Low-dose Docetaxel Research Articles

PD-1 inhibitor combined with Docetaxel exerts synergistic anti-prostate cancer effect in mice by down-regulating the expression of PI3K/AKT/NFKB-P65/PD-L1 signaling pathway.

Docetaxel is a yew compound antitumor agent with accurate antitumor efficacy, but its application is limited due to the high and serious adverse effects, and finding effective combination therapy options is a viable strategy. Immune checkpoint inhibitors have become hotspots in enhancing anti-tumor immunity by blocking immune checkpoint signaling pathways, but their response rate to monotherapy use is not high and the efficacy is minimal. To explore the anti-tumor effects and mechanisms of the combination of PD-1 inhibitors and Docetaxel through in vivo experiments and develop a feasible combination treatment for the therapy of prostate cancer. Tumor-bearing mice were subcutaneously injected with 0.1ml RM-1 cells. Treatment were taken when the tumor growed up to 3mm, after which the tumor and spleen were removed to test the antitumor effect with Flow cytometric (FACS) analysis, Immunohistochemistry, Western Blot. In this experiment, we found that PD-1 inhibitors combined with Docetaxel had a synergistic effect on mouse prostate cancer, inhibited the growth of prostate cancer, improved survival and reduced adverse reactions, increased spleen and tumor infiltrative CD4+ and CD8+ T cells, especially in group combination with low-dose Docetaxel, and were related to the PI3K/AKT/NFKB-P65/PD-L1 signaling pathway. Our study confirms that PD-1 inhibitors in combination with Docetaxel are a viable combination strategy and provide a safe and effective combination option for the clinical treatment of prostate cancer.

Long-Term Outcomes of S-1 Combined With Low-Dose Docetaxel as Neoadjuvant Chemotherapy (N-1 Study, Phase II Trial) in Patients With Operable Breast Cancer

BackgroundWe previously reported that S-1 and low-dose docetaxel (DOC) (N-1 study, phase II trial) could be a well-tolerated and effective neoadjuvant chemotherapies (NACs) for patients with operable breast cancer. Herein, we analyzed the long-term outcomes and developed clinicopathological and molecular predictors of pathological complete response (pCR). Patients and MethodsEighty-three patients received S-1 (40 mg/m2 orally on days 1-14) and DOC (40 mg/m2 intravenously on day 1) every 3 weeks for 4 to 8 cycles. Disease-free survival (DFS) and overall survival (OS) were analyzed for each population with a pCR status. To assess the relationship between pCR and clinicopathological factors such as tumor-infiltrating lymphocytes (TILs, 1+ <10%, 2+ 10%-50%, and 3+ >50%) and nuclear grade (NG), microarray was used to compare the microRNA profiles of the pCR and non-pCR groups using core needle biopsy specimens. ResultsWith a median follow-up duration of 99.0 (range, 9.0-129.0) months, the 5-year DFS and OS rates were 80.7% and 90.9%, respectively. The 5-year OS rate of the pCR group was significantly better than that of the non-pCR group (100% vs. 86.2%, p = .0176). Specifically, in triple-negative patients, the difference was significant (100% vs. 60.0%, p = .0224). Multivariate analysis revealed that high TILs (≥2–3+) and NG 2–3 independently predicted pCR. Microarray data revealed that 3 miRNAs (miR-215-5p, miR-196a-5p, and miR-196b-5p) were significantly upregulated in the pCR group. ConclusionOur NAC regimen achieved favorable long-term outcomes and significantly improved OS in the pCR group. High TILs, NG 2–3, and some miRNAs may be predictors of pCR.

A feasibility study of modified docetaxel, cisplatin, and capecitabine for advanced gastric cancer followed by gastrectomy.

To explore the feasibility of modified docetaxel, cisplatin, and capecitabine (mDCX) chemotherapy with a lower dose of docetaxel than previously reported for stage III resectable gastric cancer patients with a high risk of recurrence or for stage IV gastric cancer patients aiming for conversion surgery. Patients with stage III resectable HER2-negative gastric cancer with large type 3 or type 4 tumors or extensive lymph node metastasis (bulky N or cN3) and those who had stage IV HER2-negative gastric cancer with distant metastasis were enrolled to receive 30mg/m2 docetaxel and 60mg/m2 cisplatin on day 1, followed by 2000mg/m2 capecitabine per day for 2 weeks every 3 weeks. Five patients with stage III gastric cancer with a high risk of recurrence received three courses of mDCX, and four patients with stage IV gastric cancer received three or four courses of mDCX. In terms of grade 3 or worse adverse events, leukopenia was observed in one (11%) patient, neutropenia in two (22%) patients, anemia in one (11%) patient, anorexia in two (22%) patients and nausea in two (22%) patients. All six patients with measurable lesions achieved a partial response. All nine patients underwent subsequent surgeries. The histological responses of the nine patients revealed grade 3 in one (11%) patient, grade 2 in five (56%) patients, and grade 1a in three (33%) patients. Three of the nine patients survived without recurrence, and two of them survived for more than four years. mDCX seems to be feasible and may be helpful as neoadjuvant chemotherapy for patients at high risk of recurrence or as chemotherapy for patients who are likely to undergo conversion surgery.

Docetaxel-induced cognitive impairment in rats can be ameliorated by edaravone dexborneol: Evidence from the indicators of biological behavior and anisotropic fraction.

This study aimed to investigate the effect of Edaravone Dexborneol (ED) on impaired learning and memory in docetaxel (DTX)-treated rats using cognitive behavior assessments and magnetic resonance diffusion tensor imaging (DTI). In total, 24 male Sprague-Dawley rats were divided into control, low-dose DTX (L-DTX) model, and high-dose DTX(H-DTX) model groups, with eight rats in each group, numbered 1-8. The rats were intraperitoneally injected with 1.5 mL of either normal saline (control group), or 3 mg/kg and 6 mg/kg DTX (L-DTX and H-DTX groups, respectively), once a week for 4 weeks. The learning and memory abilities of each group were tested using a water maze. At the end of the water maze test, rats 1-4 in each group were treated with ED (3 mg/kg, 1 mL), and rats 5-8 were injected with an equal volume of normal saline once a day for 2 weeks. The learning and memory abilities of each group were evaluated again using the water maze test, and the image differences in the hippocampus of each group were analyzed using DTI. (1) H-DTX group (32.33 ± 7.83) had the longest escape latency, followed by the L-DTX group (27.49 ± 7.32), and the Control group (24.52 ± 8.11) having the shortest, with the difference being statistically significant (p < 0.05). (2) Following ED treatment, compared to rats treated with normal saline, the escape latency of the L-DTX (12.00 ± 2.79 vs. 10.77 ± 3.97, p < 0.05), and the H-DTX (12.52 ± 3.69 vs. 9.11 ± 2.88, p < 0.05) rats were significantly shortened. The residence time in the target quadrant of H-DTX rats was significantly prolonged (40.49 ± 5.82 vs. 55.25 ± 6.78, p < 0.05). The CNS damage in the L-DTX rats was repaired to a certain extent during the interval between the two water maze tests (28.89 ± 7.92 vs. 12.00 ± 2.79, p < 0.05). (3) The fractional anisotropy (FA) value of DTI in the hippocampus of rats in the different groups showed variable trends. After treatment with ED, though the FA values of most areas in the hippocampus of rats in L-DTX and H-DTX groups were higher than before, they did not reach the normal level. ED can ameliorate the cognitive dysfunctions caused by DTX in rats by improving the learning and memory impairment, which is reflected in the recovery of biological behavior and DTI indicators of the hippocampus.

Comparison of Weekly Low Dose Docetaxel with the Standard Protocol in Hormone-resistant Metastatic Prostate Cancer.

To evaluate and compare the effects and toxicity of weekly low dose with three weekly standard doses of docetaxel in hormone-resistant metastatic prostate cancer. Descriptive study. University of Health Sciences, Ankara Training and Research Hospital, Ankara, Turkey, from January 2013 to July 2021. The study was conducted on 79 patients with refractory prostate cancer. Patients were assessed in 2 groups. One group was treated with the classical standard Docetaxel dose 75 mg/m2/day (every 3-week) + Prednisolone 10 mg/day (daily), whereas the second group consisting of elderly and poor performance status received a low dose Docetaxel 25 mg/m2/day (weekly, 1-week interval) + Prednisolone 10 mg/day (daily). The overall survival and toxicity profile differences between the low dose protocol in this study and the standard treatment protocol were compared. Survival times in both groups were found as 44.3 months and 35.5 months in 1-week and 3-week interval groups, respectively (p = 0.09). The rate of hematologic toxicity associated with systemic treatment was 10% in the 1-week interval treatment group and 41% in the 3-week group (p = 0.002). In particular, the febrile neutropenia was 30.8% in the 3-week interval group and 2.5% (p = 0.001) in the 1-week interval group. The study showed that instead of using docetaxel in the standard dose and range, it is more tolerated in elderly and poor performance patients when administered in the revised dose. The disrupting effects of chemotherapy are overperforming, especially in such patients. Metastatic prostate cancer, Hormone resistant prostate cancer, Weekly docetaxel.

DDRE-39. REPURPOSING CHEMOTHERAPIES AGAINST HIGH-RISK MENINGIOMAS WITH GUIDANCE BY METHYLATION PROFILES

Abstract Meningioma is the most common primary brain tumor with nearly thirty thousand new cases in the US every year. While most meningiomas are categorized as benign, they can still impact brain structures and result in disability or lethality. Currently, there is no widely accepted chemotherapy, and our understanding of the disease’s molecular characteristics is very limited. In this study, we aimed to identify druggable molecular targets for repurposing of chemotherapies against meningiomas. We analyzed previously published dataset of 493 meningioma patients by Felix Sahm et al (Lancet Oncology, 2017) for association with progression-free survival (PFS) and searched for candidate drugs targeting the pathways linked to poor patient prognosis. Our analyses indicated 981 genes for which methylation of mapped CpG sites was found to be consistently associated with shorter or longer PFS at FDR-adjusted p &amp;lt; 0.05. Using Cytoscape/Reactome FI software, we cross-referenced current cancer drugs that target these and identified docetaxel and raloxifene hydrochloride as potential candidates. In our vitro study, docetaxel caused apoptotic cell death in established and primary patient meningioma lines of various grades. IC50s of docetaxel in the seventeen meningioma cell lines tested ranged from 0.8nM to 4.4mM, which partially corresponded to the growth rates of these cells. As monotherapy, the effects of docetaxel on meningioma were attenuated by multidrug resistance protein 1 (ABCB1) and Cytochrome P450 1B1 (CYP1B1). Docetaxel at 2µM augment double-stranded DNA damage caused by irradiation in vitro, leading to increased cell death. In animal model, low doses of docetaxel and radiation therapy had synergistic effects, increasing survival of mice intracranially implanted with human meningioma cells. Our study will advance our understanding of molecular pathways driving meningioma and identify potential targeted therapies to bridge the current gap in treatment of the disease.

Differential but Concerted Expression of HSD17B2, HSD17B3, SHBG and SRD5A1 Testosterone Tetrad Modulate Therapy Response and Susceptibility to Disease Relapse in Patients with Prostate Cancer.

Simple SummaryOver the last two decades, our improved understanding of the pathobiology of androgen-addicted prostate cancer (PCa), and documented therapeutic advances/breakthroughs have not translated into any substantial or sustained curative benefit for patients treated with traditional ADT or novel immune checkpoint blockade therapeutics. This is invariably connected with the peculiar biology and intratumoral heterogeneity of PCa. Castration-resistant PCa, constituting ~30% of all PCa, remains a clinically enigmatic and therapeutically challenging disease sub-type, that is therapy-refractory and characterized by high risk for recurrence after initial response. Our findings highlight the role and exploitability of testosterone metabolic reprogramming in prostate TME for patient stratification and personalized/precision medicine based on the differential but concerted expression of molecular components of the proposed testosterone tetrad in patients with therapy-refractory, locally advanced, or recurrent PCa. The therapeutic exploitability and clinical feasibility of our proposed approach is suggested by our preclinical findings.Background: Testosterone plays a critical role in prostate development and pathology. However, the impact of the molecular interplay between testosterone-associated genes on therapy response and susceptibility to disease relapse in PCa patients remains underexplored. Objective: This study investigated the role of dysregulated or aberrantly expressed testosterone-associated genes in the enhanced dissemination, phenoconversion, and therapy response of treatment-resistant advanced or recurrent PCa. Methods: Employing a combination of multi-omics big data analyses, in vitro, ex vivo, and in vivo assays, we assessed the probable roles of HSD17B2, HSD17B3, SHBG, and SRD5A1-mediated testosterone metabolism in the progression, therapy response, and prognosis of advanced or castration-resistant PCa (CRPC). Results: Our bioinformatics-aided gene expression profiling and immunohistochemical staining showed that the aberrant expression of the HSD17B2, HSD17B3, SHBG, and SRD5A1 testosterone metabolic tetrad characterize androgen-driven PCa and is associated with disease progression. Reanalysis of the TCGA PRAD cohort (n = 497) showed that patients with SRD5A1-dominant high expression of the tetrad exhibited worse mid-term to long-term (≥5 years) overall survival, with a profoundly shorter time to recurrence, compared to those with low expression. More so, we observed a strong association between enhanced HSD17B2/SRD5A1 signaling and metastasis to distant lymph nodes (M1a) and bones (M1b), while upregulated HSD17B3/SHBG signaling correlated more with negative metastasis (M0) status. Interestingly, increased SHBG/SRD5A1 ratio was associated with metastasis to distant organs (M1c), while elevated SRD5A1/SHBG ratio was associated with positive biochemical recurrence (BCR) status, and shorter time to BCR. Molecular enrichment and protein–protein connectivity network analyses showed that the androgenic tetrad regulates testosterone metabolism and cross-talks with modulators of drug response, effectors of cell cycle progression, proliferation or cell motility, and activators/mediators of cancer stemness. Moreover, of clinical relevance, SHBG ectopic expression (SHBG_OE) or SRD5A1 knockout (sgSRD5A1) induced the acquisition of spindle fibroblastoid morphology by the round/polygonal metastatic PC-3 and LNCaP cells, attenuated their migration and invasion capability, and significantly suppressed their ability to form primary or secondary tumorspheres, with concomitant downregulation of stemness KLF4, OCT3/4, and drug resistance ABCC1, ABCB1 proteins expression levels. We also showed that metronomic dutasteride synergistically enhanced the anticancer effect of low-dose docetaxel, in vitro, and in vivo. Conclusion: These data provide proof of concept that re-reprogramming of testosterone metabolism through “SRD5A1 withdrawal” or “SHBG induction” is a workable therapeutic strategy for shutting down androgen-driven oncogenic signals, reversing treatment resistance, and repressing the metastatic/recurrent phenotypes of patients with PCa.

Randomized phase III study comparing the first-line chemotherapy regimens in patients with driver mutation-negative advanced non-small cell lung cancer and poor performance status complicated with chronic obstructive pulmonary disease.

BackgroundPatients with non-small cell lung cancer (NSCLC) complicated with chronic obstructive pulmonary disease (COPD) with poor performance status (PS) are common in clinical practice with few related studies. Present studies have found that weekly low-dose docetaxel or gemcitabine combined with platinum is suitable for elderly or poor PS patients with advanced NSCLC.MethodsUntreated advanced driver mutation-negative NSCLC patients with COPD and PS ≥2 were enrolled in this double-blind randomized trial. Both groups controlled their COPD symptoms according to the GOLD guidelines. The anti-tumor regimens included docetaxel (37.5 mg/m2, D1, D8)/carboplatin (AUC 5.0) (DC group) and gemcitabine (1,000 mg/m2, D1, D8)/carboplatin (AUC 5.0) (GC group) were used every 3 weeks with continuous chemotherapy for 4–6 cycles or until disease progression. The primary endpoints were progression-free survival (PFS), and overall survival (OS).ResultsAmong the 52 patients (DC, n=25; GC, n=27), the median follow-up time was 12.3 months. There was no significant difference in tumor overall response rate (ORR; DC, 20.0% vs. GC, 22.2%, P=0.845) and disease control rate (DCR; DC, 72.0% vs. GC, 74.1%, P=0.064) between the 2 groups. The median PFS (GC, 6.5 vs. DC, 5.5 months; P=0.296) and the median OS (GC, 14.9 vs. DC, 12.3 months; P=0.548) of the GC group was slightly longer than the DC group. The main adverse reactions were myelosuppression and there were few adverse reactions of grade 3–4. Compared with the anti-tumor therapy only group in previous literature, the median PFS in this study was longer (6.2 months, 95% CI: 3.533–6.733 vs. 3.5 months, 95% CI: 2.432–4.568; P=0.589). There was also no significant difference in median OS and median PFS between the 2 groups (14.0 vs. 15.0 months, P=0.718). Chemotherapy cycle (P<0.001) was an independent prognostic factor for PFS, while chemotherapy cycle (P=0.011) and PS (P=0.041) were independent prognostic factors for OS.ConclusionsWeekly low-dose docetaxel or gemcitabine combined with carboplatin chemotherapy regimens can yield survival benefits and a tolerable safety profile in patients with driver mutation-negative advanced NSCLC and poor PS complicated with COPD, with no significant difference between the two regimens.Trial RegistrationChinese Clinical Trial Registry ChiCTR-IPR-15006164.

Vascular-confined multi-passage discoidal nanoconstructs for the low-dose docetaxel inhibition of triple-negative breast cancer growth

Taxane efficacy in triple negative breast cancer (TNBC) is limited by insufficient tumor accumulation and severe off-target effects. Nanomedicines offer a unique opportunity to enhance the anti-cancer potency of this drug. Here, 1,000 nm × 400 nm discoidal polymeric nanoconstructs (DPN) encapsulating docetaxel (DTXL) and the near infrared compound lipid-Cy5 were engineered. DPN were obtained by filling multiple times cylindrical wells in a poly(vinyl alcohol) template with a polymer mixture comprising poly(lactic-co-glycolic acid) (PLGA) and poly(ethylene glycol) diacrylate (PEG-DA) chains together with therapeutic and imaging agents. The resulting “multi-passage” DPN exhibited higher DTXL loading, lipid-Cy5 stability, and stiffness as compared to the conventional “single-passage” approach. Confocal microscopy confirmed that DTXL-DPN were not taken up by MDA-MB-231 cells but would rather sit next to the cell membrane and slowly release DTXL thereof. Empty DPN had no toxicity on TNBC cells, whereas DTXL-DPN presented a cytotoxic potential comparable to free DTXL (IC50 = 2.6 nM ± 1.0 nM vs. 7.0 nM ± 1.09 nM at 72 h). In orthotopic murine models, DPN accumulated in TNBC more efficiently than free-DTXL. With only 2 mg/kg DTXL, intravenously administered every 2 days for a total of 13 treatments, DTXL-DPN induced tumor regression and were associated to an overall 80% survival rate as opposed to a 30% survival rate for free-DTXL, at 120 days. All untreated mice succumbed before 90 days. Collectively, this data demonstrates that vascular confined multi-passage DPN, biomimicking the behavior of circulating platelets, can efficiently deliver chemotherapeutic molecules to malignant tissues and effectively treat orthotopic TNBC at minimal taxane doses.

Redox imbalance induced by docetaxel in the neuroblastoma SH-SY5Y cells: a study of docetaxel-induced neuronal damage

ABSTRACT Objectives In cancer survivors, chemotherapy-associated adverse neurological effects are described as side effects in non-targeted tissue. We investigated the role of redox-imbalance in neuronal damage by a relative low dose of Docetaxel (DTX). Methods The neuroblastoma cells (SH-SY5Y cells) were exposed to DTX at a dose of 1.25 nM for 6 h. Antioxidant defenses (i.e. ascorbic acid, glutathione, and catalase) and lipid oxidation products (i.e. F2-isoprostanes) were evaluated. To investigate cell ultrastructure and tubulin localisation, transmission electron microscopy (TEM) and immunofluorescence techniques were applied. Results In the SH-SY5Y cells, DTX induced a significant reduction of total glutathione (P < 0.001) and ascorbic acid (P < 0.05), and an increase in both total F2-Isoprostanes (P < 0.05) and catalase activity (P < 0.05), as compared to untreated cells. Additionally, TEM showed a significant increase in cells with apoptotic characteristics. Immunolocalisation of tubulin showed a compromised cytoskeletal organisation. Discussion The investigated sublethal dose of DTX, to which non-targeted cells may be exposed throughout the duration of chemotherapy treatment, induces a redox imbalance resulting in a specific modulation of the antioxidant response. This study provides new insights into DTX-induced cellular mechanisms useful for evaluating whether the concomitant use of antioxidants associated with chemotherapy mitigates chemotherapy side effects in cancer survivors.

Combining inhibition of galectin-3 with and before a therapeutic vaccination is critical for the prostate-tumor-free outcome

BackgroundProstate cancer (PCa) is a major health problem worldwide. Taxol derivatives-based chemotherapies or immunotherapies are usually proposed depending on the symptomatic status of the patient. In the case of immunotherapy,...

Docetaxel-dasatinib combination: A strategy to overcome unfavorable treatment outcomes due to dose reduction

Docetaxel is a highly potent chemotherapeutic agent used in the management of many cancers. Adverse effects associated with its use are the reasons clinicians usually resort to dose reduction and/or dose delays for patients. Dose reductions ≥15% are considered suboptimal doses and are reported to be associated with unfavorable treatment outcomes.The aim of this project was to redesign the delivery system of docetaxel and evaluate the dose-sparing effect of a cytostatic agent - dasatinib on docetaxel when used in combination. Using the nanoprecipitation method, docetaxel was entrapped in a polymer (Polycaprolactone) matrix as nanoparticles with poloxamer F-108 as the stabilizer. A triple negative breast cancer cell line (MDA-MB-231) was used as a model for cancer cells. The 50% inhibitory concentrations (IC50) were determined for each drug in solution and as nanoparticles using the Alamar blue proliferation assay. Simultaneous and sequential combinations of the two drug formulations were conducted and their effect on cell proliferation determined using the Alamar blue assay. The average size of nanoparticles ranged between 188.0 and 212.0 nm which is optimum for uptake and accumulation in the tumor microenvironment. The polycaprolactone matrix delayed the release the docetaxel, thus direct death of cells was avoided immediately after dosing until the drug was released. Simultaneous use of dasatinib with docetaxel yielded only mild synergy, however, pre-treating MDA-MB-231 cells with dasatinib for 2 hours prior to docetaxel administration resulted in about 10–14% more death of cells than in the group not given this regimen. Dasatinib has a dose-sparing effect on docetaxel. Further studies need to be conducted to confirm the use of dasatinib as premedication in docetaxel treatment regimen for breast cancer. Obtaining equivalent response using a lower dose of docetaxel will result in fewer adverse effects, prevent treatment delays and subsequently avoid treatment failures.

PSMA-Directed CAR T Cells Combined with Low-Dose Docetaxel Treatment Induce Tumor Regression in a Prostate Cancer Xenograft Model

While chimeric antigen receptor (CAR) T cell immunotherapy targeting CD19 has shown remarkable success in patients with lymphoid malignancies, the potency of CAR T cells in solid tumors is low so far. To improve the efficacy of CAR T cells targeting prostate carcinoma, we designed a novel CAR that recognizes a new epitope in the prostate-specific membrane antigen (PSMA) and established novel paradigms to apply CAR T cells in a preclinical prostate cancer model. In vitro characterization of the D7 single-chain antibody fragment-derived anti-PSMA CAR confirmed that the choice of the co-stimulatory domain is a major determinant of CAR T cell activation, differentiation, and exhaustion. In vivo, focal injections of the PSMA CAR T cells eradicated established human prostate cancer xenografts in a preclinical mouse model. Moreover, systemic intravenous CAR T cell application significantly inhibited tumor growth in combination with non-ablative low-dose docetaxel chemotherapy, while docetaxel or CAR T cell application alone was not effective. In conclusion, the focal application of D7-derived CAR T cells and their combination with chemotherapy represent promising immunotherapeutic avenues to treat local and advanced prostate cancer in the clinic.

Anticancer bioactive peptide combined with docetaxel and its mechanism in the treatment of breast cancer.

Breast cancer remains a worldwide public-health issue. Novel drugs that increase the sensitivity and reduce the toxic side effects of chemotherapeutic agents are urgently required. The present study investigated the effect and mechanism of the short-term intermittent administration of an anticancer bioactive peptide (ACBP), docetaxel (DTX), ACBP combined with DTX (MIX) and ACBP combined with low dose DTX (L-MIX) to nude mice bearing human breast cancer tumors. The body weight, tumor length, tumor diameter, diet and water consumption of the tumor-bearing nude mice were calculated. The protein and mRNA expression levels of p53, p21 and Ki67 were detected via immunohistochemistry and reverse transcription-quantitative PCR, respectively. The results revealed that the activity level of each group of mice was consistent. However, the food and water consumption of the ACBP group was significantly increased compared with the NS group. Compared with the normal saline group, the tumor weights and volumes of the treatment groups were significantly decreased, indicating an inhibitory effect of the treatment. However, the MIX group exhibited lower tumor weights and volumes compared with the ACBP and DTX groups. Furthermore, no significant cell necrosis, edema or inflammatory cell infiltration was observed upon hematoxylin & eosin staining of the liver and spleen in all groups. The results also revealed that the p21, p53 and Ki67 protein and mRNA levels were decreased in the ACBP, DTX and MIX groups compared with the control group. Additionally, when compared with those in the MIX and L-MIX groups, the p21 and Ki67 protein, and p53 and Ki67 mRNA levels in the ACBP and DTX groups were significantly increased. The results suggested that the short-term intermittent use of ACBP alone had an inhibitory effect on tumor growth and improved the food and water consumption of tumor-bearing nude mice. Furthermore, the combination of ACBP and DTX reduced toxic side effects and the dosage requirement of drugs to achieve therapeutic effects on the tumor-bearing nude mice. Therefore, the antitumor effect of ACBP may be associated with the improvement of immune function in tumor-bearing nude mice and ACBP may serve an antitumor role via the p53-p21 signaling pathway in breast cancer.

A Pilot Study of Extended Adjuvant Therapy with Metronomic Docetaxel for Patients with Operable Triple-Negative Breast Cancer.

Background:Triple-negative breast(TNBC) cancer is a molecular subtype of breast cancer with poor prognosis and did not get approved targeted therapy till now. In the last years, metronomic chemotherapy (mCTH) was investigated to improve treatment outcomes in TNBC patients both in early and metastatic setting due to its anti-angiogenic and immune-stimulatory mechanisms. The aim of this study is to evaluate the efficacy and safety of extended adjuvant chemotherapy with metronomic docetaxel for patients with operable TNBC. Methods:31 women with clinically and pathologically proved operable TNBC, either node-negative or node-positive with tumor size ≥ 0,5 cm were enrolled after finishing the primary standard of care treatment. The patients were subjected to extended adjuvant therapy for 6 months with metronomic low dose docetaxel with starting dose of 15mg/m2 in weekly bases for 4 weeks then the dose was escalated to 20 mg/m2 once per week if there were no side effects. Results:After a median follow up of 36 months (range 6-52), 24 patients (77.4%) were still alive. During the period of follow-up, 12 patients (38.7%) showed disease relapse and 19(61.3%) cases remain free of the disease. The estimated mean of DFS in our study was 38.26 months (95%CI; 31.87 – 44.65) with 2 and 3 years DFS rate of 70.5 % and 56.4% respectively while the estimated mean of OS was 43.75 months (95% CI; 38.35 – 49.16) with 2 and 3 years OS rates 83.3% and 78.1% respectively, Generally the treatment was tolerated with mild to moderate hematological and non hematological adverse events, all are grade 1,2 and treatment-related deaths were not observed. Conclusion:Extended adjuvant treatment for 6 months with metronomic docetaxel after the primary standard of care therapy was tolerated and has an encouraging survival benefit in patients with operable TNBC and these results need further evaluation in randomized control studies.

Weekly docetaxel monotherapy for metastatic extramammary Paget's disease: Retrospective single-institute analysis.

Monthly docetaxel (DTX) monotherapy is the first-line regimen that is preferably used for metastatic extramammary Paget's disease (EMPD). However, the high-dose DTX regimen frequently causes severe hematological adverse events (AE). To overcome such safety concerns, a weekly low-dose DTX monotherapy has been proposed for use in the treatment of various cancer types. In this study, we aimed to evaluate the feasibility and efficacy of weekly DTX (25mg/m2 ) monotherapy for metastatic EMPD by retrospectively analyzing the clinical courses of 14 patients treated with this regimen. Weekly DTX monotherapy was well tolerated and all patients completed the treatment schedule without treatment withdrawal, dose reduction or treatment-related death. While five cases (35.7%) experienced hematological AE, their severity was mild. The response rate was 35.7% (5/14 cases), which included five partial responses. The mean progression-free survival (PFS) and overall survival were 7.1 (95% confidence interval [CI], 5.1-9.1) and 26.4months (95% CI, 16.7-36.1), respectively. Furthermore, the median PFS was 7.3months (95% CI, 4.5-10.0) in patients aged 65years and younger and 7.1months (95% CI, 4.4-9.9) in patients older than 65years. These results suggest that weekly DTX monotherapy may be a useful regimen that has a high treatment continuation rate with low levels of hematological toxicity, regardless of the patient's age for metastatic EMPD.

Low-dose docetaxel enhances the anti-tumour efficacy of a human umbilical vein endothelial cell vaccine

Our previous studies have indicated that human umbilical vein endothelial cell (HUVEC) vaccination appears to be a potentially promising anti-angiogenesis therapy, but the modest therapeutic anti-tumour efficiency limits its clinical use. This highlights the importance of identifying more potent therapeutic HUVEC vaccine strategies for clinical testing. In the present study, the immune-modulating doses of docetaxel (DOC) was combined with 1 × 106 viable HUVECs as a means to enhance the therapeutic anti-tumour efficiency of the HUVEC vaccine. Our results demonstrated that 5 mg/kg DOC administrated prior to HUVEC vaccine could most effectively assist HUVEC vaccine to display a remarkable suppression of tumour growth and metastasis as wells as a prolongation of survival time in a therapeutic procedure. CD31 immunohistochemical analysis of the excised tumours confirmed a significant reduction in vessel density after treatment with the HUVEC vaccine with 5 mg/kg DOC. Additionally, an increased HUVEC-specific antibody level, activated CTLs and an elevated IFN-γ level in cultured splenocytes were revealed after treatment with HUVEC vaccine with 5 mg/kg DOC. Finally, 5 mg/kg DOC coupled with the HUVEC vaccine led to induction of significant increases in CD8+T cells and decrease in Tregs in the tumour microenvironment. Taken together, all the results verified that 5 mg/kg DOC could assist HUVEC vaccine to elicit strong HUVEC specific humoral and cellular responses, which could facilitate the HUVEC vaccine-mediated inhibition of cancer growth and metastasis. These findings provide the immunological rationale for the combined use of immune-modulating doses of DOC and HUVEC vaccines in patients with cancer.

Low-dose Docetaxel Enhanced the Anticancer Effect of Temsirolimus by Overcoming Autophagy in Prostate Cancer Cells.

Chemotherapy with docetaxel (DTX) is used for castration-resistant prostate cancer (CRPC), but it is inadequate. We evaluated the effect of the combination treatment DTX and the mTOR inhibitor temsirolimus (TEM) in the PC3 prostate cancer cell line, by focusing on the induction of autophagy and apoptosis. TEM induced autophagy but not apoptosis even at a high dose, whereas DTX induced apoptosis. The combination of low-dose DTX and TEM caused a 34% suppression in cell proliferation compared to monotherapy with a higher dose of DTX. The induction of apoptosis was increased by their combination. The combination with DTX overcame the induction of autophagy by TEM. The combination treatment suppressed tumor growth 72% less than the control group after 14 days of treatment in vivo. The combination of TEM and DTX induced apoptosis by overcoming autophagy and enhanced the anticancer effect compared to monotherapy.

Abstract 3960: Low doses of Docetaxel in combination with anti-prostate cancer immunotherapy lead to complete tumor-free outcome through Galectin-3 silencing

Abstract Based on animal model results and the analysis of clinical data from metastatic and castration resistant prostate cancer (mCRPC) patients, we were able to demonstrate the advantages and the mechanisms by which Docetaxel(DTX)-based chemotherapy induces the correct pre-conditioning of the tumour microenvironment to allow high cytotoxic T cell activity to avoid prostate tumour growth and recurrence. First, analysis of the gene expression of human PCa cells showed that treatment with DTX decreases the expression of Galectin-3 (Gal-3) in either chemo-sensitive or -resistant prostate cancer (PCa) cell lines. In addition, using a murine PCa model (derived from TRAMP mice), treatment of TRAMP-C1 (TC1) cells or tumors with a low dose of DTX lowered the expression of Gal-3 but not Gal-1 (among others) in this cell line and tumors as well (reversible silencing of about 98% (in vitro) and 55% (in vivo)). More importantly, Gal-3 downregulation was confirmed in clinical samples of mCRPC patients treated by taxane-based chemotherapy. To evaluate whether this DTX-dependent Gal-3 downregulation in PCa tumors could be one of the principal molecular factors responsible for chemotherapy enhancement of immunotherapy, we decide to inoculate mice with an autologous BM-DC vaccine loaded with lysates from TC1 cells pretreated by DTX in vitro or expressing an anti-Gal-3 shRNA. This protocol completely protects the animals to the growth of Gal-3 deficient-PCa tumors. We then decided to go further in the understanding of the mechanisms that promote this effective anti-PCa immune response, and analysed the proliferation ability of lymphocytes in the presence or absence of TC1 tumor cells, expressing or not Gal-3. The results were encouraging as we demonstrated that Gal-3 down-regulation in tumors (through the use of TC1-shGal-3 cells or TC1-treated with low doses of DTX) was sufficient to restore the capability of CD8+ T cells to be activated and to proliferate as well as in the absence of tumor cells. Interestingly, we showed by ex vivo cytotoxicity assays that these activated and proliferating CD8+ T lymphocytes after vaccination of mice with TC1-lysate loaded BM-DC are capable of killing Gal-3 downregulated TC1 cells and protect prostate cancer recurrence and metastasis development in mice after primary tumor-resection. In conclusion, our results strongly suggest that Gal-3 is one of the principal immunosuppressor in prostate cancer that limits the success of immunotherapy. We then show that DTX-based chemotherapy would promote a decrease of Gal-3 expression by the tumors to create a permissive tumor microenvironment for successful immunotherapy. Finally, we propose a rational protocol combining no toxic/low doses of Docetaxel with simplified immunotherapy to completely control tumor recurrence for all PCa patients and chemoresistant as well. Citation Format: Daniel Compagno, Carolina Tiraboschi, Lucas Gentilini, Enrique Corapi, Felipe M. Jaworski, Anne Chauchereau, Diego J. Laderach. Low doses of Docetaxel in combination with anti-prostate cancer immunotherapy lead to complete tumor-free outcome through Galectin-3 silencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3960.

Concurrent chemoradiotherapy with weekly docetaxel versus cisplatin in the treatment of locoregionally advanced nasopharyngeal carcinoma: a propensity score-matched analysis

BackgroundPromising efficacy and manageable toxicity of docetaxel-based concurrent chemoradiotherapy (CCRT) were reported in head and neck cancer. In addition, the effect of CCRT in combination with cisplatin and/or 5-fluorouracil on both locoregionally advanced and metastatic/recurrent nasopharyngeal carcinoma (NPC) was verified. However, CCRT with docetaxel for locoregionally advanced NPC are not well studied. This study aimed to compare effectiveness and toxicities of CCRT with weekly docetaxel versus tri-weekly cisplatin for locoregionally advanced NPC.MethodsClinical data of patients with locoregionally advanced NPC newly diagnosed between January 2010 and December 2014 receiving CCRT with either weekly docetaxel (15 mg/m2) or tri-weekly cisplatin (80–100 mg/m2) were reviewed. Propensity score matching at a 1:1 ratio was performed to balance baseline characteristics. Adverse events and survival were compared between the two groups.ResultsA total of 962 patients were included as the whole cohort, and 448 patients were matched and were regarded as the matched cohort. The median follow-up duration was 48 months for the whole cohort. The 3-year nodal recurrence-free survival rate was significantly increased for patients treated with docetaxel in both the whole (hazard ratio [HR] = 0.37, 95% confidence interval [CI] 0.19–0.72, P = 0.030) and matched cohorts (HR = 0.33, 95% CI 0.14–0.79, P = 0.023). However, no significant differences were observed in overall survival, local recurrence-free survival, and distant metastasis-free survival between the two groups in both cohorts. Significantly higher rates of grade 3 radiodermatitis (6.7% vs. 1.8%, P = 0.001), mucositis (74.5% vs. 37.9%, P < 0.001), and leucopenia (2.2% vs. 11.6%, P < 0.001) were observed in the docetaxel group, but any grade of renal injury (1.8% vs. 15.1%, P < 0.001), vomiting (18.8% vs. 88.3%, P < 0.001), and ALT elevation (19.2% vs. 31.3%, P = 0.027) were more common in the cisplatin group.ConclusionsCCRT with weekly low-dose docetaxel is an effective and tolerable therapeutic regimen for locally advanced NPC. It provides a survival benefit mainly by improving the control of regional lymph node metastases, especially for patients with low pretreatment EBV DNA levels.