Combination Of Docetaxel Research Articles

Enhanced chemotherapeutic efficacy of docetaxel in human lung cancer cell line via GLUT1 inhibitor.

The dose-dependent adverse effects of anticancer agents neednew methods with lesser toxicity. The objective of the current research was to evaluate the efficacy of GLUT1 inhibitor, as an inhibitor of glucose consumption in cancer cells, in augmenting the efficiency of docetaxel with respect to cytotoxicity and apoptosis. Cell cytotoxicity was assessed by using methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay. Annexin V/PI double staining was employed to evaluate apoptosis percentage. Quantitative real-time polymerase chain reaction(RT-PCR) analysis was accomplished to detect the expression of genes involved in the apoptosis pathway. The IC50 values for docetaxel and BAY-876 were 3.7 ± 0.81and 34.1 ± 3.4 nM, respectively. The severity of synergistic mutual effects of these agents on each other was calculated by synergy finder application. It showed that the percentage of apoptotic cells following co-administration of docetaxel and BAY-876 increased to 48.1 ± 2.8%. In comparison without GLUT1 co-administration, the combined therapy decreased significantly the transcriptome levels of the Bcl-2 and Ki-67 and a remarkable increase in the level of the Bax as proapoptotic protein(p < 0.05). Co-treatment of BAY-876 and docetaxel depicted a synergistic effect which was calculated using the synergy finder highest single agent(HSA) method (HSA synergy score: 28.055). These findings recommend that the combination of GLUT-1 inhibitor and docetaxel can be considered as a promising therapeutic approach for the treatment of patients with lung cancer.

Curcumin Enhances the Efficacy of Docetaxel by Promoting Anti-Tumor Immune Response in Head and Neck Squamous Cell Carcinoma

This study evaluated the feasibility of curcumin and docetaxel (DTX) combination therapy for head and neck squamous cell carcinoma (HNSCC). Animal assay demonstrated DTX has certain limitations in improving immunosuppressive microenvironment. Treatment with curcumin overcame this inhibition and reduced tumor progression. Curcumin synergized DTX showed significantly greater reduction in tumor burden than either treatment alone via down-regulation of MDSCs, M2 macrophages and up-regulation of CD8+ T cells, NK cells, M1 macrophages. Meanwhile, the secretion of CXCL1 was decreased in tumor. Conversely, the secretion of interferon-γ and tumor necrosis factor-α were increased. Our study provided a promising therapeutic strategy for HNSCC.

A different yet traditional approach to neoadjuvant treatment of breast cancer: The combination of epirubicin and docetaxel

A different yet traditional approach to neoadjuvant treatment of breast cancer: The combination of epirubicin and docetaxel

Evidence-based pharmacoeconomic evaluation of palbociclib in combination with letrozole versus docetaxel in combination with epirubicin in the first-line treatment of advanced breast cancer with epirubicin

Evidence-based pharmacoeconomic evaluation of palbociclib in combination with letrozole versus docetaxel in combination with epirubicin in the first-line treatment of advanced breast cancer with epirubicin

Abiraterone-Docetaxel scheduling for metastatic castration-resistant prostate cancer based on evolutionary dynamics.

Patients with metastatic castration-resistant prostate cancer (mCRPC) are divided into three groups based on their response to Abiraterone treatment: best responder, responder, and non-responder. In the latter two groups, successful outcomes may not be achieved due to the development of drug-resistant cells in the tumor environment during treatment. To overcome this challenge, a secondary drug can be used to control the population of drug-resistant cells, potentially leading to a longer period of disease inhibition. This paper proposes using a combination of Docetaxel and Abiraterone in some polytherapy methods to control both the overall cancer cell population and the drug-resistant subpopulation. To investigate the competition and evolution of mCRPC cancer phenotypes, as in previous studies, the Evolutionary Game Theory (EGT) has been used as a mathematical modeling of evolutionary biology concepts.

Synergistic effect of docetaxel and gambogic acid on bone metastasis of lung cancer

Gambogic acid (GA) as an active compound isolated from Gamboge, have been investigated for many years and proved to be a promising natural anticancer agent for clinical treatment. This study aimed to investigate the inhibitory effect of docetaxel (DTX) combined with gambogic acid on bone metastasis of lung cancer. The anti-proliferation effect of the combination of DTX and GA on Lewis lung cancer (LLC) cells was determined by MTT assays. The anticancer effect of the combination of DTX and GA on bone metastasis of lung cancer in vivo was explored. Evaluation of the efficacy of drug therapy was performed by comparing the degree of bone destruction and the pathological section of bone tissue of the treated mice with that of the control mice. In vitro cytotoxicity, cell migration, and osteoclast-induced formation assay showed that GA enhanced the therapeutic effect of DTX in Lewis lung cancer cell with a synergistic effect. In an orthotopic mouse model of bone metastasis, the average survival of the DTX+GA combination group (32.61d±1.06 d) was significantly increased compared with that of the DTX group (25.75 d±0.67 d) or GA group (23.99 d±0.58 d), *P<0.01. The combination of DTX and GA has synergistic effect and resulted in more effective inhibition of tumor metastasis, providing a strong preclinical rationale for the clinical development of the DTX+GA combination for treating bone metastasis of lung cancer.

Abstract P3-07-09: Pan-NOS Inhibitor L-NMMA in combination with Docetaxel Enhances Antitumor Effect in Obesity-associated Triple Negative Breast Cancer

Abstract Background: Obesity is associated with increased risk of triple negative breast cancer (TNBC). Obese patients with TNBC have worse outcomes compared to patients with normal weight. Both obesity and TNBC are associated with chronic inflammation including elevated nitric oxide (NO). In a recently completed Phase I/II clinical trial using a pan-NOS inhibitor L-NMMA in combination with chemotherapy docetaxel in chemorefractory and metastatic TNBC, a higher response rate was observed in obese patients. Furthermore, tumor microenvironment analysis from responders revealed a neutrophil phenotype shift from protumor N2 to antitumor N1. We thus hypothesize that combining pan-NOS inhibitor L-NMMA with docetaxel can modulate neutrophil mediated pathways, and further enhance antitumor effect in obese mice with TNBC. Methods: Three-week old syngeneic female C57/black mice were randomized to high fat diet (HFD, 18% protein, 21% carbohydrates, and 61% fat, n=50) and normal diet (ND, 20% protein, 70% carbohydrates, and 10% fat, n=50) for 10 weeks. Mouse weights were measured weekly. After 10 weeks on their respective diets, glucose tolerance test, serum cytokine and leptin analysis were performed. At week 13, TNBC E0771 tumor cells (1 × 105) were injected into the right mammary fat pads. Tumor progression was monitored twice weekly and tumor volume [0.5 × (long dimension) × (short dimension)2] was calculated. Once the tumor reached 80-100 mm3, mice in both HFD and ND groups were randomized to vehicle [saline, intraperitoneal (IP), n=10], docetaxel (20 mg/kg, IP, n=10), L-NMMA (400 mg/kg on day 1, 200 mg/kg on days 2-5, n=10), docetaxel and L-NMMA combination (same doses and schedule as in single agent groups, n=10). Tumor volume was measured throughout the experiment and tumor growth was calculated (tumor volume on day X/tumor volume at baseline). RNA sequencing of tumors from vehicle and combination groups in HFD and ND (n=6 in each arm) was performed (Azenta/Genewiz, NJ) and BioJupies was utilized for pathway analysis. GraphPad Software (La Jolla, CA, USA) was used to perform two-tailed Student’s t test and ANOVA statistical analysis. A p-value&amp;lt; 0.05 was considered statistically significant. Results: Compared to ND group, HFD group mice had significantly higher weight gain (64.8% vs 83.2%, p&amp;lt; 0.0001); they also demonstrated significant glucose intolerance, and higher serum leptin level consistent with metabolic changes observed in diet-induced obesity. After tumor injection, tumor growth rate was much higher in HFD mice compared to that in ND mice. At end-of-treatment, compared with vehicle, a significantly slower tumor growth in HFD mice (p=.015), and a trend of slower tumor growth was observed in ND mice (p=.92) in docetaxel and L-NMMA combination treatment. The reduction of tumor growth was significantly higher in HFD mice than that in ND mice (median of differences -2.0, p=.031). Differential gene expressions from RNA sequencing showed that HFD mice displayed higher expression of genes related to neutrophil degranulation and neutrophil mediated immunity compared to ND mice at baseline; while treatment with L-NMMA and docetaxel combination downregulated these genes. Conclusion: HFD mice had significantly faster tumor growth and higher expression of genes related to neutrophil mediated pathways, while treatment with pan-NOS inhibitor L-NMMA and docetaxel combination downregulated these genes. The combination treatment resulted in a more significant anti-tumor effect in HFD mice, likely through remodeling neutrophils. Future spatial analysis including CODEX and immunophenotyping are planned to further explore the role neutrophils play in the pathogenesis of obesity associated TNBC and its response to combination treatment. Citation Format: Kai Sun, Ann C. anselme, Wei Qian, Jianying Zhou, Robert Cheng, Roberto Rosato, Jenny Chang. Pan-NOS Inhibitor L-NMMA in combination with Docetaxel Enhances Antitumor Effect in Obesity-associated Triple Negative Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-07-09.

Abstract OT1-02-01: 4CAST: A Phase 1b dose exploration and dose expansion, open-label study evaluating the safety and efficacy of INO-464 in combination with Chemotherapy in patients with metASTatic breast cancer

Abstract Abstract: Trials in progress Authors: Dr Rachel Dear, A/Prof Christine Chaffer, Dr Beatriz Perez San Juan Title: 4CAST: A Phase 1b dose exploration and dose expansion, open-label study evaluating the safety and efficacy of INO-464 in combination with Chemotherapy in patients with metASTatic breast cancer. Problem statement: Metastatic triple negative breast cancer (mTNBC) has poor outcomes, with rapid progression and a median overall survival of 16 months. Standard treatment includes chemotherapy, with a possible role for immunotherapy. The antibody-drug conjugate sacituzumab govitecan was been granted recent approval. The development of new targeted treatments remains an unmet need. The androgen receptor is a mediator of chemotherapy-resistance in triple-negative breast cancer. Taxane and platinum-based chemotherapy induces cell plasticity and the emergence of chemotherapy-resistance. The androgen receptor (AR) antagonist, INO-464, but not abiraterone or enzalutamide, blocks chemotherapy induced cell plasticity to inhibit and primary and metastatic tumour growth. Three early-phase prospective clinical studies investigating anti-androgen therapy have demonstrated clinical benefit of single-agent AR-targeted agents in women with metastatic AR positive TNBC. The 450 mg daily start dose of INO-464 was well-tolerated and declared the recommended phase 2 dose. Preliminary laboratory data demonstrates an increase in survival and suppression of metastatic TNBC when INO-464 is used in combination with docetaxel. Methods: To determine the feasibility, safety and efficacy of INO-464 in combination with chemotherapy for the treatment of metastatic breast cancer. In Part 1 (dose exploration) of the trial we aim to establish the tolerability and safety and determine the recommended phase 2 dose of INO-464 when used in combination with docetaxel. Part 1 will recruit 6-18 females or males with locally advanced or metastatic breast cancer ie hormone receptor positive, HER2-positive or triple-negative breast cancer. In Part 2 (dose expansion) the clinical activity INO-464 and docetaxel in participants with metastatic triple negative breast cancer will be assessed. Results: Ethics approval for Part 1 of the trial was granted in May 2021. The trial received governance approval from St Vincent’s Hospital governance in June 2022. Recruitment commenced on the 1 July 2022. The trial has received 40 enquiries, of which three patients were eligible and one patient has consented to the trial and will be ready to start in the next two weeks. Conclusion: This investigator-initiated trial is an example of a collaborative effort between the Garvan Institute of Medical Research and the Kinghorn Cancer Centre at St Vincent’s Hospital. If the combination of INO-464 and docetaxel is shown to be safe we look forward to recruiting to the part 2 dose expansion phase across multiple Australian sites. This is study is registered with ClinicalTrials.gov NCT04947189. Disclosure of interests: A/Prof Christine Chaffer is the Managing Director of Kembi Therapeutics that is providing the investigational product for the clinical trial. Citation Format: Rachel F. Dear, Kathleen Batty, Beatriz Perez, Christine Chaffer. 4CAST: A Phase 1b dose exploration and dose expansion, open-label study evaluating the safety and efficacy of INO-464 in combination with Chemotherapy in patients with metASTatic breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT1-02-01.

Abstract P4-08-17: Repurposing proteasome inhibitors for improved treatment of triple-negative breast cancer

Abstract Background: The de novo drug development process is expensive and challenging, with a high risk of failure. Drug repurposing can ideally identify novel therapeutic indications for FDA-approved drugs with pre-existing pre-clinical and clinical evidence. Both aspirin and tamoxifen drugs are good examples of successful drug repurposing in oncology. Although proteasome inhibitors such as bortezomib and carfilzomib are currently only used to treat multiple myeloma and basal cell lymphoma, we and others have shown that triple-negative breast cancer (TNBC) is particularly sensitive to proteasome inhibition. TNBC is an aggressive form of breast cancer with an urgent need for novel treatment options. Here, we evaluate the potency of proteasome inhibitors and other clinically relevant chemotherapeutic agents on TNBC cell lines. Methods: We performed a high-throughput drug sensitivity screen with eight cell lines representing the four TNBC subtypes (basal-like 1: HCC70 and MDA-MB-468; basal-like 2: HCC1806 and MDA-MB-436; mesenchymal-like: BT-549 and HCC38; luminal androgen receptor: CAL-148 and MDA-MB-435) and MCF-7 as control (estrogen and progesterone receptor-positive) exposed to 18 drugs (11 proteasome inhibitors, 2 mitosis inhibitors, 2 topoisomerase inhibitors, and 3 platinum agents) for 24 hours. Drug potency was determined using the IC50, GR50, GRmax drug metrics. IDACombo was then used to predict efficacious drug combinations, followed by calculation of synergistic drug combinations with SynergyFinder. Results: TNBC cell lines were generally more sensitive to proteasome inhibitors with significantly reduced cell viability than clinically relevant drugs, e.g. paclitaxel. Although the potency of different proteasome inhibitors varied, the most potent proteasome inhibitors included bortezomib, carfilzomib, delanzomib, epoxomicin, and MLN-2238. According to the GR50 values, HCC38 (range, 8.2-382.7 nM) and MDA-MB-468 (range, 10.8-110.6 nM) were most sensitive to proteasome inhibition, whereas the least sensitive TNBC cell lines were HCC1806 (range, 289.9-Inf nM) and BT-549 (range, 101.0-Inf nM). Using the drug sensitivity screening results for single drugs, IDACombo predicted potent drug combinations for different combinations of bortezomib, carboplatin, carfilzomib, delanzomib, docetaxel, doxorubicin, epirubicin, epoxomicin, MLN-2238, MLN-9708, and nedaplatin. Conclusions: In summary, some proteasome inhibitors (e.g. bortezomib) had a substantial impact on TNBC cell survival. These findings indicate that proteasome inhibitors, together with other forms of chemotherapy, may be further explored as a novel complement treatment for TNBC. Citation Format: Peter Larsson, Daniella Pettersson, Maxim Olsson, Eva Forssell-Aronsson, Anikó Kovács, Per Karlsson, Khalil Helou, Toshima Z. Parris. Repurposing proteasome inhibitors for improved treatment of triple-negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-08-17.

Growth and invasion inhibition of T47D ductal carcinoma cells by the association of docetaxel with a bioactive agent in neutral nanosuspension.

Introduction: The approach for drug delivery has impressively developed with the emergence of nanosuspension, particularly the targeted nanoemulsions (NEs). It can potentially improve the bioavailability of drugs, enhancing their therapeutic efficiency. This study aims to examine the potential role of NE as a delivery system for the combination of docetaxel (DTX), a microtubule-targeting agent, and thymoquinone (TQ) in the treatment of human ductal carcinoma cells T47D. Methods: NEs were synthesized by ultra-sonication and characterized physically by dynamic light scattering (DLS). A sulforhodamine B assay was performed to evaluate cytotoxicity, and a flow cytometry analysis for cell cycle, apoptosis, autophagy, and cancer stem cell evaluations. A quantitative polymerase chain reaction further assessed the epithelial-mesenchymal transition gene expirations of SNAIL-1, ZEB-1, and TWIST-1. Results: The optimal sizes of blank-NEs and NE-DTX+TQ were found at 117.3 ± 8 nm and 373 ± 6.8 nm, respectively. The synergistic effect of the NE-DTX+TQ formulation significantly inhibited the in vitro proliferation of T47D cells. It caused a significant increase in apoptosis, accompanied by the stimulation of autophagy. Moreover, this formulation arrested T47D cells at the G2/M phase, promoted the reduction of the breast cancer stem cell (BCSC) population, and repressed the expression of TWIST-1 and ZEB-1. Conclusion: Co-delivery of NE-DTX+TQ may probably inhibit the proliferation of T47D via the induction of apoptosis and autophagy pathways and impede the migration by reducing the BCSC population and downregulating TWIST-1 expression to decrease the epithelial-to-mesenchymal transition (EMT) of breast cancer cells. Therefore, the study suggests the NE-DTX+TQ formula as a potential approach to inhibit breast cancer growth and metastasis.

Additional cycles of docetaxel in combination with androgen deprivation therapy (D-ADT) in metastatic hormone-sensitive prostate cancer (mHSPC): Efficacy and feasibility analysis.

185 Background: Several phase III trials have assessed efficacy and safety of 6 cycles of docetaxel combined to androgen deprivation therapy (ADT). This is the current standard of care for a subgroup of patients. We aimed to assess whether treatment beyond 6 cycles of docetaxel prove to be more effective than the standard of care. Methods: We retrospectively analyzed patients with histologically confirmed adenocarcinoma of the prostate and radiologically proven metastatic disease from a large tertiary care center. All patients with mHSPC were treated in first line with ADT in combination with docetaxel (75 mg/m2) (D-ADT) intravenously on the first day of each 21-day cycle. A subset of patients was treated beyond the standard of 6 cycles. Clinical and pathological variables were analyzed, progression free survival on D-ADT (PFS1), progression free survival on subsequent therapy (PFS2) and overall survival (OS) were the endpoints analyzed by log- rank test. Results: Between 2018-2022 a total of 74 mHSPC patients were followed-up for a median time of 13.7 months. Mean age was 66.2 years (range 50.1-82.4), and 79.7% had GS≥8, 73% a CHAARTED high-volume and 76% LATITUDE high risk disease. 43 pts. were treated with ≤ 6 cycles (D-ADTstand) (2.4 % 1-2 cycles; 97.6 % ≥3 cycles; mean 5.3 cycles) and 31 were treated with &gt;6 cycles docetaxel (D-ADTadd) (25.8 % 7-8 cycles; 74.2% ≥9-10 cycles, mean 9.2 cycles). No significant differences were observed in median PFS1 (12.4 vs. 13.7 mos.) and PFS2 (5.4 vs. 9.6 mos.). Median OS in the D-ADTstand group was 39.8 mos., median OS in the D-ADTadd group was not yet reached. Conclusions: While more than 6 cycles of D-ADT in mHSPC proved to be feasible without significant additional toxicity, efficacy is not superior compared to the standard of 6 cycles. Overall survival data is not mature yet, but the benefit of more chemotherapy upfront is debatable and leverages further studies in light of the upcoming triplet combinations in mHSPC, that presumably will render D-ADT obsolete in future. [Table: see text]

Design, Synthesis, and Biological Activity of Marinacarboline Analogues as STAT3 Pathway Inhibitors for Docetaxel-Resistant Triple-Negative Breast Cancer.

Metastatic triple-negative breast cancer (mTNBC) is a fatal type of breast cancer (BC), and signal transducer and activator of transcription 3 (STAT3) has emerged as an effective target for mTNBC. In the present study, compound MC0704 was found to be a novel synthetic STAT3 pathway inhibitor, and its potential antitumor activity was demonstrated using in vitro and in vivo models in docetaxel-resistant TNBC cells. Based on marinacarboline (MC), a series β-carboline derivatives were synthesized and investigated for their antitumor activities against docetaxel-resistant MDA-MB-231 (MDA-MB-231-DTR) cells. Combining antiproliferation and STAT3 inhibitory activities, MC0704 was selected as the most promising β-carboline compound. MC0704 effectively impeded the metastatic potential of MDA-MB-231-DTR cells in vitro, and the combination of MC0704 and docetaxel exhibited potent antitumor activities in a xenograft mouse model. These findings suggested that MC0704 can be a lead candidate as a target therapeutic agent for TNBC patients with docetaxel resistance.

Utilizing mixture design response surface methodology to determine effective combinations of plant derived compounds as prostate cancer treatments.

Prostate cancer (PC) is estimated to cause 13.1% of all new cancer cases in the United States in 2021. Natural bioactive compounds have drawn the interest of researchers worldwide in their efforts to find novel treatments for PC. Many of these bioactive compounds have been identified from traditional Chinese medicine (TCM) remedies often containing multiple bioactive compounds. However, in vitro studies frequently focus on the compounds in isolation. We used mixture design response surface methodology (MDRSM) to assess changes in PC cell viability after 48 h of treatment to identify the optimal mixture of all 35 three-compound combinations of seven bioactive compounds from TCM. We used berberine, wogonin, shikonin, curcumin, triptolide, emodin, and silybin to treat PC3 and LNCaP human PC cells at their IC50 concentrations that we calculated. These compounds modulate many chemotherapeutic pathways including intrinsic and extrinsic apoptosis, increasing reactive oxygen species, decreasing metastatic pathways, inhibiting cell cycle progression. We hypothesize that because these compounds bind to unique molecular targets to activate different chemotherapeutic pathways, they will act synergistically to decrease tumor cell viability. Results from MDRSM showed that two-way combinations were more effective than three-way or single compounds. Most notably wogonin, silybin, emodin and berberine responded well in two-compound combinations with each other in PC3 and LNCaP cells. We then conducted cell viability tests combining two bioactive compound ratios with docetaxel (Doc) and found significant results within the LNCaP cell line. In particular, mixtures of berberine and wogonin, berberine and silybin, emodin and berberine, and emodin and silybin reduced LNCaP cell viability up to an average of 90.02%. The two-compound combinations were significantly better than docetaxel treatment of LNCaP cells. Within the PC3 cells, we show that a combination of berberine, wogonin and docetaxel is just as effective as docetaxel alone. Thus, we provide new combination treatments that are highly effective in vitro for treating androgen-dependent and androgen-independent PC.

Docetaxel Enhances Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand-Mediated Apoptosis in Prostate Cancer Cells via Epigenetic Gene Regulation by Enhancer of Zeste Homolog 2.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising cancer therapeutic agent because of its tumor selectivity and its ability to induce apoptosis in cancer cells while sparing most normal cells. We evaluated whether docetaxel enhances TRAIL-mediated apoptosis in prostate cancer (PCa) cells and its mechanism. LNCap-LN3, PC3, and DU 145 PCa cell lines were used to investigate the effects of TRAIL with docetaxel treatment (dosages, 1, 3, 5, and 10 nmol). To evaluate the mechanism, death receptor 4 (DR4), DR5, enhancer of zeste homolog 2 (EZH2) and E2F1 levels were assessed in PCa cells. Hormone-sensitive LNCap-LN3 showed apoptosis in proportion to the concentration of docetaxel. Castration-resistant PC3 and DU 145 showed no change irrespective of the docetaxel concentration. However, combinations of docetaxel (2 nM) and TRAIL (100 ng/mL) had a significant effect on apoptosis of DU 145 cells. In DU 145 cells, docetaxel reduced EZH2 and elevated expression of DR4. The decrease of EZH2 by docetaxel was correlated with the E2F1 level, which was considered as the promoter of EZH2. DZNep reduced EZH2 and elevated DR4 in all PCa cells. Additionally, DZNep-enhanced TRAIL mediated reduction of PCa cell viability. Docetaxel and the EZH2 inhibitor reduced EZH2 and elevated expression of DR4 in all PCa cell lines. Docetaxel-enhanced TRAIL mediated apoptosis in PCa via elevation of DR4 through epigenetic regulation by EZH2. To improve the efficacy of TRAIL for PCa treatment, adding docetaxel or EZH2 inhibitors to TRAIL may be promising.

Suppression of TLR signaling by IRAK-1 and -4 dual inhibitor decreases TPF-resistance-induced pro-oncogenic effects in HNSCC.

Combination of docetaxel, cisplatin and 5-FU, known as TPF, is an FDA-approved treatment for head and neck squamous cell carcinoma (HNSCC). Acquired chemo-resistance to TPF, a primary reason for non-responsiveness to the treatment and relapse of tumor is a major concern for treatment failure, especially in elder patients. In this study, we investigated the role of Interleukin-1 receptor-associated kinases (IRAK) mediated Toll-like receptor (TLR)-signaling in chemo-resistance using a cell line-based in-vitro TPF-resistant HNSCC model of laryngeal origin. TPF chemo-resistant state showed over-expression and phosphorylation of the active downstream kinases IRAK-1 and IRAK-4 along with enhanced proliferative potential, survival, stemness and metastatic capability as compared to the parent cell line. Pharmacological inhibition of IRAK-1 and -4 had a cytostatic effect on chemo-resistant cells and re-sensitized them to chemotherapy. The treatment also decreased the pro-oncogenic effects of the chemo-resistant cells. Our study provides insights into the pro-oncogenic role of amplified IRAK-1 and-4 mediated TLR signaling in TPF-resistant HNSCC. Pharmacological inhibition of IRAK-1 and-4 signaling is a promising therapeutic strategy for TPF-resistant HNSCC. It can also be used as a combination therapy or a chemo-drug sparing regimen in HNSCC.

Conformation and energy investigation of microtubule longitudinal dynamic instability induced by natural products.

The natural products plinabulin, docetaxel, and vinblastine are microtubule targeting agents (MTAs). They have been used alone or in combination in cancer treatment. However, the exact nature of their effects on microtubule (MT) polymerization dynamics is poorly understood. To elucidate the longitudinal conformational and energetic changes during MT dynamics, a total of 140 ns molecular dynamic simulations combined with binding free energy calculations were performed on seven tubulin models. The results indicated that the drugs disrupted MT polymerization by altering both MT conformation and binding free energy of the neighboring tubulin subunits. The combination of plinabulin and docetaxel destabilized MT polymerization due to bending MT and weakening the polarity of tubulin polymerization. The new combination of docetaxel and vinblastine synergistically enhanced MT depolymerization and bending, while plinabulin and vinblastine had no synergistic inhibitory effects. The results were verified by the tubulin assembly assay. Our study obtained a comprehensive understanding of the action mechanisms of three natural drugs and their combinations on MT dynamic, provided theoretical guidance for new MTA combinations, and would promote the optimal use of MTA and contribute to developing new MTAs as anticancer agents.

Additional effect of anthracycline in preoperative chemotherapy with a sequential anthracycline‑containing regimen preceded by pertuzumab, trastuzumab and docetaxel combination therapy.

The proper use of anthracycline-containing regimens in combination with anti-HER2-targeted therapy in a neoadjuvant setting for patients with HER2-positive breast cancer has not been resolved. Regimens preceded by anthracyclines have become the standard of care, and although the order has no significant impact on HER2-negative breast cancer, it is inconclusive as to whether a taxane-first sequence would have a similar effect on HER2-positive breast cancer. The present study aimed to investigate the benefit of a taxane-first sequence and of adriamycin and cyclophosphamide (AC) in patients with non-clinical complete response (non-cCR) to pertuzumab, trastuzumab and docetaxel (PTD). The present single-center prospective observational study was performed to investigate PTD followed by AC, and aimed to clarify the cCR rate after PTD alone and the pathological clinical response (pCR) rate after subsequent AC in patients without cCR after PTD alone. A total 24 patients were analyzed; of these, 14 achieved pCR (pCR rate, 58.3%). While four of 14 patients (28.6%) in the intention-to-treat population achieved pCR, nine of 14 patients (64.3%) achieved pCR with AC but not cCR after PTD. The median tumor reduction rate after four cycles of PTD was 58.9% (range, 20.8-100%) in all 24 patients, whereas the reduction rate after PTD-AC was 76.9% (range, 31.1-100%). Cardiac serious adverse events occurred in three patients (12.5%). In conclusion, a high pCR rate was observed for the taxane-first sequence. Patients were highly responsive to PTD, but some cases achieved additional antitumor effects after AC, which resulted in pCR without cCR after PTD alone. Since cardiotoxicity remains a significant problem, a higher risk-benefit treatment strategy is required to aim for AC omission. Trial registration number: UMIN000046338, name of registry: UMIN-CTR, date of registration: December 10, 2021.

Effect of Secondary Prophylactic G-CSF on the Occurrence of Febrile Neutropenia in Breast Cancer.

Docetaxel and cyclophosphamide (TC) combination therapy is widely used as adjuvant chemotherapy for early-stage breast cancer and is associated with a high incidence of febrile neutropenia (FN). Granulocyte colony-stimulating factor (G-CSF) is recommended in the primary prevention of febrile neutropenia (FN). This study aimed to evaluate the FN-suppressing effect of G-CSF in patients with breast cancer receiving TC. We performed 272 treatment cycles after FN onset in 106 patients with breast cancer receiving TC. We retrospectively evaluated the effect of G-CSF as secondary prophylaxis. The frequency of FN was calculated based on the treatment cycles to adjust for differences in the number of cycles per case and FN occurrence. FN occurred in 58 cycles (21.3%). The incidence of FN with and without secondary prophylactic G-CSF was 10.1% and 25.9%, respectively (p=0.003). Multivariate analysis showed secondary prophylactic G-CSF administration to be an independent predictor of FN incidence [odds ratio (OR)=0.33, 95% confidence interval (CI)=0.14-0.74, p=0.007]. Secondary prophylaxis with G-CSF is recommended for patients with breast cancer undergoing TC chemotherapy to reduce the incidence of FN.

Impact of oral hygiene on febrile neutropenia during breast cancer chemotherapy.

Oral hygiene is crucial in the management of oral and febrile complications during chemotherapy for cancer. This study aimed to investigate the impact of oral hygiene on the incidence of febrile neutropenia (FN) throughout the course of chemotherapy for breast cancer. A total of 137 patients with breast cancer who underwent four cycles of adjuvant chemotherapy with docetaxel and cyclophosphamide (TC) combination therapy or docetaxel alone were assessed for oral hygiene by quantifying the number of oral bacteria they harbored. These patients received professional oral health care (POHC). Eighteen patients underwent primary prophylaxis with granulocyte colony-stimulating factors. The relationship between oral bacteria count and FN incidence was retrospectively assessed. The FN incidence rate was 47.4% throughout all treatment cycles (32.8%, 13.5%, 14.3%, and 14.4% in cycles 1, 2, 3, and 4, respectively). The oral bacteria count decreased with each treatment cycle (cycle 1: 9.10 × 106 colony-forming units (CFU)/mL, cycle 2: 5.89 × 106CFU/mL, cycle 3: 4.61 × 106CFU/mL, cycle 4: 5.85 × 106CFU/mL, P = 0.004). Among 281 treatment cycles, FN occurred in 63 (22.4%). In the treatment cycle-based analysis, high oral bacteria count was an independent risk factor for FN. FN incidence decreased with each treatment cycle and was associated with changes in oral bacteria counts. The oral bacterial count was one of risk factors for FN development in breast cancer.

306 (PB086) - Reversal of resistance to docetaxel and cabazitaxel in prostate cancer cells with ritonavir

Background: The taxanes docetaxel and cabazitaxel are indicated for treatment of metastatic castration-resistant prostate cancer (mCRPC). Resistance to docetaxel often develops during treatment, which can be due to an increased efflux of docetaxel via P-glycoprotein (P-gp) from the intracellular site of action. Ritonavir is an inhibitor of both cytochrome P4503A4 (CYP3A4) and P-gp. In this study we investigated whether ritonavir could improve the efficacy of docetaxel through inhibition of P-gp in docetaxel-resistant prostate cancer cells. Methods: Prostate cancer cell lines DU-145 and 22Rv1 were exposed to increasing doses of docetaxel to generate resistant sublines, DU145-DOC10 and 22Rv1DOC8 respectively. Gene expression of the resistant clones was compared to that of the parental cell lines. The parental cell lines and the docetaxel resistant cell lines were treated with several drug combinations in an 8*2 matrix 3D tumor clonogenic assay. The following drug combinations were tested: docetaxel/ritonavir, docetaxel/elacridar and cabazitaxel/ritonavir. The IC50 values of single agent drugs and drug combinations as well as combination effects between drugs (using a Bliss independence dose-response evaluation) were determined in all cell lines. Results: The most differentially upregulated gene in the resistant cell lines was ABCB1 (P-gp). Western blotting showed that both resistant cell lines expressed more P-gp than the parental cell lines. A comparison of the observed docetaxel and cabazitaxel IC50 values has been summarized in the below table.Table(abstract: 306 (PB086))DU-145DU-145DOC10DU-145DOC1022Rv122Rv1DOC822Rv1DOC8Docetaxel IC50 (nM)2.99.52.8*with 10 μM ritonavir,1.354.63.0**with 32 μM ritonavir.Cabazitaxel IC50 (nM)0.61.50.6*with 10 μM ritonavir,0.79.50.7**with 32 μM ritonavir.* with 10 μM ritonavir,** with 32 μM ritonavir. Open table in a new tab We found that docetaxel resistance conferred cross-resistance to cabazitaxel. With the addition of 10 μM ritonavir (DU-145DOC10) and 32 μM ritonavir (22Rv1DOC8) the cytoxicity of docetaxel and cabazitaxel returned to the level of observed in the parental cell lines. A similar experiment with the specific P-gp inhibitor elacridar showed that a concentration of 0.3 μM was sufficient to reverse docetaxel resistance to the same level as in the parental cell lines, confirming this as an important mechanism-of-action. In DU-145-DOC10 and 22Rv1DOC8 cells strong synergistic effects were seen of the docetaxel/ritonavir as well as the cabazitaxel/ritonavir combination, in contrast to the lack of synergy seen in the parental cell lines with these combinations. Conclusions: We demonstrated the potential for the combination of docetaxel and ritonavir to reverse or offset resistance to docetaxel (and, by implication due to its cross-resistance, also to cabazitaxel), primarily mediated through inhibition of P-gp. This provides a strong rationale to clinically test these taxanes in combination with ritonavir in patients with mCRPC. Conflict of interest: Ownership: Jos Beijnen is a shareholder of Modra Pharmaceuticals. Board of Directors: Colin Freund and Eric van der Putten are directors of Modra Pharmaceuticals.