Paclitaxel Combination Therapy Research Articles

A DPC Database Study on the Safety of Atezolizumab/Bevacizumab/Carboplatin/Paclitaxel in Non-small Cell Lung Cancer in Japanese Patients.

Atezolizumab, bevacizumab, carboplatin, and paclitaxel (ABCP) combination therapy is a standard of care for advanced non-squamous non-small cell lung cancer (NSQ-NSCLC); however, the lack of safety data limits its clinical application in Japan. This study compared the safety of ABCP with that of bevacizumab, carboplatin, and paclitaxel (BCP) combination for the treatment of advanced NSQ-NSCLC in Japanese patients by evaluating the clinical background and incidence of adverse events (AEs) based on data extracted from the Diagnosis Procedure Combination (DPC) database. Incidence rates and restricted mean survival times (RMSTs) for up to 1 year were analyzed for 19 clinically important AEs. Covariates were adjusted using the inverse probability weighting method. A search conducted using the International Statistical Classification of Diseases and Related Health Problems 10th Revision codes identified 350,987 patients, of whom 202 were included in the ABCP cohort and 232 in the BCP cohort. Among the 19 AEs, the incidence of skin disorder and febrile neutropenia (FN) was significantly higher in the ABCP cohort versus the BCP cohort. The adjusted incidence rate ratios were 2.65 [95%confidence interval (CI) 1.43-4.91] for skin disorder and 1.70 (95% CI 1.01-2.85) for FN. The adjusted RMST differences were-64.2 days (95% CI-93.0 to-35.4 days) and-46.0days (95% CI-73.5 to-18.5 days) for skin disorder and FN, respectively. These results were comparable to those of other pivotal clinical trials. The findings of this DPC database study highlight the safety of ABCP in Japanese clinical practice, and this methodology may facilitate more efficient research in real-world settings. UMIN Clinical Trials Registry ID UMIN000041507.

Combination of polymeric micelle formulation of TGFβ receptor inhibitors and paclitaxel produces consistent response across different mouse models of Triple‐negative breast cancer

AbstractTriple‐negative breast cancer (TNBC) is notoriously difficult to treat due to the lack of targetable receptors and sometimes poor response to chemotherapy. The transforming growth factor beta (TGFβ) family of proteins and their receptors (TGFRs) are highly expressed in TNBC and implicated in chemotherapy‐induced cancer stemness. Here, we evaluated combination treatments using experimental TGFR inhibitors (TGFβi), SB525334 (SB), and LY2109761 (LY) with paclitaxel (PTX) chemotherapy. These TGFβi target TGFR‐I (SB) or both TGFR‐I and TGFR‐II (LY). Due to the poor water solubility of these drugs, we incorporated each of them in poly(2‐oxazoline) (POx) high‐capacity polymeric micelles (SB‐POx and LY‐POx). We assessed their anticancer effect as single agents and in combination with micellar PTX (PTX‐POx) using multiple immunocompetent TNBC mouse models that mimic human subtypes (4T1, T11‐Apobec and T11‐UV). While either TGFβi or PTX showed a differential effect in each model as single agents, the combinations were consistently effective against all three models. Genetic profiling of the tumors revealed differences in the expression levels of genes associated with TGFβ, epithelial to mesenchymal transition (EMT), TLR‐4, and Bcl2 signaling, alluding to the susceptibility to specific gene signatures to the treatment. Taken together, our study suggests that TGFβi and PTX combination therapy using high‐capacity POx micelle delivery provides a robust antitumor response in multiple TNBC subtype mouse models.

Natural products to enhance anti-tumor effects of trastuzumab and paclitaxel on the SKBR3, which is human breast cancer cell line.

e13051 Background: Neoadjuvant chemotherapy (ChT) with targeted therapy is the standard treatment for human epidermal growth factor 2 (HER2)- positive breast cancer (BC). In this context, Trastuzumab (Tz) and ChT significantly improved the pathological complete response (pCR) rate. Tz and Paclitaxel (PTX) combination therapy is also one of the neoadjuvant treatments used in HER2+BC, and despite the effectiveness of this treatment, there is a critical need for innovative approaches and further research that will improve the neoadjuvant response rate. Addressing this, the NaturaProDB tool presents a novel avenue for predicting in silico natural non-toxic compounds with potential anti-cancer properties. Our study aims to investigate synergistic effect of natural products proposed by this database on theurapeutic action of Tz and PTX on BC. Methods: The NaturaProDB database was searched using the ‘Target Cancer’ option in order to identify those natural products with anti-BC potential and the corresponding experimentally verified target genes. Using this database, Biochanin A (BCA) and Delphinidin (Dp) were selected as natural compounds because they both commonly inhibit the MAPK signaling pathway. We used the HER2+ SKBR3 cell line to determine IC20, IC30 and IC50 doses for BCA, Dp, Tz, and PTX through MTT assay. Notably, all experiments were done after 72 hrs treatment of all compounds. Further, various combinations within different concentrations of natural products and Tz and PTX were tested to define additive anti-proliferative effects on SKBR3 cell line. Results: We first defined two natural products with drug-like properties, BCA and Dp, which have anti-proliferative effect on BC. Treatment of SKBR3 with increasing concentrations of BCA and Dp caused dose-dependent proliferation inhibition and IC50 dose of compounds were defined as 42,70uM and 40,70uM, respectively. In addition, IC20 dose of Tz was 2,8µM, while IC30 dose of PTX was 2,3nM.Then, we showed that combinations of increasing doses of Dp (from 30µM to 90 µM) with IC20 Tz caused significant dose-dependent cell death compared to the control group (p<0.0001). And the combinations of increasing doses of BCA (from 45µM to 360 µM) with IC20 Tz led similar significant results (p<0.0001). Conclusions: Herein, it is shown that combining natural compounds (Dp, BCA) with conventional treatments (PTX,Tz) predicted for the SKBR3 cell line can enhance the inhibitory effect on cell proliferation. This study is one of the rare first cell line studies in which the synergistic effect of BCA and Dp, which are natural compounds selected using the NaturaProDB database, were combined with ChT and Tz to show their synergistic effect, and these findings indicate that synergistic combination treatments acting through different pathways (MAPK signaling pathway) can be used in the treatment of HER2+ and TN BC. It opens avenues for further research.

Adverse Event Profile of Atezolizumab, Bevacizumab, Carboplatin, and Paclitaxel Combination Therapy Based on JADER.

There have been advances in the development of immune checkpoint inhibitors for monotherapy and combination therapy with other anticancer agents in recent years. The combination of bevacizumab, carboplatin, and paclitaxel with atezolizumab, an anti-programmed death ligand 1 antibody (ABCP therapy), has been reported to be effective for treating non-small cell lung cancer. However, reports on its adverse events are limited. In this study, a survey and disproportionality analysis based on the Japanese Adverse Drug Event Report (JADER) database was conducted to elucidate the adverse event profile of ABCP therapy. The reporting odds ratio (ROR) and information component were used as indicators for the disproportionality analysis. The ROR was also used to assess the changes in the reporting intensity with combination therapy, and the mutual exclusivity of the 95% confidence interval between the compared groups was considered. The reported adverse events of ABCP therapy mirrored those of the individual drugs that constituted it. ABCP therapy enhanced the reporting intensity of adverse events related to leukocytes and the skin, while decreased those related to interstitial lung disease and hepatic function abnormality as immune-related adverse events caused by atezolizumab, and gastrointestinal perforation caused by bevacizumab. Our analysis of data from the JADER database has revealed the adverse event profile of ABCP therapy. Our findings emphasize the importance of effectively managing febrile neutropenia and skin-related adverse events in ABCP therapy.

Optimizing combination therapy in prostate cancer: mechanistic insights into the synergistic effects of Paclitaxel and Sulforaphane-induced apoptosis

BackgroundCombination therapies in cancer treatment have demonstrated synergistic or additive outcomes while also reducing the development of drug resistance compared to monotherapy. This study explores the potential of combining the chemotherapeutic agent Paclitaxel (PTX) with Sulforaphane (SFN), a natural compound primarily found in cruciferous vegetables, to enhance treatment efficacy in prostate cancer.MethodsTwo prostate cancer cell lines, PC-3 and LNCaP, were treated with varying concentrations of PTX, SFN, and their combination. Cell viability was assessed using the thiazolyl blue tetrazolium bromide (MTT) assay to determine the EC50 values. Western blot analysis was conducted to evaluate the expression of Bax, Bcl2, and Caspase-3 activation proteins in response to individual and combined treatments of PTX and SFN. Fluorescent microscopy was employed to observe morphological changes indicative of apoptotic stress in cell nuclei. Flow cytometry analysis was utilized to assess alterations in cell cycle phases, such as redistribution and arrest. Statistical analyses, including Student’s t-tests and one-way analysis of variance with Tukey’s correction, were performed to determine significant differences between mono- and combination treatments.ResultsThe impact of PTX, SFN, and their combination on cell viability reduction was evaluated in a dose-dependent manner. The combined treatment enhanced PTX’s effects and decreased the EC50 values of both drugs compared to individual treatments. PTX and SFN treatments differentially regulated the expression of Bax and Bcl2 proteins in PC-3 and LNCaP cell lines, favoring apoptosis over cell survival. Our data indicated that combination therapy significantly increased Bax protein expression and the Bax/Bcl2 ratio compared to PTX or SFN alone. Flow cytometry analysis revealed alterations in cell cycle phases, including S-phase arrest and an increased population of apoptotic cells. Notably, the combination treatments did not have a discernible impact on necrotic cells. Signs of apoptotic cell death were confirmed through Caspase-3 cleavage, and morphological changes in cell nuclei were assessed via western blot and fluorescent microscopy.ConclusionThis combination therapy of PTX and SFN has the potential to improve prostate cancer treatment by minimizing side effects while maintaining efficacy. Mechanistic investigations revealed that SFN enhances PTX efficacy by promoting apoptosis, activating caspase-3, inducing nuclear morphology changes, modulating the cell cycle, and altering Bax and Bcl2 protein expression. These findings offer valuable insights into the synergistic effects of PTX and SFN, supporting the optimization of combination therapy and providing efficient therapeutic strategies in preclinical research.

Efficacy of adding levofloxacin to gemcitabine and nanoparticle-albumin-binding paclitaxel combination therapy in patients with advanced pancreatic cancer: study protocol for a multicenter, randomized phase 2 trial (T-CORE2201)

BackgroundAdvanced pancreatic cancer is one of the leading causes of cancer-related deaths. For patients with advanced pancreatic cancer, gemcitabine and nanoparticle albumin-binding paclitaxel (nabPTX) combination (GEM/nabPTX) therapy is one of the recommended first-line treatments. Several retrospective studies have suggested that the addition of levofloxacin improves the efficacy of GEM/nabPTX therapy in patients with advanced pancreatic cancer. This prospective study aims to evaluate whether the addition of antibiotics improves the treatment efficacy of GEM/nabPTX as a first-line chemotherapy in patients with advanced pancreatic cancer.MethodsThis multicenter, prospective, randomized, phase 2 trial will included 140 patients. Patients with advanced pancreatic cancer will be randomized in a 1:1 ratio to either the GEM/nabPTX therapy group or the GEM/nabPTX plus levofloxacin group. The primary endpoint for the two groups is median progression-free survival time (mPFS) for the full analysis set (FAS). The secondary endpoints for the two groups are median overall survival (mOS), response rate (RR), disease control rate (DCR), and adverse event (AE) for the FAS and mPFS, mOS, RR, DCR, and AE for the per-protocol set. This study will enroll patients treated with GEM/nabPTX as the first-line chemotherapy for stage IV pancreatic adenocarcinoma.DiscussionGEM/nabPTX is a standard first-line chemotherapy regimen for patients with advanced pancreatic cancer. Recently, the superiority of 5-fluorouracil, liposomal irinotecan, and oxaliplatin combination therapy (NALIRIFOX) to GEM/nabPTX as first-line therapy for pancreatic cancer has been reported. However, the efficacy of NALIRIFOX is inadequate. Based on previous retrospective studies, it is hypothesized that treatment efficacy will improve when levofloxacin is added to GEM/nabPTX therapy. If the AEs (such as leukopenia, neutropenia, and peripheral neuropathy) that occur at an increased rate with levofloxacin and GEM/nabPTX combination therapy can be carefully monitored and properly managed, this simple intervention can be expected to improve the prognosis of patients with advanced pancreatic cancer.Trial registrationThis study was registered with the Japan Registry of Clinical Trials (jRCT; registry number: jRCTs021230005).

The interim analysis of a single-arm, open-label, phase II study investigating ALLEN regimen (durvalumab plus albumin paclitaxel and lenvatinib) in patients with unresectable biliary tract cancers (BTCs).

504 Background: BTCs are a heterogeneous group of malignancies with a poor prognosis. Despite the improved outcome achieved by the addition of the anti-PD-L1 antibody durvalumab to standard chemotherapy, the benefits were modest and cannot satisfy the clinical demands adequately. This study aimed to evaluate the efficacy and safety of the combination therapy of Albumin paclitaxel, Durvalumab and Lenvatinib (ALLEN regimen) in unresectable BTCs. Methods: This single-arm, single-center, open-label, phase I/Ⅱ study enrolled patients with locally advanced or metastatic BTCs. Eligible patients with ECOG score 0-2 were treated with ALLEN regimen. Durvalumab (1000mg IV, q3w) in combination with albumin paclitaxel (180-220 mg/m2 IV q3w) and lenvatinib (8mg PO QD) were given regularly until disease progression. The primary endpoint was objective response rate (ORR) evaluated by investigators according to RECIST 1.1. The secondary endpoints were disease control rate (DCR), progression-free survival (PFS) and treatment-related adverse events (TRAEs). Results: From September 2021 to September 2023, fourteen patients were enrolled including three patients who were failed to prior anti-PD-1 antibody treatment. The median follow-up was 6.8 months (95% CI 1.9, 10.9). The median age of the patients was 59.0 years, and male patients accounted for 35.7%. The ORR and DCR were 35.7% and 100%, respectively. The median PFS was 7.3 months (95% CI 4.9, 8.2). TRAEs of any grade occurred in 13 (92.9%) patients without grade 3 or higher. The most common TRAEs were alopecia (13/14, 92.9%), peripheral sensory neuropathy (10/14, 71.4%), decreased appetite and nausea (9/14, 64.3%), hypertension (6/14, 42.9%), rash (5/14, 35.7%), diarrhoea (4/14, 28.6%), and asthenia (4/14, 28.6%). Conclusions: The ALLEN regimen demonstrated encouraging anti-tumor activity with a tolerable safety profile in unresectable BTCs. The preliminary results were promising, which deserved further investigation in a larger population. Clinical trial information: NCT05327582 .

The interim analysis of a single-arm, open-label, phase II study investigating ALLEN regimen (durvalumab plus albumin paclitaxel and lenvatinib) in patients with metastatic pancreatic cancer (mPC).

658 Background: Metastatic pancreatic cancer is a leading cause of cancer death worldwide with limited treatment options. Durvalumab, the anti- PD-L1 inhibitor has revealed remarkable efficacy in solid malignancies including hepatobiliary cancers. We conducted a study to evaluate the efficacy and safety of a combination therapy of Durvalumab, Albumin paclitaxel and Lenvatinib (ALLEN Regimen) in patients with mPC. Methods: This open-label, single-center, single-arm, phase Ⅱ clinical trial investigated patients with metastatic pancreatic cancer. Durvalumab (1000mg IV, q3w), albumin paclitaxel(180-220 mg/m2 IV q3w) and lenvatinib (8mg PO QD) were given regularly until disease progression. The primary endpoint was objective response rate (ORR) evaluated by investigators according to RECIST 1.1. The secondary endpoints were disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and treatment-related adverse events (TRAEs). Results: Between September 2021 and September 2023, seventeen patients with ECOG score 0-2 were enrolled, including 8 patients (47%) who were refractory to at least one systemic chemotherapy.The median follow-up was 6.0 months (95% CI 4.0, 8.4). 17 patients were evaluable, with a median age of 58 years. 9 patients (52.9%) were male. The ORR and DCR were 64.7% and 94.1%, respectively. The median PFS was 7.8 months (95% CI 3.1, 11.4), and the median OS was 8.1 months (95% CI 4.7, 13.5). TRAEs (all grades) occurred in 16 (94.1%) patients. The most common grade 1-2 TRAEs were nausea 8 (47.1%), diarrhoea 5(29.4%), peripheral sensory neuropathy 3 (17. 6% ) and hypertension 3(17.6% ). No grade 3 or higher TRAEs occurred. Conclusions: The ALLEN regimen demonstrated promising antitumor activity and well acceptable toxicity in metastatic pancreatic cancer. Further randomized controlled studies will be required in a larger patient population. Clinical trial information: NCT05327582 .

Research Advances in Clinical Applications, Anticancer Mechanism, Total Chemical Synthesis, Semi-Synthesis and Biosynthesis of Paclitaxel.

Paclitaxel, a natural secondary metabolite isolated and purified from the bark of the Taxus tree, is considered one of the most successful natural anticancer drugs due to its low toxicity, high potency and broad-spectrum anticancer activity. Taxus trees are scarce and slow-growing, and with extremely low paclitaxel content, the contradiction between supply and demand in the market is becoming more and more intense. Therefore, researchers have tried to obtain paclitaxel by various methods such as chemical synthesis, artificial culture, microbial fermentation and tissue cell culture to meet the clinical demand for this drug. This paper provides a comprehensive overview of paclitaxel extraction, combination therapy, total synthesis, semi-synthesis and biosynthesis in recent years and provides an outlook, aiming to provide a theoretical basis and reference for further research on the production and application of paclitaxel in the future.

Regulation of Protein-Induced Apoptosis and Autophagy in Human Hepatocytes Treated with Metformin and Paclitaxel In Silico and In Vitro.

Metformin and paclitaxel therapy offer promising outcomes in the treatment of liver cancer. Combining paclitaxel with metformin enhances treatment effectiveness and mitigates the adverse effects associated with paclitaxel alone. This study explored the anticancer properties of metformin and paclitaxel in HepG2 liver cancer cells, MCF-7 breast cancer cells, and HCT116 colon cancer cells. The results demonstrated that the combination of these agents exhibited a lower IC50 in the tested cell lines compared to paclitaxel monotherapy. Notably, treating the HepG2 cell line with this combination led to a reduction in the G0/G1 phase and an increase in the S and G2/M phases, ultimately triggering early apoptosis. To further investigate the interaction between the cellular proteins with paclitaxel and metformin, an in silico study was conducted using proteins chosen from a protein data bank (PDB). Among the proteins studied, AMPK-α, EGFRK, and FKBP12-mTOR exhibited the highest binding free energy, with values of -11.01, -10.59, and -15.63 kcal/mol, respectively, indicating strong inhibitory or enhancing effects on these proteins. When HepG2 cells were exposed to both paclitaxel and metformin, there was an upregulation in the gene expression of AMPK-α, a key regulator of the energy balance in cancer growth, as well as apoptotic markers such as p53 and caspase-3, along with autophagic markers including beclin1 and ATG4A. This combination therapy of metformin and paclitaxel exhibited significant potential as a treatment option for HepG2 liver cancer. In summary, the combination of metformin and paclitaxel not only enhances treatment efficacy but also reduces side effects. It induces cell cycle alterations and apoptosis and modulates key cellular proteins involved in cancer growth, making it a promising therapy for HepG2 liver cancer.

NRF2 Suppression Enhances the Susceptibility of Pancreatic Cancer Cells, Miapaca-2 to Paclitaxel.

Pancreatic cancer is one of the most deadly diseases, with a very high metastasis and low survival rate. High levels of NRF2 have been detected in numerous malignancies, including head, neck, lung, and colon cancers, promoting the expansion and survival of cancer cells and chemical resistance to stressful conditions and affecting the response to treatment. To evaluate the possibility that modulation of NRF2 expression could be effective in treating pancreatic cancer cells, we explored the effect of knockdown of the NRF2 gene by NRF2-specific siRNA and its influence in combination with paclitaxel on pancreatic cancer cells. Miapaca-2 cell line, due to the high expression of the NRF2 gene, was selected for this study. Then, Miapaca-2 cells in different groups were treated with NRF2 siRNA and paclitaxel separately and in combination. After that, cell viability was measured by MTT assay and apoptosis induction by Annexin V-FITC/PI staining test. Cell cycle and autophagy were examined by flow cytometry, and cell migration was assessed by wound-healing assay. Finally, the expression of genes involved in apoptosis, Bax, Caspase-3, Caspase-9, and genes related to migration pathway, MMP-2, and MMP-9 in different groups were measured using qRT-PCR. Combined use of NRF2-specific siRNA with paclitaxel significantly reduced NRF2 gene expression in pancreatic cancer cells. NRF2 siRNA transfection significantly reduced cell viability. In addition, paclitaxel combination therapy with NRF2 siRNA strengthens the anti-tumor effects, such as inhibiting cell migration and provoking apoptosis, and autophagy and the cell cycle arrest in the G2 phase. NRF2 suppression augmented the expression of Bax, Caspase-3, and Caspase-9 genes and lowered the expression of Bcl-2, MMP-2, and MMP-9 genes, which play crucial roles in the pathways of apoptosis and cell migration, respectively. NRF2 siRNA enhances the susceptibility of Miapaca-2 cells to paclitaxel in pancreatic cancer cells. Thereby, suppressing NRF2 in combination with paclitaxel can be a new and efficacious treatment approach in treating pancreatic cancer.

Serum vascular endothelial growth factor associated with the progression of granulosa cell tumor: a report of two cases

BackgroundGranulosa cell tumors (GCTs) account for approximately 2% of ovarian malignancies and are considered a rare type of ovarian cancer. GCTs are characterized by irregular genital bleeding after menopause due to female hormone production as well as late recurrence around 5–10 years after initial treatment. In this study, we investigated two cases of GCTs to find a biomarker that can be used to evaluate the treatment and predict recurrence.Case presentationCase 1 was a 56-year-old woman who presented to our hospital with abdominal pain and distention. An abdominal tumor was found, and GCTs were diagnosed. Serum vascular endothelial growth factor (VEGF) levels decreased after surgery. Case 2 involved a 51-year-old woman with refractory GCTs. Carboplatin–paclitaxel combination therapy and bevacizumab were administered after the tumor resection. After chemotherapy, a decline in VEGF levels was observed, but serum VEGF levels increased again with disease progression.ConclusionsVEGF expression may be of clinical importance in GCTs as a clinical biomarker for disease progression, which may be used to determine the efficacy of bevacizumab against GCTs.

A multi-cohort phase I/IIa clinical trial to evaluate the safety, tolerability, and pharmacokinetics of TST001 administered as a monotherapy, with nivolumab or standard of care in patients with locally advanced or metastatic solid tumors: TransStar101.

TPS4176 Background: Gastric cancer (GC) remains the 4th leading cause of cancer death worldwide, accounting for about 7.7% of all cancer related mortality. Despite recent approval of nivolumab in combination with chemotherapy, the median survival of treatment naïve Gastric Cancer/gastroesophageal junction cancer (G/GEJ) cancer is only approximately 14 months, even in patients with high CPS PD-L1. Targeting claudin 18.2 (CLDN18.2) in combination with chemotherapy is a clinically validated approach for patients with CLDN18.2 expressing advanced G/GEJ cancer. TST001 is a humanized monoclonal antibody with improved affinity to human CLDN18.2 and enhanced antibody-dependent cellular cytotoxicity (ADCC). In pre-clinical studies, TST001 treatment upregulates PD-L1 expression on CLDN18.2-positive tumor cells. The in vivo analysis showed anti-tumor efficacy of TST001 combined with anti-PD-1 antibody and chemotherapy was superior to combination of anti-PD-1 antibody with chemotherapy or combination of TST001 with chemotherapy. Promising anti-tumor activities have been observed in patients with advanced G/GEJ cancer who have been treated with TST001 alone or in combination with chemotherapy, making the combination of TST001, nivolumab and chemotherapy attractive. Methods: This is a multi-cohort, open-label, multi-center phase I/II first in human (FIH) study of TST001 administered as single agent, in combination with nivolumab or standard of care in the treatment of patients with locally advanced or metastatic solid tumors. Primary endpoints include characterization of TST001 safety profile and the maximum tolerated dose / recommended phase 2 dose. Secondary endpoints include pharmacokinetics, immunogenicity, pharmacodynamics, and efficacy. The study includes two parts. Part A (completed) is a dose escalation of TST001 as a monotherapy. Part B (ongoing) consists of three independent cohorts: cohort A includes combination TST001 + nivolumab+ leucovorin calcium (folinic acid), fluorouracil, and oxaliplatin (mFOLFOX6) as 1st line treatment for G/GEJ cancer; cohort B includes TST001 in combination with nivolumab in advanced pre-treated G/GEJ cancer; cohort C includes combination therapy of TST001, gemcitabine, and nanoparticle albumin-bound paclitaxel as 1st line treatment for advanced/metastatic pancreatic cancer. Multiple doses and schedules will be assessed during Part B. Conclusions: Combination of TST001 with nivolumab and chemotherapy has the potential to improve the outcomes of patients with advanced or metastatic CLDN18.2 expressing G/GEJ cancer. Data from this trial will support the selection of the optimal dose and dose regimen of TST001 in these combinations. Enrollment in the trial is ongoing. Clinical trial information: NCT04396821 .

Targeting ATAD3A-PINK1-mitophagy axis overcomes chemoimmunotherapy resistance by redirecting PD-L1 to mitochondria

Only a small proportion of patients with triple-negative breast cancer benefit from immune checkpoint inhibitor (ICI) targeting PD-1/PD-L1 signaling in combination with chemotherapy. Here, we discovered that therapeutic response to ICI plus paclitaxel was associated with subcellular redistribution of PD-L1. In our immunotherapy cohort of ICI in combination with nab-paclitaxel, tumor samples from responders showed significant distribution of PD-L1 at mitochondria, while non-responders showed increased accumulation of PD-L1 on tumor cell membrane instead of mitochondria. Our results also revealed that the distribution pattern of PD-L1 was regulated by an ATAD3A-PINK1 axis. Mechanistically, PINK1 recruited PD-L1 to mitochondria for degradation via a mitophagy pathway. Importantly, paclitaxel increased ATAD3A expression to disrupt proteostasis of PD-L1 by restraining PINK1-dependent mitophagy. Clinically, patients with tumors exhibiting high expression of ATAD3A detected before the treatment with ICI in combination with paclitaxel had markedly shorter progression-free survival compared with those with ATAD3A-low tumors. Preclinical results further demonstrated that targeting ATAD3A reset a favorable antitumor immune microenvironment and increased the efficacy of combination therapy of ICI plus paclitaxel. In summary, our results indicate that ATAD3A serves not only as a resistant factor for the combination therapy of ICI plus paclitaxel through preventing PD-L1 mitochondrial distribution, but also as a promising target for increasing the therapeutic responses to chemoimmunotherapy.

Vitamin D enhances the sensitivity of breast cancer cells to the combination therapy of photodynamic therapy and paclitaxel

PurposeGiven that Vitamin D (VD) has been confirmed to reinforce the toxic effects of 5-aminolevulinic acid-based photodynamic therapy (ALA-PDT) towards breast cancer, this study was designed to decipher the combined effects of VD, ALA-PDT and paclitaxel (PTX). MethodsThiazolyl blue tetrazolium bromide assay was conducted to gauge the viability of breast cancer cells treated with ALA-PDT and PTX alone or in combination. The cell migration, invasion and apoptosis were measured by wound healing, transwell and flow cytometry assays, respectively. Xenograft tumor models were established and tumor volume and weight were recorded. The expression of Bcl-2, Bax and cleaved caspase-3 in cells and tumor tissues was determined by western blot assay. ResultsBoth ALA-PDT and PTX alone inhibited viability in a dose-dependent manner, blocked migration and invasion, boosted apoptosis, down-regulated Bcl-2 expression and upregulated the expression of Bax and cleaved caspase-3 in breast cancer cells. More significant effects on the above-mentioned factors were induced by ALA-PDT and PTX in combination. Moreover, ALA-PDT and PTX in combination also suppressed the growth of xenograft tumors and Bcl-2 expression while promoting the expression of Bax and cleaved caspase-3 in tumors. In contrast, VD had no effect on tumor growth and the expression of Bcl-2, Bax and cleavedcaspase-3, but intensified the combined effects of ALA-PDT and PTX. ConclusionVD could enhance the therapeutic effects of ALA-PDT combined with PTX on tumor growth and cell apoptosis.

Paclitaxel and Myrrh oil Combination Therapy for Enhancement of Cytotoxicity against Breast Cancer; QbD Approach

Paclitaxel (PX), plant alkaloid, is a chemotherapeutic agent intended for treating a wide variety of cancers. The objective of the present study was to formulate and evaluate the anticancer activity of PX loaded into a nanocarrier, mainly PEGylated nanoemulsion (NE) fabricated with myrrh essential oil. Myrrh essential oil has been estimated previously to show respectable anticancer activity. Surface modification of the formulation with PEG-DSPE would help in avoiding phagocytosis and prolong the residence time in blood circulation. Various NE formulations were developed after operating (22) factorial design, characterized for their particle size, in vitro release, and hemolytic activity. The optimized formula was selected and compared to its naked counterpart in respect to several characterizations. Quantitative amount of protein absorbed on the formulation surfaces and in vitro release with and without serum incubation were evaluated. Ultimately, MTT assay was conducted to distinguish the anti-proliferative activity. PEGylated PX-NE showed particle size 170 nm, viscosity 2.91 cP, in vitro release 57.5%, and hemolysis 3.44%, which were suitable for intravenous administration. A lower amount of serum protein adsorbed on PEGylated PX-NE surface (16.57 µg/µmol) compared to naked counterpart (45.73 µg/µmol). In vitro release from PEGylated NE following serum incubation was not greatly affected (63.3%), in contrast to the naked counterpart (78.8%). Eventually, anti-proliferative effect was obtained for PEGylated PX-NE achieving IC50 38.66 µg/mL. The results obtained recommend PEGylated NE of myrrh essential oil as a candidate nanocarrier for passive targeting of PX.

Inhibition of GP130/STAT3 and EMT by combined bazedoxifene and paclitaxel treatment in ovarian cancer.

The interleukin 6 (IL-6)/glycoprotein 130 (GP130)/signal transducer and activator of transcription 3 (STAT3) signalling pathway, with GP130 as an intermediate membrane receptor, is involved in the survival, metastasis, and resistance of ovarian cancer. Bazedoxifene, an FDA-approved drug, is an inhibitor of GP130 and a selective estrogen modulator (SERM). We studied the mechanism of the combination therapy of bazedoxifene and paclitaxel in inhibiting the IL-6-mediated GP130/STAT3 signaling pathway in ovarian cancer. Surface plasmon resonance (SPR) was used to assess the binding of bazedoxifene to GP130. Migration, invasion, and apoptosis of ovarian cancer cells were assessed using bazedoxifene and paclitaxel. In addition, we determined the effects of bazedoxifene and paclitaxel alone or in combination on the GP130/STAT3 pathway and epithelial-mesenchymal transition (EMT). The results revealed that the combination of bazedoxifene and paclitaxel suppressed cell viability, migration, and invasion in the ovarian cancer cells. In addition, the combination treatment increased apoptosis. Furthermore, bazedoxifene combined with paclitaxel inhibited the growth of ovarian cancer cells in a xenograft tumour model. This combination reduced STAT3 phosphorylation and suppressed gene expression and EMT. In conclusion, inhibition of GP130/STAT3 signalling and EMT via a combination of bazedoxifene and paclitaxel could be used as a therapeutic strategy by which to overcome ovarian cancer.

Nanoparticle albumin-bound paclitaxel and PD-1 inhibitor (sintilimab) combination therapy for soft tissue sarcoma: a retrospective study

BackgroundThere is increasing evidence that combination therapy with nanoparticle albumin-bound paclitaxel (nab-paclitaxel) and programmed cell death protein 1 (PD-1) inhibitor is safe and efficacious in treating many types of malignant tumors. However, clinical data demonstrating the effect of this treatment combination for patients with metastatic soft tissue sarcoma (STS) are currently limited.MethodsThe clinical data of patients with metastatic STS who received nab-paclitaxel plus PD-1 inhibitor (sintilimab) therapy between January 2019 and February 2021 were retrospectively analyzed. The effectiveness and safety of the combined treatment were evaluated in terms of the median progression-free survival (PFS), estimated using the Kaplan–Meier method. The univariate Cox proportional hazards model was used to analyze the relationship between clinicopathological parameters and PFS. All statistical analyses were two-sided; P < 0.05 was considered statistically significant.ResultsA total of 28 patients treated with nab-paclitaxel plus sintilimab were enrolled in this study. The objective response rate was 25%, the disease control rate was 50%, and the median PFS was 2.25 months (95% CI = 1.8–3.0 months). The most common grade 1 or 2 adverse events (AEs) were alopecia (89.3%; 25/28), leukopenia (25.0%; 7/28), fatigue (21.4%; 6/28), anemia (21.4%; 6/28), and nausea (21.4%; 6/28). The most common grade 3 AEs were neutropenia (10.7%; 3/28) and peripheral neuropathy (10.7%; 3/28). No grade 4 AEs were observed. Among the present study cohort, patients with angiosarcoma (n = 5) had significantly longer PFS (P = 0.012) than patients with other pathological subtypes, including undifferentiated pleomorphic sarcoma (n = 7), epithelioid sarcoma (n = 5), fibrosarcoma (n = 4), synovial sarcoma (n = 3), leiomyosarcoma (n = 2), pleomorphic liposarcoma (n = 1), and rhabdomyosarcoma (n = 1); those who experienced three or more AEs had significantly longer median PFS than those who experienced less than three AEs (P = 0.018).ConclusionNab-paclitaxel plus PD-1 inhibitor is a promising treatment regimen for advanced STS. Randomized controlled clinical trials are required to further demonstrate its efficacy and optimal application scenario.

The Herbal Formula JI017 Induces ER Stress via Nox4 in Breast Cancer Cells.

Chemotherapy is a powerful anti-tumor therapeutic strategy; however, resistance to treatment remains a serious concern. To overcome chemoresistance, combination therapy with anticancer drugs is a potential strategy. We developed a novel herbal extract, JI017, with lower toxicity and lesser side effects. JI017 induced programmed cell death and excessive unfolded protein response through the release of intracellular reactive oxygen species (ROS) and calcium in breast cancer cells. JI017 treatment increased the expression of endoplasmic reticulum (ER) stress markers, including p-PERK, p-eIF2α, ATF4, and CHOP, via the activation of both exosomal GRP78 and cell lysate GRP78. The ROS inhibitors diphenyleneiodonium and N-acetyl cysteine suppressed apoptosis and excessive ER stress by inhibiting Nox4 in JI017-treated breast cancer cells. Furthermore, in paclitaxel-resistant breast cancer cell lines, MCF-7R and MDA-MB-231R, a combination of JI017 and paclitaxel overcame paclitaxel resistance by blocking epithelial-mesenchymal transition (EMT) processes, such as the downregulation of E-cadherin expression and the upregulation of HIF-1α, vimentin, Snail, and Slug expression. These findings suggested that JI017 exerts a powerful anti-cancer effect in breast cancer and a combination therapy of JI017 and paclitaxel may be a potential cancer therapy for paclitaxel resistant breast cancer.

Paclitaxel anticancer activity is enhanced by the MEK 1/2 inhibitor PD98059 in vitro and by PD98059-loaded nanoparticles in BRAFV600E melanoma-bearing mice

Melanoma, the most malignant form of skin cancer, shows resistance to traditional anticancer drugs including paclitaxel (PTX). Furthermore, over 50% of melanoma cases express the BRAFV600E mutation which activates the MAPK pathway increasing cell proliferation and survival. In the current study, we investigated the capacity of the combination therapy of PTX and the MAPK inhibitor, PD98059, to enhance the cytotoxicity of PTX against melanoma and therefore improve treatment outcomes. Synergistic in vitro cytotoxicity was observed when soluble PTX and PD98059 were used to treat the A375 melanoma cell line as evidenced by a significant reduction in the cell viability and IC50 value for PTX. Then, in further studies, TPGS-emulsified PD98059-loaded PLGA nanoparticles (NPs) were prepared, characterized in vitro and assessed for therapeutic efficacy when used in combination with soluble PTX. The average particle size (180 nm d.), zeta potential (−34.8 mV), polydispersity index (0.081), encapsulation efficiency (20%), particle yield (90.8%), and drug loading (6.633 µg/mg) of the prepared NPs were evaluated. Also, cellular uptake and in vitro cytotoxicity studies were performed with these PD98059-loaded NPs and compared to soluble PD98059. The PD98059-loaded NPs were superior to soluble PD98059 in terms of both cellular uptake and in vitro cytotoxicity in A375 cells. In in vivo studies, using A375 challenged mice, we report improved survival in mice treated with soluble PTX and PD98059-loaded NPs. Our findings suggest the potential for using this combinatorial therapy in the management of patients with metastatic melanoma harboring the BRAF mutation as a means to improve survival outcomes.