerstones in cancer therapies. The idea that cancer cells usually divide almost uncontrolled and far more rapidly than normal cells have led us to think about such compounds that would take advantage of this difference and target the division of such cells. Many groups of such compounds with different modes of action have been reported so far. In this review article, the main approaches on how to target cancer cell mitosis are described, involving microtubule inhibition, targeting aurora and polo-like kinases and kinesins inhibition. The main representatives of all groups of compounds are discussed and attention has also been paid to the presence and future of the clinical use of these compounds as well as their novel derivatives, reviewing the finished and ongoing clinical trials.
Topics: Animals; Antineoplastic Agents; Colchicine; Docetaxel; Humans; Mitosis; Paclitaxel
PubMed: 33053667
DOI: 10.3390/molecules25204632 -
BJU International Apr 2021To evaluate the safety and efficacy of cabozantinib combined with docetaxel. (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
To evaluate the safety and efficacy of cabozantinib combined with docetaxel.
PATIENTS AND METHODS
This was a phase 1/2 multicentre study in patients with metastatic castration-resistant prostate cancer (mCRPC). Docetaxel (75 mg/m every 3 weeks with daily prednisone 10 mg) was combined with escalating doses of daily cabozantinib (20, 40 and 60 mg). Based on the results of the phase 1 study, the investigation was expanded into a randomized study of docetaxel with prednisone (hereafter 'docetaxel/prednisone') plus the maximum tolerated dose (MTD) of cabozantinib compared with docetaxel/prednisone alone.
RESULTS
A total of 44 men with mCRPC were enrolled in this phase 1/2 trial. An MTD of 40 mg cabozantinib plus docetaxel/prednisone was determined. Dose-limiting toxicities were neutropenic fever and palmar-plantar erythrodysesthesia, and there was one death attributable to a thromboembolic event. In addition, grade 3 or 4 myelosuppression, hypophosphataemia and neuropathy were seen in three or more patients. In the phase 1 study, the median time to progression (TTP) and overall survival (OS) time were 13.6 and 16.3 months, respectively. In the phase 2 study, which was terminated early because of poor accrual, the median TTP and OS favoured the combination (n = 13) compared to docetaxel/prednisone alone (n = 12; 21.0 vs 6.6 months; P = 0.035 and 23.8 vs 15.6 months; P = 0.072, respectively).
CONCLUSION
Despite the limited number of patients in this study, preliminary data suggest that cabozantinib can be safely added to docetaxel/prednisone with possible enhanced efficacy.
Topics: Aged; Aged, 80 and over; Anilides; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Humans; Male; Middle Aged; Neoplasm Metastasis; Prednisone; Prostatic Neoplasms, Castration-Resistant; Pyridines; Treatment Outcome
PubMed: 32969563
DOI: 10.1111/bju.15227 -
Chinese Clinical Oncology Jun 2023In the last two decades, the incidence of gastroesophageal junction (GEJ) adenocarcinomas (AC) has increased, in part due to the increasing prevalence of obesity and... (Review)
Review
In the last two decades, the incidence of gastroesophageal junction (GEJ) adenocarcinomas (AC) has increased, in part due to the increasing prevalence of obesity and untreated gastroesophageal reflux disease (GERD). Esophageal and GEJ cancers have become one of the leading causes of cancer deaths worldwide due to its aggressive nature. While the mainstay of treatment for locally advanced gastroesophageal cancers (GECs) remains surgery, several studies have now shown that multimodality approach yields better outcomes. GEJ cancers have historically been included both in esophageal cancer as well as gastric cancer trials. Therefore, both approaches, neoadjuvant chemoradiation (CRT) or perioperative chemotherapy are considered standard treatment options. thereon the same token, there yet remains a debate for the 'gold standard' treatment of locally advanced GEJ cancers. The landmark trials, fluorouracil, leucovorin, oxaliplatin, docetaxel (FLOT) and ChemoRadiotherapy for Oesophageal cancer followed by Surgery Study (CROSS), have shown similar improvements in overall survival (OS) and disease-free survival (DFS) for patients with resectable locoregional GEJ cancers. In this review, the authors attempt to highlight the historical evolution of current standard treatments and provide a sneak peek into the future of treatment of GEJ cancers. Several factors must be borne in mind when making the optimal choice for a patient. Some of these include surgical candidacy, tolerance to chemotherapy, eligibility for radiation (RT) as well as institutional preferences.
Topics: Humans; Stomach Neoplasms; Docetaxel; Oxaliplatin; Leucovorin; Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Esophageal Neoplasms; Esophagogastric Junction; Neoadjuvant Therapy
PubMed: 37303220
DOI: 10.21037/cco-23-5 -
Drug Delivery Dec 2022To realize the synergistic anti-tumor effect of chemotherapy and photodynamic therapy, the mono sulfide-modified docetaxel (DTX) prodrugs (DSD) provided by our...
To realize the synergistic anti-tumor effect of chemotherapy and photodynamic therapy, the mono sulfide-modified docetaxel (DTX) prodrugs (DSD) provided by our laboratory and hematoporphyrin (HP) were used to physically prepare co-assembled nanoparticles (DSD/HP NPs) by nano-precipitation. For the first time, this study showed its characteristics, anti-tumor activity, pharmacokinetic behavior in rats, distribution, and pharmacodynamic effects on 4T1 tumor-bearing Bal b/c mice. DSD/HP NPs optimized by single-factor and response surface optimization had several distinct characteristics. First, it had dark purple appearance with particle size of 105.16 ± 1.24 nm, PDI of 0.168 ± 0.15, entrapment efficiency and drug loading of DSD and HP in DSD/HP NPs of 96.27 ± 1.03% and 97.70 ± 0.20%, 69.22 ± 1.03% and 20.03 ± 3.12%, respectively. Second, it had good stability and could release DTX and HP slowly in the media of pH 7.4 PBS with 10 mM DTT (HO). Moreover, DSD/HP NPs along with NiR treatment significantly inhibited 4T1 cells proliferation, and induced more reactive oxygen species and cells apoptosis. pharmacokinetic and pharmacodynamic studies showed that DSD/HP NPs could prolong the drug circulation time in rats, increase drug distribution in tumor site, obviously inhibit tumor growth, and decrease the exposure of drug to normal tissues. Therefore, DSD/HP NPs as a promising co-assembled nano-drug delivery system could potentially improve the therapeutic efficiency of chemotherapeutic drug and achieve better anti-tumor effects due to the combination of chemotherapy and photodynamic therapy.
Topics: Rats; Mice; Animals; Hematoporphyrins; Docetaxel; Photochemotherapy; Prodrugs; Hydrogen Peroxide; Drug Carriers; Nanoparticles; Neoplasms
PubMed: 36397301
DOI: 10.1080/10717544.2022.2147280 -
Drug Resistance Updates : Reviews and... Mar 2024This study aims to explore the function and mechanism of G Protein-coupled receptor class C group 5 member A (GPRC5A) in docetaxel-resistance and liver metastasis of...
AIMS
This study aims to explore the function and mechanism of G Protein-coupled receptor class C group 5 member A (GPRC5A) in docetaxel-resistance and liver metastasis of breast cancer.
METHODS
Single-cell RNA transcriptomic analysis and bioinformatic analysis are used to screen relevant genes in breast cancer metastatic hepatic specimens. MeRIP, dual-luciferase analysis and bioinformation were used to detect m6A modulation. Mass spectrometry (MS), co-inmunoprecipitation (co-IP) and immunofluorescence colocalization were executed to explore the mechanism of GPRC5A in breast cancer cells.
RESULT
GPRC5A was upregulated in triple-negative breast cancer (TNBC) and was associated with a poor prognosis. In vitro and in vivo experiments demonstrated that knockdown of GPRC5A alleviated metastasis and resistance to docetaxel in TNBC. Overexpression of GPRC5A had the opposite effects. The m6A methylation of GPRC5A mRNA was modulated by METTL3 and YTHDF1, which facilitates its translation. GPRC5A inhibited the ubiquitination-dependent degradation of LAMTOR1, resulting in the recruitment of mTORC1 to lysosomes and activating the mTORC1/p70s6k signaling pathway.
CONCLUSION
METTL3/YTHDF1 axis up-regulates GPRC5A expression by m6A methylation. GPRC5A activates mTORC1/p70s6k signaling pathway by recruiting mTORC1 to lysosomes, consequently promotes docetaxel-resistance and liver metastasis.
Topics: Humans; Docetaxel; Triple Negative Breast Neoplasms; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; Methylation; Liver Neoplasms; Receptors, G-Protein-Coupled; TOR Serine-Threonine Kinases; Mechanistic Target of Rapamycin Complex 1; Methyltransferases
PubMed: 38335844
DOI: 10.1016/j.drup.2024.101063