taxane and cabazitaxel

The second-generation taxane cabazitaxel has been clinically approved for the treatment of metastatic castration-resistant prostate cancer after docetaxel failure. Compared with the first-generation taxanes paclitaxel and docetaxel, cabazitaxel has potent anticancer activity and is less prone to drug resistance due to its lower affinity for the P-gp efflux pump. The relatively high hydrophobicity of cabazitaxel and the poor aqueous colloidal stability of the commercial formulation, following its preparation for injection, presents opportunities for new cabazitaxel formulations with improved features. This review provides an overview of cabazitaxel drug formulations and hydrophobic taxane drug delivery systems in general, and particularly focuses on emerging cabazitaxel delivery systems discovered in the past 5 years. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Therapeutic Approaches and Drug Discovery > Emerging Technologies.

Topics: Antineoplastic Agents; Docetaxel; Drug Delivery Systems; Humans; Male; Taxoids

Taxanes have been used as monotherapy for metastatic prostate cancer for two decades.. The current status of docetaxel and cabazitaxel in the treatment sequence for metastatic prostate cancer needs to be clarified.. Overview of the existing literature regarding approval, dosage and new combination options for metastatic castration-resistant prostate cancer (mCRPC).. Taxanes represent one, but no longer the only treatment option for mCRPC. Previously, monotherapy was standard of care in the first and second line for mCRPC; nowadays taxanes are thrusted in the background due to new encouraging drug options. Based on the promising data of docetaxel in triple therapy setting for hormone-sensitive stage, its role as monotherapy in mCRPC needs to be clarified. Cabazitaxel is an alternative to PSMA radioligand therapy after failure of novel hormonal therapy (NHT) and docetaxel. Therapy adherence for taxanes can be significantly improved by dosage adjustments. Both treatment-related neuroendocrine prostate cancer (t-NEPC) and aggressive variant of prostate cancer (AVPC) represent a challenge for experienced uro-oncologists. Here, the combination of taxane plus platinum represents a promising option.. Taxanes are indicated in different stages of metastatic prostate cancer. Their use, particularly in combination with other drugs, appears to be promising. Traditional sequential taxane monotherapy regimens will be challenged by novel systemic therapy approaches.. HINTERGRUND: Seit 2 Jahrzehnten werden Taxane in der Monotherapie des metastasierten Prostatakarzinoms eingesetzt.. Es gilt den Stellenwert von Docetaxel und Cabazitaxel in der Therapiesequenz des metastasierten Prostatakarzinoms zu klären.. Der Beitrag gibt eine Übersicht der vorhandenen Literatur bezüglich Zulassung, Dosierung und neuer Therapieoptionen beim metastasierten kastrationsresistenten Prostatakarzinom (mCRPC).. Taxane stellen eine, aber nicht mehr DIE Therapieoption beim mCRPC dar. Vormals DER Standard als Monotherapie in der Erst- und Zweitlinie bei mCRPC, stehen Taxane aufgrund neuer vielversprechender Medikamentenoptionen nicht mehr im primären Vordergrund. Aufgrund der Einsatzmöglichkeit von Docetaxel im hormonsensitiven Stadium gilt es, seinen sinnvollen Einsatz als Monotherapie beim mCRPC zu klären. Cabazitaxel ist eine Alternative zur PSMA-Radioligandentherapie („prostate-specific membrane antigen“) nach Versagen von NHT (neue hormonelle Therapie) und Docetaxel. Durch Anpassung der Medikamentendosis an die Komorbiditäten des mCRPC-Patienten kann die Therapieakzeptanz deutlich verbessert werden. Sowohl das behandlungsinduzierte neuroendokrine Prostatakarzinom (t-NEPC) als auch die aggressiven Prostatakarzinomvarianten (AVPC) stellen eine Herausforderung für erfahrene Uroonkolog*innen dar. Hier ist die Kombination aus Taxan plus Platinderivat eine vielversprechende Option.. Taxane haben ihre Indikation in verschiedenen Stadien des metastasierten Prostatakarzinoms. Ihr Einsatz insbesondere in Kombination mit anderen Substanzklassen erscheint vielversprechend. Traditionelle sequenzielle Monotherapieschemata der Taxane müssen durch neuartige Systemtherapieansätze hinterfragt werden.

Topics: Docetaxel; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Taxoids

The Six Transmembrane Epithelial Antigen of the Prostate 1 (STEAP1) protein has been indicated as an overexpressed oncoprotein in prostate cancer (PCa), associated with tumor progression and aggressiveness. Taxane-based antineoplastic drugs such as paclitaxel, docetaxel, or cabazitaxel, have been investigated in PCa treatment, namely for the development of combined therapies with the improvement of therapeutic effectiveness. This study aimed to evaluate the expression of STEAP1 in response to taxane-based drugs and assess whether the sensitivity of PCa cells to treatment with paclitaxel, docetaxel, or cabazitaxel may change when the

Topics: Antigens, Neoplasm; Antineoplastic Agents; Cell Line, Tumor; Docetaxel; Humans; Male; Oxidoreductases; Paclitaxel; Prostate; Prostatic Neoplasms; Taxoids

: Epithelial-mesenchymal transition (EMT) is a critical mechanism that promotes cancer cells to metastasis. Therefore, EMT regulation has become an important target in anticancer therapy approaches in recent years. However, in metastatic prostate cancer (PC), the EMT regulatory effect has not fully understood for cabazitaxel (Cbx), a third line taxane-based chemotherapeutic for metastatic castration-resistant PC.. In this study, we investigated the antimetastatic and EMT-regulatory effects of Cbx on hormone-sensitive metastatic PC cells.. The anticancer effects of Cbx were assessed by WST-1 and Annexin V analysis. The antimetastatic effect of Cbx was evaluated by wound healing and quantitative reverse transcription polymerase chain reaction through EMT-mesenchymal-to-epithelial transition (MET) markers as well as EMT-repressor microRNAs (miRNAs) in Cbx-treated LNCaP cells.. Our results showed that, in addition to its apoptotic and anti-migratory activities, Cbx exhibited the EMT-repressor effects through the prominent downregulation of matrix metalloproteinase-9 and Snail levels as EMT-promoting factors, and the significant upregulation of the certain miRNAs, including miR-205, miR-524, and miR-124, which play a role in EMT-repressing by targeting regulators of the EMT-associated genes.. Although further evaluations are needed to improve the findings, we showed that, in addition to its classical taxane function, Cbx has a regulatory effect on EMT-MET cycling in hormone-sensitive metastatic PC.

Topics: Cell Line, Tumor; Cell Movement; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic; Hormones; Humans; Male; MicroRNAs; Prostatic Neoplasms; Taxoids

Androgen ablation therapy is the standard of care for newly diagnosed prostate cancer (PC) patients. PC that relapsed after hormonal therapy, referred to as castration-resistant PC (CRPC), often presents with metastasis (mCRPC) and is the major cause of disease lethality. The few available therapies for mCRPC include the Taxanes Docetaxel (DTX) and Cabazitaxel (CBZ). Alas, clinical success of Taxanes in mCRPC is limited by high intrinsic and acquired resistance. Therefore, it remains essential to develop rationally designed treatments for managing therapy-resistant mCRPC disease. The major effect of Taxanes on microtubule hyper-polymerization is a prolonged mitotic block due to activation of the Spindle Assembly Checkpoint (SAC). Taxane-sensitive cells eventually inactivate SAC and exit mitosis by mitotic catastrophe, resulting in genome instability and blockade of proliferation. Resistant cells remain in mitotic block, and, upon drug decay, resume mitosis and proliferation, underlying one resistance mechanism. In our study we explored the possibility of forced mitotic exit to elevate Taxane efficacy. Inactivation of the SAC component, mitotic checkpoint kinase Mps1/TTK with a small molecule inhibitor (Msp1i), potentiated efficacy of Taxanes treatment in both 2D cell culture and 3D prostasphere settings. Mechanistically, Mps1 inhibition forced mitotic catastrophe in cells blocked in mitosis by Taxanes. Androgen receptor (AR), the main driver of PC, is often mutated or truncated in mCRPC. Remarkably, Mps1i significantly potentiated CBZ cytotoxicity regardless of AR status, in both AR-WT and in AR-truncated CRPC cells. Overall, our data demonstrate that forced mitotic exit by Mps1 inhibition potentiates Taxanes efficacy. Given that several Mps1i's are currently in different stages of clinical trials, our results point to Mps1 as a new therapeutic target to potentiate efficacy of Taxanes in mCRPC patients.

Topics: Androgens; Bridged-Ring Compounds; Cell Cycle Proteins; Docetaxel; Drug Resistance, Neoplasm; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Protein Serine-Threonine Kinases; Protein-Tyrosine Kinases; Receptors, Androgen; Taxoids

Organoid-based studies have revolutionized in vitro preclinical research and hold great promise for the cancer research field, including prostate cancer (PCa). However, experimental variability in organoid drug testing complicates reproducibility. For example, we observed PCa organoids to be less affected by cabazitaxel, abiraterone and enzalutamide as compared to corresponding single cells prior to organoid assembly. We hypothesized that three-dimensional (3D) organoid organization and the use of various 3D scaffolds impact treatment efficacy. Live-cell imaging of androgen-induced androgen receptor (AR) nuclear translocation and taxane-induced tubulin stabilization was used to investigate the impact of 3D scaffolds, spatial organoid distribution and organoid size on treatment effect. Scaffolds delayed AR translocation and tubulin stabilization, with Matrigel causing a more pronounced delay than synthetic hydrogel as well as incomplete tubulin stabilization. Drug effect was further attenuated the more centrally organoids were located in the scaffold dome. Moreover, cells in the organoid core revealed a delayed treatment effect compared to cells in the organoid periphery, underscoring the impact of organoid size. These findings indicate that analysis of organoid drug responses needs careful interpretation and requires dedicated read-outs with consideration of underlying technical aspects.

Topics: Benzamides; Bridged-Ring Compounds; Humans; Nitriles; Organoids; Phenylthiohydantoin; Receptors, Androgen; Taxoids

Despite widespread use of taxanes, mechanisms of action and resistance in vivo remain to be established, and there is no way of predicting who will respond to therapy. This study examined prostate cancer (PCa) xenografts and patient samples to identify in vivo mechanisms of taxane action and resistance. Docetaxel drug-target engagement was assessed by confocal anti-tubulin immunofluorescence to quantify microtubule bundling in interphase cells and aberrant mitoses. Tumor biopsies from metastatic PCa patients obtained 2 to 5 days after their first dose of docetaxel or cabazitaxel were processed to assess microtubule bundling, which correlated with clinical response. Microtubule bundling was evident in PCa xenografts 2 to 3 days after docetaxel treatment but was decreased or lost with acquired resistance. Biopsies after treatment with leuprolide plus docetaxel showed extensive microtubule bundling as did biopsies obtained 2 to 3 days after initiation of docetaxel or cabazitaxel in 2 patients with castration-resistant PCa with clinical responses. In contrast, microtubule bundling in biopsies 2 to 3 days after the first dose of docetaxel was markedly lower in 4 nonresponding patients. These findings indicate that taxanes target both mitotic and interphase cells in vivo and that resistance is through mechanisms that impair drug-target engagement. Moreover, the findings suggest that microtubule bundling after initial taxane treatment may be a predictive biomarker for clinical response.

Topics: Animals; Bridged-Ring Compounds; Cell Line, Tumor; Docetaxel; Drug Resistance, Neoplasm; Humans; Male; Mice; Mice, Nude; Microtubules; Prostatic Neoplasms; Taxoids

Advancements in research have added several new therapies for castration-resistant prostate cancer (CRPC), greatly augmenting our ability to treat patients. However, CRPC remains an incurable disease due to the development of therapeutic resistance and the existence of cross-resistance between available therapies. Understanding the interplay between different treatments will lead to improved sequencing and the creation of combinations that overcome resistance and prolong survival. Whether there exists cross-resistance between docetaxel and the next-generation taxane cabazitaxel is poorly understood. In this study, we use C4-2B and DU145 derived docetaxel-resistant cell lines to test response to cabazitaxel. Our results demonstrate that docetaxel resistance confers cross-resistance to cabazitaxel. We show that increased ABCB1 expression is responsible for cross-resistance to cabazitaxel and that inhibition of ABCB1 function through the small-molecule inhibitor elacridar resensitizes taxane-resistant cells to treatment. In addition, the antiandrogens bicalutamide and enzalutamide, previously demonstrated to be able to resensitize taxane-resistant cells to docetaxel through inhibition of ABCB1 ATPase activity, are also able to resensitize resistant cells to cabazitaxel treatment. Finally, we show that resensitization using an antiandrogen is far more effective in combination with cabazitaxel than docetaxel. Collectively, these results address key concerns in the field, including that of cross-resistance between taxanes and highlighting a mechanism of cabazitaxel resistance involving ABCB1. Furthermore, these preclinical studies suggest the potential in using combinations of antiandrogens with cabazitaxel for increased effect in treating advanced CRPC.

Topics: Androgen Antagonists; ATP Binding Cassette Transporter, Subfamily B; Bridged-Ring Compounds; Cell Line, Tumor; Docetaxel; Drug Resistance, Neoplasm; Humans; Male; Prostatic Neoplasms; Receptors, Androgen; Taxoids

ATP-binding cassette subfamily B member 1 (ABCB1) and subfamily C member 10 (ABCC10) proteins are efflux transporters that couple the energy derived from ATP hydrolysis to the translocation of toxic substances and chemotherapeutic drugs out of cells. Cabazitaxel is a novel taxane that differs from paclitaxel by its lower affinity for ATP-binding cassette (ABC) transporters.. We determined the effects of cabazitaxel, a novel tubulin-binding taxane, and paclitaxel on paclitaxel-resistant, ABCB1-overexpressing KB-C2 and LLC-MDR1-WT cells and paclitaxel-resistant, ABCC10-overexpressing HEK293/ABCC10 cells by calculating the degree of drug resistance and measuring ATPase activity of the ABCB1 transporter.. Decreased resistance to cabazitaxel compared with paclitaxel was observed in KB-C2, LLC-MDR1-WT, and HEK293/ABCC10 cells. Moreover, cabazitaxel had low efficacy, whereas paclitaxel had high efficacy in stimulating the ATPase activity of ABCB1, indicating a direct interaction of both drugs with the transporter.. ABCB1 and ABCC10 are not primary resistance factors for cabazitaxel compared with paclitaxel, suggesting that cabazitaxel may have a low affinity for these efflux transporters.

Topics: ATP Binding Cassette Transporter, Subfamily B; ATP-Binding Cassette Transporters; Bridged-Ring Compounds; Cell Line, Tumor; Drug Resistance, Multiple; Drug Resistance, Neoplasm; HEK293 Cells; Humans; Multidrug Resistance-Associated Proteins; Paclitaxel; Taxoids

Metastatic castration-resistant prostate cancer (mCRPC) currently benefits from a wealth of treatment options, yet still remains lethal in the vast majority of patients. It is becoming increasingly understood that this disease entity continues to evolve over time, acquiring additional and diverse resistance mechanisms with each subsequent therapy used. This dynamic relationship between treatment pressure and disease resistance can be challenging for the managing clinician. The recent discovery of alternate splice variants of the androgen receptor (AR) is one potential mechanism of escape in mCRPC, and recognizing this resistance mechanism might be important for optimal treatment selection for our patients. AR-V7 appears to be the most relevant AR splice variant, and early clinical data suggest that it is a negative prognostic marker in mCRPC. Emerging evidence also suggests that detection of AR-V7 may be associated with resistance to novel hormonal therapy (abiraterone and enzalutamide) but may be compatible with sensitivity to taxane chemotherapy (docetaxel and cabazitaxel). Adding to this complexity is the observation that AR-V7 is a dynamic marker whose status may change across time and depending on selective pressures induced by different therapies. Finally, it is possible that AR-V7 may represent a therapeutic target in mCRPC if drugs can be designed that degrade or inhibit AR splice variants or block their transcriptional activity. Several such agents (including galeterone, EPI-506, and bromodomain/BET inhibitors) are now in clinical development.

Topics: Androstenes; Androstenols; Benzamides; Bridged-Ring Compounds; Docetaxel; Drug Resistance, Neoplasm; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Protein Isoforms; Receptors, Androgen; Taxoids

Taxane antineoplastic agents are extensively taken up into hepatocytes by OATP1B-type transporters before metabolism and excretion. Because the biodistributional properties imposed upon these agents by different solubilizers drive clinically important pharmacodynamic endpoints, we tested the hypothesis that the in vitro and in vivo interaction of taxanes with OATP1B transporters is affected by the choice of drug delivery system. Transport of paclitaxel, docetaxel, and cabazitaxel was studied in vitro using various cell lines transfected with OATP1B1, OATP1B3, or the rodent equivalent OATP1B2. Pharmacokinetic studies were done in wild-type and OATP1B2-knockout mice in the presence or absence of polysorbate 80 (PS80) or Kolliphor EL (formerly Cremophor EL; CrEL). Paclitaxel and docetaxel, but not cabazitaxel, were transported substrates of OATP1B1, OATP1B3, and OATP1B2, and these in vitro transport processes were strongly reduced in the presence of clinically relevant concentrations of PS80 and CrEL. When paclitaxel was administered without any solubilizers, deficiency of OATP1B2 in mice was associated with a significantly decreased systemic clearance because of a liver distribution defect (P=0.000484). However, this genotype dependence of paclitaxel clearance was masked in the presence of PS80 or CrEL because of significant inhibition of OATP1B2-mediated hepatocellular uptake of the drug (P<0.05). Our findings confirm the importance of OATP1B-type transporters in the hepatic elimination of taxanes and indicate that this process can be inhibited by PS80 and CrEL. These results suggest that the likelihood of drug-drug interactions mediated by these transporters is strongly dependent on the selected taxane solubilizer.

Topics: Animals; Antineoplastic Agents; Biological Transport; Bridged-Ring Compounds; Cell Line; Chemistry, Pharmaceutical; CHO Cells; Cricetulus; Docetaxel; Drug Interactions; HEK293 Cells; Humans; Liver; Liver-Specific Organic Anion Transporter 1; Mice; Mice, Inbred DBA; Mice, Knockout; Oocytes; Organic Anion Transporters; Paclitaxel; Taxoids; Tissue Distribution; Xenopus laevis