Docetaxel Treatment Research Articles

Abstract 1687: ATPase copper transporting beta (ATP7B) contributes to acquired docetaxel resistance in human prostate cancer

Abstract Docetaxel has been the standard first-line chemotherapy for lethal metastatic prostate cancer (mPCa) since 2004, but the resistance to docetaxel treatment is common. The molecular mechanisms of docetaxel resistance remain largely unknown and could be amenable to interventions that mitigate resistance. We have recently discovered that several docetaxel resistant mPCa cell lines exhibit less uptake of cellular copper and express markedly higher levels of ATP7B protein without significant changes in the protein expression levels of other copper transporters, such as ATPase copper transporting alpha (ATP7A) and high affinity copper uptake protein 1 (CTR1). Knock-down of ATP7B by silencing RNAs sensitized docetaxel resistant-mPCa cells to the growth inhibitory and apoptotic effects of docetaxel. Importantly, deletions of ATP7B in mPCa tissues predict significantly better survival of patients after their first chemotherapy than those with wild-type ATP7B (P = 0.0006). In addition, Disulfiram (DSF), an FDA approved drug for treatment of alcohol dependence, in combination with copper, significantly enhanced the in vivo antitumor effects of docetaxel in a docetaxel resistant xenograft tumor model. Our analyses also revealed that DSF and copper engaged with ATP7B to decrease protein levels of COMM domain-containing protein 1 (COMMD1), S-phase kinase associated protein 2 (Skp2) and clusterin and markedly increase protein expression of cyclin-dependent kinase inhibitor 1 (p21/WAF1). Taken together, our results suggest that ATP7B is a clinically relevant and key target for improving the efficacy of docetaxel for treatment of mPCa. Citation Format: Liankun Song, Vyvyan Nguyen, Jun Xie, Matthew Tippin, Le TP Truong, Christopher A. Blair, Beverly Wang, Edward Uchio, Xiaolin Zi. ATPase copper transporting beta (ATP7B) contributes to acquired docetaxel resistance in human prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1687.

Abstract 375: Smoking induces Wee1 expression through miRNA deregulation, promoting docetaxel resistance in esophageal adenocarcinoma

Abstract Esophageal Adenocarcinoma (EAC) is the most common subtype of Esophageal Cancer in Western countries, and its incidence rate has increased over the past few decades. The overall five-year survival rate of EAC is less than 20%. Smoking is a major risk factor for EAC development. WEE1 kinase plays a crucial role in the cell cycle by regulating the G2/M checkpoint, providing a time frame for the cells to repair DNA damage. Thus, targeting WEE1 using an inhibitor could potentiate the effect of chemotherapeutic drugs. This study investigated how smoking induces WEE1 protein expression, promoting docetaxel resistance in EAC. IHC staining for WEE1 in the normal esophagus and EAC tissue sections revealed significant over-expression of WEE1 protein in EAC. Nicotine, Nicotine derived Nitrosamine Ketone (NNK), and 2% cigarette smoke extract (CSE) treatment induced WEE1 expression with a concomitant increase in CDC2 phosphorylation (p-CDC2, Y15), a well-established read-out of WEE1 activity in EAC cells. In addition, we found that smoking upregulates WEE1 expression by decreasing miR-195-5p expression levels in EAC. Based on the differential gene expression signatures in EAC cell lines FLO1 and OE33 following WEE1 knockdown, drug and small molecule induced gene expression signatures analysis, L1000 fireworks display (L1000FWD), predicted that docetaxel is one of the best drug candidates which can synergize with the WEE1 inhibitor MK1775. Smoking-induced docetaxel resistance in EAC cells measured by cell viability assay. Down-regulating WEE1 expression with siRNA or pharmacological inhibition using MK1775 significantly sensitized EAC cells to docetaxel treatment, as evidenced by a remarkable decrease in the IC50 value of docetaxel. Inhibition of WEE1 combined with docetaxel can be considered an ideal therapeutic strategy due to its superior anti-tumor efficacy compared to the standard single-agent treatment. In conclusion, our data provide a firm rationale for the clinical combination of docetaxel with MK1775 in EAC patients. Citation Format: Krishnapriya Thangaretnam, Islam MD Obaidul, Heng Lu, Dunfa Peng, Nadeem Sidiq Bhat, Mohammed Soutto, Zheng Chen. Smoking induces Wee1 expression through miRNA deregulation, promoting docetaxel resistance in esophageal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 375.

Abstract 1754: Targeting the mitochondrial protein MAGMAS increases sensitivity to docetaxel in neuroendocrine prostate cancer cells

Abstract Metastatic prostate cancer (PCa) is the leading cause of PCa-associated deaths and one of the leading causes of cancer mortality in men. Novel therapeutics, such as Prostate Specific Membrane Antigen (PSMA) ligand therapy, are emerging as effective treatment strategies for metastatic prostate cancer. However, neuroendocrine differentiated (NED) metastatic PCa, which lacks the PSMA antigen, is deprived of effective biomarkers for disease treatment. Magmas, a 13.8 kDa mitochondrial protein, imports nuclear-encoded mitochondrial proteins into the mitochondrial matrix. Magmas is overexpressed in several aggressive tumors, such as breast cancer, glioblastoma, and prostate cancer. When overexpressed, Magmas plays a role as a cytoprotective protein by acting as a reactive oxygen species (ROS) scavenger that maintains sufficient ROS levels to promote cell proliferation, but below the threshold levels that could lead to apoptosis. This study was designed to investigate the pro-survival and therapy-resistance functions of Magmas in PCa cells expressing NED markers. Predictively, we observed that the docetaxel (DTX)-resistant PC3-DR and DU145-DR PCa cell lines expressed significantly higher levels of Magmas compared to their drug-sensitive parental cell lines. We hypothesized that inhibiting Magmas reduces the aggressive properties of highly proliferative DTX- resistant metastatic PCa cell lines and re-sensitize them to DTX. Magmas knockdown in DTX-sensitive and DTX-resistant PC3 and DU145 cells in the presence of increasing DTX treatments enhanced sensitivity to DTX. Consistent with these results, pharmacological inhibition of Magmas with the novel BT#9 inhibitor in combination with increasing DTX concentrations also enhanced sensitivity to DTX in these cell lines. Additional studies using clonogenic assays, cell migration/invasion assays, and tumorsphere formation assays are currently underway to further establish Magmas as a potential therapeutic target to attenuate the aggressive properties of chemoresistant PCa cells. Lastly, we will investigate the diagnostic potential of Magmas as a biomarker for NED and BT#9 as an imaging/therapeutic-specific agent for NED. Citation Format: Alfonso M. Durán, Christian H. Yoo, Jennifer D. Tran, Krystal Santiago, Adil S. Mohammed, Carlos A. Casiano, Frankis A. Almaguel. Targeting the mitochondrial protein MAGMAS increases sensitivity to docetaxel in neuroendocrine prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1754.

Real-life data of abiraterone acetate and enzalutamide treatment in post-chemotherapy metastatic castration-resistant prostate cancer in Poland.

Abiraterone acetate (ABI) and Enzalutamide (ENZA) are second-generation hormone drugs that show breakthrough activity in post-chemotherapy, metastatic castration-resistant prostate cancer (mCRPC). The leading oncological and urological guidelines indicate both drugs with the same strong recommendation. There is a lack of randomized trials which compare the efficacy of ABI and ENZA. The current study aimed to compare the effectiveness of the drugs with an analysis of prognostic factors related to those drugs. The study included 420 patients with docetaxel (DXL) pretreated mCRPC from seven Polish cancer centers. Patients were treated according to inclusion and exclusion criteria in the Polish national drug program (1000 mg ABI and 10 mg prednisone, n=76.2%; ENZA, 160 mg; n=23.8%). The study retrospectively analyzed the overall survival (OS), time to treatment failure (TTF), PSA 50% decline rate (PSA 50%) and selected clinic-pathological data. In the study group, the median OS was 17 months (95% CI: 15.6-18.3). The median OS (26.1 vs. 15.7 mo.; p<0.001), TTF (14.2 vs. 7.6 mo.; p<0.001) and PSA 50% (87.5 vs. 56%; p<0.001) were higher in ENZA than in ABI treatment. Multivariate analysis shows that ENZA treatment and PSA nadir <17.35 ng/mL during or after DXL treatment were related to longer TTF. ENZA treatment, DXL dose ≥750 mg, PSA nadir <17.35 ng/mL during or after DXL treatment was related to longer OS. ENZA treatment may be related to more favorable oncological outcomes than ABI treatment in the studied Polish population of patients. A 50% decline in PSA is an indicator of longer TTF and OS. Due to the non-randomized and retrospective nature of the analysis, the current results require prospective validation.

STEAP1 Knockdown Decreases the Sensitivity of Prostate Cancer Cells to Paclitaxel, Docetaxel and Cabazitaxel.

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 STEAP1 gene is silenced. Thus, wild-type and STEAP1 knockdown LNCaP and C4-2B cells were exposed to paclitaxel, docetaxel or cabazitaxel, and STEAP1 expression, cell viability, and survival pathways were evaluated. The results obtained showed that STEAP1 knockdown or taxane-based drugs treatment significantly reduced the viability and survival of PCa cells. Relatively to the expression of proliferation markers and apoptosis regulators, LNCaP cells showed a reduced proliferation, whereas apoptosis was increased. However, the effect of paclitaxel, docetaxel, or cabazitaxel treatment was reversed when combined with STEAP1 knockdown. Besides, these chemotherapeutic drugs may stimulate the cell growth of PCa cells knocked down for STEAP1. In conclusion, this study demonstrated that STEAP1 expression levels might influence the response of PCa cells to chemotherapeutics drugs, indicating that the use of paclitaxel, docetaxel, or cabazitaxel may lead to harmful effects in PCa cells with decreased expression of STEAP1.

Synergistic action of lactoferrin in enhancing the safety and effectiveness of docetaxel treatment against prostate cancer.

Tumor metastasis is promoted by an immunosuppressive environment. Lactoferrin (Lf) is known to regulate immunological activity in tumor cells and inhibit processes associated with tumor metastasis. A delivery of lactoferrin with docetaxel (DTX) in prostate cancer cells in the form of DTX-loaded lactoferrin nanoparticles (DTX-LfNPs) would provide a dual activity wherein the lactoferrin affects metastasis and DTX chemotherapeutically inhibits mitosis and cell division. DTX-LfNPs were prepared using sol-oil chemistry, and particles were characterized using transmission electron microscopy. Antiproliferation activity was analyzed in prostate cancer Mat Ly Lu cells. The target localization and efficacy of DTX-LfNPs were studied in an orthotopic prostate cancer induced by Mat Ly Lu cells in a rat model. Biomarkers were estimated using ELISA and biochemical reactions. DTX was loaded in pure Lf nanoparticles without involving any chemical modification and conjugation, thus when these nanoparticles are delivered in cancer cells both DTX and Lf will be present in biologically active forms. DTX-LfNps exhibit a spherical morphology of dimension of 60 ± 10nm with DTX Encapsulation Efficiency of 62.06 ± 4.07%. Competition experiments using soluble Lf confirm that DTX-LfNPs enter prostate cancer cells through the Lf receptor. DTX-LfNPs exhibit an improved anti-proliferative activity by 2.5 times compared to DTX. Further, analysis of the bioavailability of the drug in the prostate showed that DTX-LfNPs increased drug bioavailability in the prostate by two times more than the DTX. The analysis of efficacy in the Mat Ly Lu cells-induced orthotopic prostate cancer model showed that DTX-LfNPs significantly enhanced the anti-cancer activity compared to DTX in terms of regression of weight and volume of prostate tissue, the efficacy was confirmed by histochemical analysis. Lf provides synergistic activity along with DTX in inhibiting metastasis as assessed by the reduction of lactate dehydrogenase, alkaline phosphatase, TNF alpha, and IFNγ. LfNPs facilitate higher DTX localization along with Lf-mediated protection from DTX-associated toxicity to neutrophils and kidneys as assessed by C-reactive protein, creatinine, and uric acid. Thus, DTX LfNPs show a dual action by enhancing DTX bioavailability in prostate along with Lf-mediated suppression of metastasis as well as DTX-associated toxicity. In conclusion, DTX-LfNPs enhance the bioavailability of DTX in the prostate along with Lf-assisted improvement in inhibition of tumor metastasis and drug-associated toxicity.

Lactobacillus rhamnosus GG alleviates colitis caused by chemotherapy via biofilm formation.

Severe colitis is a common side effect of chemotherapy in cancer patients. In this study, we attempted to enhance the viability of probiotics in a gastric acid environment and improve the colitis induced by dextran sulfate sodium (DSS) and docetaxel. We purified Lactobacillus from yogurt and estimated their growth at pH 6.8 and pH 2.0. In the further investigation, the bacterial biofilm formation was used to define the mechanism by which administration of Lactobacillus rhamnosus (LGG) via oral gavage alleviates the colitis and intestine permeability of the mice induced by DSS and docetaxel. The potential benefit of probiotics on the treatment of breast cancer metastasis has been assessed as well. Lactobacillus from yogurt growth was unexpectedly faster in the pH 2.0 than in the neutral pH medium during the first hour. LGG administered in the fasting state via oral gavage significantly improved the preventive effect in the colitis caused by DSS and docetaxel. LGG reduced the permeability of the intestine and decreased the expression of proinflammatory cytokines, TNF-α, IL-1β, and IL-6, in colitis by biofilm formation. Increasing the docetaxel dose may reduce breast tumor growth and metastasis in the lung but did not benefit survival due to severe colitis. However, the LGG supplement significantly improved the survival of tumor-bearing mice following a high dose of docetaxel treatment. Our findings provide new insights into the potential mechanism of probiotic protection of the intestine and provide a novel therapeutic strategy to augment the chemotherapeutic treatment of tumors.

Abstract OT1-17-01: Protocol Description of Genetics and Inflammatory Markers to predict Chemotherapy-Induced Peripheral Neuropathy among Early Stage Breast Cancer Patients Receiving Taxane Therapy – GENIE Study

Abstract Background Chemotherapy induced peripheral neuropathy (CIPN) is one of the most common dose-limiting side effects seen among patients with early stage breast cancer and received taxane-containing regimens. The primary clinical manifestation of CIPN is sensory neuropathy such as numbness, tingling and pain in hands and feet, which negatively affect the patient’s quality of life (QoL). Although in most patients, CIPN improves over time, in a subset of patients, it remains a substantial debilitating problem, significantly affecting QoL. To date, there are no effective prevention strategies- or sufficient treatment due to the limited understanding of CIPN pre-disposing factors or pathophysiology. We hypothesize that a multimodal integration of biomarkers with CIPN progression analysis will be required to understand the pathophysiology and to consistently predict patient susceptibility. Further, we hypothesize that this multimodal approach may be leveraged to identify targets for CIPN treatment and/or prevention. This abstract describes the study protocol used to explore this hypothesis. Objective This study is designed to 1) identify genetic, transcriptional, epigenetic, metabolic, inflammatory biomarkers predictive of CIPN development among patients with early stage breast cancer receiving a taxane containing therapy; 2) With these biomarkers, develop an algorithm to identify patients who are at risk of developing CIPN before or during taxane therapy. Methods This is a longitudinal, multicenter, observational study. Patients with early-stage breast cancer who are receiving a taxane-containing (paclitaxel, docetaxel or nab-paclitaxel) treatment regimen, without preexisting peripheral neuropathy are eligible. Estimated enrollment is 400 patients. Demographic and clinical data are collected after patients consent to participate. Molecular data and patient reported outcomes (PRO) are collected prior to initiation of taxane therapy, the 4th, 8th, and 12th week of taxane therapy, and at 3, 6, and 9 months after completion of taxane therapy. Blood samples are collected for molecular data which include genetic, transcriptional, epigenetic (DNA-methylation), and metabolic data. PRO are assessed using (i) the European Organization for Research and Treatment of Cancer CIPN20 questionnaire, (ii) the Brief Pain Inventory, (iii) the Pain Catastrophizing Scale, and (iv) the PRO Measurement System for anxiety, depression and pain interference. Initial data analysis will characterize the association of biomarkers in each modality (e.g., genetic, epigenetic, etc.) with the presence or absence of CIPN, and machine learning will be used to build candidate biomarker signatures to predict CIPN before and during taxane treatment. Two distinct multi-modal prediction models will be constructed: 1) a pre-treatment model to predict risk of developing CIPN, and 2) an on-treatment model to predict the onset of CIPN. The goal is to develop a parsimonious, clinically translatable model for robust and accurate predictions of taxane-induced CIPN. Trial Status: Active, 135 subjects enrolled. Trial Centers: 1) Cleveland Clinic Foundation (8 regional sites in Ohio and 1 in Florida); 2) Huntsman Cancer Institute, University of Utah Research Funding: National Institute of Neurological Disorder and Stroke. Grant No.: 1R61NS113258-01A1 Citation Format: Mei Wei, Anukriti Sharma, Ken Johnson, Bihua Bie, courtney hershberger, Alper Sen, Emily E. Rhoades, Chi-Fan Hocking, George Budd, N. Lynn Henry, Charis Eng, Joseph Foss, daniel rotroff. Protocol Description of Genetics and Inflammatory Markers to predict Chemotherapy-Induced Peripheral Neuropathy among Early Stage Breast Cancer Patients Receiving Taxane Therapy – GENIE Study [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 OT1-17-01.

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.

Effect of neuroendocrine differentiation on therapeutic efficacy of abiraterone and docetaxel as first-line therapy in metastatic castration-resistant prostate cancer.

216 Background: This study aims to explore the prognostic value of neuroendocrine differentiation (NED) in patients with metastatic castration-resistant prostate cancer (mCRPC) receiving abiraterone or docetaxel therapy. Methods: We retrospectively analyzed data of 262 mCRPC patients treated with abiraterone or docetaxel as first-line therapy. NED status was evaluated using prostate biopsy samples at the time of mCRPC by immunohistochemical staining. Kaplan-Meier curves and Cox regression were used to assess the association between NED and treatment outcomes including PSA progression-free survival (PSA-PFS), radiographic progression-free survival (rPFS), and overall survival (OS). Results: In total, NED was confirmed in 100/262 (38.2%) mCRPC patients, with 76/100 (76.0%) and 24/100 (24.0%) men harboring NED&lt;10% and NED≥10%, respectively. In abiraterone treatment, NED was associated with a significantly shorter median PSA-PFS (mPSA-PFS, 7.5-Mo vs. 10.3-Mo, P&lt;0.001), median rPFS (mrPFS, 15.9-Mo vs. 19.5-Mo, P=0.010), and median OS (mOS, 23.2-Mo vs. 34.3-Mo, P=0.014). Likewise, for mCRPC patients receiving docetaxel-based chemotherapy, the positive detection of NED also predicted shorter mPSA-PFS (3.8-Mo vs. 5.9-Mo, P=0.052), mrPFS (8.4-Mo vs. 20.4-Mo, P=0.016) and mOS (13.6-Mo vs. 29.0-Mo, P=0.033). The adverse prognostic trait of NED is consistent in most subgroups. Additionally, patients’ survival outcomes deteriorated as the NED proportion grew in both therapies. Both abiraterone and docetaxel exerted similar and unfavorable efficacy on NED-positive mCRPC patients. Conclusions: For mCRPC patients receiving abiraterone or docetaxel treatment, NED and its proportion were critical prognostic factors. NED detection at mCRPC might aid in predicting patients’ outcomes and optimizing treatment decisions.

Phase II trial evaluating olaparib maintenance in patients with metastatic castration resistant prostate cancer (mCRPC) after docetaxel treatment, reaching partial or stable response: SOGUG-IMANOL study.

168 Background: Prostate cancer is the second most common cancer in men. A number of important systemic therapies have been developed to treat mCRPC and now comprise the current therapeutic landscape. Docetaxel became the first systemic therapy to improve survival in these men in a randomized study demonstrating superiority versus mitoxantrone (18.9 months versus 16.5, p=0,004). But, inexorably, after stopping, disease progresses. Methods: A prospective phase II trial was designed to test Olaparib maintenance efficacy, in terms of progression free survival (PFS), in patients with mCRPC with DNA-repair defects that have achieved partial or complete response after being treated with systemic therapy (at least six cycles of docetaxel). Results: 134 mCRPC patients were included since Feb-2018 to Nov-2020 and were tested for DDR alterations. 19.4% of patients had somatic mutations (30.8% BRCA2, 3.8% BRCA1, 19.2% ATM, 7.7% CHEK2, 7.7% PALB2). 53,8% received Olaparib maintenance treatment, with a median follow-up of 23.3 months. Median age was 73 years. Median basal PSA was 17 ng/dL. 100% were metastatic (14.3% de novo and 85.7% relapsed after primary treatment), 78.6% had bone metastasis, 35.7% visceral and 35.7% adenopathies. 42.9% had previous treatment with abiraterone and 35.7% with enzalutamide. 46.2% received at least 8 cycles of docetaxel. 7.1% achieved a partial response and 92.9% a disease stabilization. Response to Olaparib treatment was 14.3% partial response, 71.4% stabilization and 7.1% disease progression.14.3% had a PSA50 decrease. Median duration of response was 8.27 months. Median PFS was 10.1 months. Median PSA-PFS was 3.5 months. G3/4 adverse events were 21.4% asthenia,14.3% anemia and 7.1% neutropenia. Conclusions: Olaparib maintenance after at least six cycles of docetaxel shows promising activity in mCRPC with DDR alterations, with an acceptable toxicity profile. Our pathogenic mutations percentage (19,4%) is in line with previous publications. Clinical trial information: NCT03434158 .

CAPItello-280: A phase III study of capivasertib and docetaxel versus placebo and docetaxel in metastatic castration-resistant prostate cancer.

TPS287 Background: Docetaxel is the standard first-line chemotherapy for patients with metastatic castration-resistant prostate cancer (mCRPC) whose disease progressed on an androgen receptor-targeted agent (ARTA; typically, abiraterone, enzalutamide, apalutamide, or darolutamide). However, most patients develop chemotherapy resistance, and median overall survival (OS) remains under 3 years. Preclinical studies have associated phosphoinositide 3-kinase (PI3K)/protein kinase (AKT)/phosphatase and tensin homolog (PTEN) pathway signaling with the development of mCRPC and with resistance to taxane chemotherapy. The ProCAID Phase II trial (NCT02121639) examined whether adding capivasertib, a potent, selective inhibitor of all three AKT isoforms (AKT1/2/3), to docetaxel chemotherapy improved clinical outcomes. Although no difference in the primary endpoint (composite progression-free survival [PFS]) was detected, OS, a secondary endpoint, was extended in the capivasertib plus docetaxel treatment group. A subsequent follow-up analysis at advanced maturity suggested that the OS benefit in ProCAID was restricted to patients who had received prior treatment with an ARTA. Methods: CAPItello-280 is a Phase III study to confirm the efficacy and safety of capivasertib in combination with docetaxel compared with placebo and docetaxel in patients with mCRPC who have not previously received chemotherapy for mCRPC, but whose disease has progressed despite treatment with an ARTA in any setting. Approximately 790 patients will be randomized 1:1 to receive either capivasertib or matching placebo (320 mg orally, twice daily [BD], 4 days on, 3 days off) plus docetaxel (75 mg/m2 on day 1 of each 21-day cycle for 6–10 cycles, with prednisone or prednisolone 5 mg BD or 10 mg once daily) with a background of continued androgen deprivation therapy until disease progression, unacceptable toxicity, death, or withdrawal of consent. The primary endpoint is OS; secondary endpoints include radiographic PFS, time to pain progression, symptomatic skeletal events, safety, and tolerability. Recruitment began in March 2022 and is planned at 207 study sites in 20 countries, including the USA, Canada, Europe, South America, and Asia-Pacific. Clinical trial information: NCT05348577 .

High-volume mCRPC is associated with decreased cancer specific survival in patients on second-generation hormone therapy in the post docetaxel setting.

192 Background: In the setting of disease progression of metastatic castrate resistant prostate cancer (mCRPC) on docetaxel, abiraterone acetate (AA) and enzalutamide are two commonly used second line therapies with data demonstrating survival benefits. Less is known about patient specific factors that contribute to success with these therapies. The objective of this study is to improve patient selection for post-docetaxel second generation hormone therapy (AA or enzalutamide) by evaluating whether overall metastatic burden is associated with treatment response in this setting. Methods: By retrospective chart review, patients with mCRPC treated with AA or enzalutamide following docetaxel failure (defined as PSA rise and radiographic progression) were identified. Patients were categorized into low volume and high volume metastatic disease based on the number of pre-treatment metastatic lesions; where low volume disease describes patients with ≤ 5 metastatic lesions (e.g. oligometastatic disease), and high volume disease represents patients with &gt; 5 individual lesions. The primary endpoint was cancer-specific mortality and the secondary endpoint was radiographic progression free survival. Median follow-up time was 29.5 months. Results: 75 patients were identified and included in our analysis: 39 with high volume metastatic disease, and 36 with low volume metastatic disease. Baseline characteristics of age and pre-treatment ECOG were not statistically different between these groups. Pre-treatment high-volume disease burden was significantly associated with increased risk of radiographic disease progression (HR 4.21, 95%CI 1.97-8.99, p &lt; 0.0001) and cancer specific mortality (HR 5.84, 95% CI 1.58-21.53, p = 0.0026) during treatment with second generation androgen deprivation therapy. Conclusions: High volume metastatic disease burden is associated with significantly increased cancer specific mortality and decreased progression free survival for patients on second line therapy with AA or enzalutamide following docetaxel treatment failure.

Whole-genome sequencing identified novel mutations in a Chinese family with lynch syndrome.

Lynch syndrome (LS) is caused by a germline mutation in one of the mismatch repair genes (MLH1, MSH2, MSH6, and PMS2) or in the EPCAM gene. The definition of Lynch syndrome is based on clinical, pathological, and genetic findings. Therefore, the identification of susceptibility genes is essential for accurate risk assessment and tailored screening programs in LS monitoring. In this study, LS was diagnosed clinically in a Chinese family using Amsterdam II criteria. To further explore the molecular characteristics of this LS family, we performed whole genome sequencing (WGS) to 16 members in this family and summarized the unique mutational profiles within this family. We also used Sanger sequencing technology and immunohistochemistry (IHC) to verify some of the mutations identified in the WGS analysis. We showed that mutations in mismatch repair (MMR) related genes, as well as pathways including DNA replication, base excision repair, nucleotide excision repair, and homologous recombination were enhanced in this family. Two specific variants, MSH2 (p.S860X) and FSHR (p.I265V) were identified in all five members with LS phenotypes in this family. The MSH2 (p.S860X) variant is the first reported variant in a Chinese LS family. This mutation would result in a truncated protein. Theoretically, these patients might benefit from PD-1 (Programmed death 1) immune checkpoint blockade therapy. The patients who received nivolumab in combination with docetaxel treatments are currently in good health. Our findings extend the mutation spectrum of genes associated with LS in MLH2 and FSHR, which is essential for future screening and genetic diagnosis of LS.

Identification of Potential Serum Protein Biomarkers in Thymoma with Myasthenia Gravis After Docetaxel Treatment.

Myasthenia gravis (MG) is a devastating acquired autoimmune disease that can seriously affect the patient's quality of life. It is also a common complication of thymoma. Previous studies have shown that docetaxel alleviates myasthenic symptoms in thymoma with MG (TMG). However, little is known about the protein expression profiles and biomarkers for efficacy after docetaxel treatment. We recruited 9 healthy controls and 30 patients with TMG for the serum proteomics study with data-independent acquisition (DIA) technology. We further recruited additional 30 patients for the key protein validation by enzyme-linked immunosorbent assay (ELISA). We identified 43 proteins by trend analysis and analyzed the interaction between these proteins and MG pathogenic proteins from the DisGNET database and the correlation analysis with clinical data of patients with TMG. Among these, KRAS and SELP were screened out and validated. KRAS and SELP increased in patients with TMG and decreased significantly after docetaxel treatment. Our study revealed that the serum proteins were differentially expressed after docetaxel treatment, suggesting their important role in patients with TMG, as well as the critical role of KRAS and SELP as biomarkers in evaluating the efficacy of docetaxel treatment.

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.

Transcription factor E2F8 is a therapeutic target in the basal-like subtype of breast cancer.

Tumorigenesis in breast cancers usually accompanied by the dysregulation of transcription factors (TFs). Abnormal amplification of TFs leads aberrant expression of its downstream target genes. However, breast cancers are heterogeneous disease with different subtypes that have distinguished clinical behaviours, and the identification of prognostic TFs may enable to provide diagnosis and treatment of breast cancer based on subtypes, especially in Basal-like breast cancer. The RNA-sequencing was performed to screen differential TFs in breast cancer subtypes. The GEPIA dataset analysis was used to analyze the genes expression in invasive breast carcinoma. The expression of MYBL2, HOXC13, and E2F8 was verified by qRT-PCR assay in breast cancers. The depiction analysis of co-expressed proteins was revealed using the STRING datasets. The cellular infiltration level analysis by the TISIDB and TIMER databases. The transwell assay was performed to analyze cellular migration and invasion. CCK-8 assay was used to evaluate cellular drug susceptibility for docetaxel treatment. Predicted targeted drugs in breast cancers by GSCA Lite database online. Kaplan-Meier plotter suggested that high expression of both E2F8 and MYBL2 in Basal-like subtype had a poor relapse-free survival. Functional enrichment results identified that apoptosis, cell cycle, and hormone ER pathway were represented the crucial regulation pathways by both E2F8 and MYBL2. In the meantime, database analysis indicated that high expression of E2F8 responded to chemotherapy, while those patients of high expression of MYBL2 responded to endocrinotherapy, and a positive correlation between the expression of E2F8 and PD-L1/CTLA4. Our cell line experiments confirmed the importance of E2F8 and MYBL2 in proliferation and chemotherapy sensitivity, possibly, the relationship with PD-L1. Additionally, we also observed that the up-regulation of E2F8 was accompanied with higher enrichments of CD4+ T cells and CD8+ T cells in breast cancers. Taken together, our findings elucidated a prospective target in Basal-like breast cancer, providing underlying molecular biomarkers for the development of breast cancer treatment.

Abirateron ve Docetaxel Tedavileri Metastatik Prostat Kanseri Hücrelerinde Phospho-PTEN Ekspresyonunu Arttırır

Aim: Prostate cancer is the second leading cause of death in cancer-related deaths in men. Docetaxel and abiraterone acetate are widely used in the treatment of castration-resistant metastatic prostate cancer. Phospho-PTEN triggers proliferation, migration, angiogenesis and survival in cells by causing oncogenic Akt hyperactivation. This study, it is aimed to investigate the effects of docetaxel and abiraterone acetate agents, which are widely used in the treatment of prostate cancer, on the expression of phospho-PTEN, which stimulates the oncogenic pathway. Material and Methods: The effects of docetaxel and abiraterone acetate on phospho-PTEN expression in androgen receptor (+) and androgen receptor (-) metastatic prostate cancer cell lines were investigated in vitro by immunofluorescence method. Results: Findings were compatible in both androgen receptor (+) and androgen receptor (-) metastatic prostate cancer cell lines. No statistically significant difference in phospho-PTEN expression was observed between the control and abiraterone acetate groups. Phospho-PTEN expression was increased statistically significant in docetaxel and abiraterone acetate+docetaxel groups compared to control. This increase was greater statistically significant in the combined group given the two agents compared to the docetaxel group. Conclusion: A significant increase in phospho-PTEN was observed in the docetaxel and combined treatment groups. The increase of Phospho-PTEN causes oncogenic Akt hyperactivation. According to this information, docetaxel and combined drug treatments may support the oncogenic pathway in cells by increasing phospho-PTEN in patients. To eliminate these effects in patients, the administration of agents that dephosphorylate PTEN or agents that will stimulate the pathways that provide dephosphorylation may increase the total survival of the patients.

Strong instrumental variables biased propensity scores in comparative effectiveness research: A case study in oncology

Background and ObjectivesSome medications require specific medical procedures in the weeks before their start. Such procedures may meet the definition of instrumental variables (IVs). We examined how they may influence treatment effect estimation in propensity score (PS)-adjusted comparative studies, and how to remedy. Study Design and SettingDifferent covariate assessment periods (CAPs) did and did not include the month preceding treatment start were used to compute PS in the French claims database (Sytème National des Données de Santé-SNDS), and 1:1 match patients with metastatic castration resistant prostate cancer initiating abiraterone acetate or docetaxel. The 36-month survival was assessed. ResultsAmong 1, 213 docetaxel and 2, 442 abiraterone initiators, the PS distribution resulting from the CAP [-12; 0 months] distinctly separated populations (c = 0.93; 273 matched pairs). The CAPs [-12;-1 months] identified 765 pairs (c = 0.81). Strong docetaxel treatment predictors during the month before treatment start were implantable delivery systems (1% vs. 59%), which fulfilled IV conditions. The 36-month survival was not meaningfully different under the [-12; 0 months] CAP but differed by 10% points (38% vs. 28%) after excluding month −1. ConclusionIn the setting of highly predictive pretreatment procedures, excluding the immediate pre-exposure time from the CAP will reduce the risk of including potential IVs in PS models and may reduce bias.

Effectiveness of Adding Docetaxel to Androgen Deprivation Therapy for Metastatic Hormone-Sensitive Prostate Cancer in Korean Real-World Practice.

Evidence in favor of adding docetaxel in treatment of metastatic hormone-sensitive prostate cancer (mHSPC) has led to docetaxel in conjunction with androgen deprivation therapy (ADT) as standard therapy. The aim of this study was to examine the effectiveness of docetaxel with ADT for Korean patients with mHSPC in real-world practice. A retrospective cohort study was performed at six Korean hospitals for patients with mHSPC treated with docetaxel plus ADT. Patients were treated every 3 weeks for up to six cycles with 75 mg/m² of docetaxel. The primary endpoint was time to castration resistant prostate cancer (CRPC). This study included 46 eligible patients from June 2016 to February 2021. Median age was 68.5 years (range, 52-84) and all patients present with de novo M1 with high-volume disease. The median prostate-specific antigen (PSA) level at ADT initiation was 205.4 (7.7-1933) ng/mL, and time from ADT to docetaxel was 2.4 months (0-5.3). All six planned cycles of docetaxel were delivered in 36 patients (78%), 7 patients (15%) discontinued treatment due to adverse events, and 3 patients (7%) discontinued due to progression. At the time of the analysis, CRPC had developed in 34 patients (74%), and the median time to CRPC was 18.0 (95% confidence interval, 14.1-21.9) months. PSA <0.2 ng/mL was achieved in 11 patients (24%) after 6 months of ADT and in 10 patients (22%) after 12 months. At last follow-up, 35 patients (76%) were alive; the median overall survival was not reached. The effect of docetaxel combined with ADT for Korean patients with mHSPC is comparable with prior results in Western studies.