Failure Of Chemotherapy Research Articles

Robotic Versus Open Placement of Hepatic Artery Infusion Pumps.

A growing number of centers offer hepatic artery infusion pump (HAIP) chemotherapy for advanced liver malignancies. While small series have demonstrated feasibility of robotic HAIP placement, comparison of outcomes with open placement is lacking. We compared outcomes after robotic versus open HAIP placement. We retrospectively reviewed HAIP placement without concurrent hepatectomy at Memorial Sloan Kettering Cancer Center from 1 January 2011 to 15 September 2022, and Duke Health from 1 November 2018 to 18 May 2023. Patients with prior liver surgery or who required catheterization of a non-standard vessel were excluded. Propensity score matching weights (PSMW) were calculated using age, sex, race, body mass index, American Society of Anesthesiologists class, neoadjuvant chemotherapy, colorectal procedure, and institution. Survey-weighted generalized linear models assessed the relationship between approach and outcomes. Of 2002 consecutive HAIP placements, 819 (645 open/174 robotic) met the inclusion criteria. A higher proportion of open procedures involved combined colorectal procedures; other patient characteristics were similar. Overall, 15% of patients experienced an HAIP-specific complication and 12% required re-intervention; 2.7% had HAIP failure ≤ 90 days. After PSMW, the robotic approach had a longer operative time (β=68min, 95% confidence interval [CI] 55-81, p<0.001) but shorter length of stay (β=- 1.8 days, 95% CI - 2.3 to 1.3, p<0.001). The robotic approach was associated with increased HAIP-specific complications (odds ratio [OR] 1.72, p=0.025) and re-intervention (OR 2.33, p<0.001), with no difference in time to initiation of HAIP chemotherapy or HAIP failure. Robotic HAIP placement was associated with increased postoperative complications and significantly shorter length of stay, with similar time to initiation of HAIP therapy. There was no difference in the rate of early HAIP failure versus the open approach. These results suggest robotic HAIP placement is feasible and effective.

Impact of HER2 Expression on the Prognosis of Muscle-Invasive Bladder Cancer Patients Treated with Bladder-Preservation Comprehensive Therapy

BackgroundHER2 expression has been confirmed to be associated with bladder cancer aggressiveness. Anti-HER2 RC48-ADC is approved in China for the treatment of patients with advanced urothelial carcinoma with failed chemotherapy who are HER2 positive (IHC 2 + or 3 +). The discovery of HER2 positivity in urothelial carcinoma and the development of anti-HER2 drugs have brought new hope for bladder preservation treatment in MIBC.ObjectiveTo investigate HER2 expression in MIBC patients and its correlations with clinical characteristics, to analyze the impact of HER2 expression on the prognosis of MIBC patients administered bladder-preservation comprehensive therapy, and to explore the efficacy and safety of RC48-ADC in MIBC patients administered bladder-preservation comprehensive therapy.MethodsWe retrospectively collected information on MIBC patients. All 217 patients underwent cTURBT, of whom 175 received GC chemotherapy, while the remaining 42, due to intolerance to GC chemotherapy and HER2 positivity (IHC 2 + or 3 +), received RC48-ADC treatment. Of the 175 patients administered cTURBT combined with GC chemotherapy, 92 and 83 were HER2-negative and HER2-positive, respectively. Recurrence-free survival (RFS) and overall survival (OS) in HER2-negative and HER2-positive patients were compared to analyze the correlation between HER2 expression and prognosis. RFS and OS in the 83 HER2-positive patients administered cTURBT combined with GC chemotherapy and the 42 HER2-positive patients administered cTURBT combined with RC48-ADC were compared to analyze the differences in prognosis between the two treatment methods. The adverse reactions of GC and RC48-ADC were also compared.ResultsAmong the 217 included patients, 125 (57.6%) were HER2 positive (IHC 2 + or 3 +). HER2 positivity was significantly associated with tumor size, multifocality, pathological grade, tumor stage, and pelvic lymph node metastasis (P < 0.05). Totally 175 patients underwent cTURBT combined with GC chemotherapy, including 92 HER2-negative and 83 HER2-positive cases. There were no significant differences in gender, age, smoking status, tumor location, and ECOG score between the two groups (P > 0.05), but the proportions of patients with tumors > 3 cm, multifocal tumors, T3 stage, high-grade tumors, and pelvic lymph node metastasis were higher in the HER2-positive group versus the HER2-negative group (P < 0.05). Tumor recurrence rate in the 83 HER2-positive patients was 67.5%, with a median RFS of 19.0 months (95% CI: 10.3–27.7). Totally 22 deaths occurred during the follow-up period, with a median OS of 56.0 months (95% CI: 45.7–66.3). In the 92 HER2-negative patients, the tumor recurrence rate was 56.5%, with a median RFS of 36.0 months (95% CI: 26.1–45.9); 4 deaths occurred during the follow-up period, with the median OS not reached. After cTURBT, of the 125 HER2-positive patients examined, 83 were included in the GC treatment group versus 42 in the RC48-ADC group. There were no differences in gender, age, smoking status, tumor location, tumor size, multifocality, clinical T stage, pathological grade, pelvic lymph node metastasis, and ECOG score between the two groups (P > 0.05). In the GC group, 56 recurrences (67.5%) were detected during the follow-up period, with a median RFS of 19.0 months (95% CI: 10.3–27.7); meanwhile, 22 deaths (52.4%) occurred, with a median OS of 56.0 months (95% CI: 45.7–66.3). In the RC48-ADC group, 15 recurrences (35.7%) were recorded during the follow-up period, with the median RFS not reached; there were 2 deaths (4.8%), with the median OS not reached. The incidence rates of any-grade and grade ≥ 3 adverse reactions were both lower in the RC48-ADC group than in the GC treatment group.ConclusionsThis study confirms that cTURBT combined with RC48-ADC treatment for HER2-positive MIBC is superior to combined GC treatment in terms of RFS and OS, representing an effective treatment regimen for bladder preservation in MIBC patients.

Development and validation of a high-performance liquid chromatography method with fluorescence detection for the quantification of the resistance protein P-gp in cancer cells.

A method using high-performance liquid chromatography coupled with fluorescence detection (HPLC-FLD) was developed and validated to quantify the innovative tool LightSpot®-FL-1, a selective permeability-glycoprotein (P-gp)-targeted fluorescent conjugate used to measure P-gp expression in cell samples. Quantifying P-gp is a major challenge in oncology as its overexpression in many cancer cells results in Multidrug Resistance (MDR) associated with chemotherapy failure. To develop the method reported herein, both sample preparation and analysis parameters were investigated. Optimal chromatographic conditions were achieved with 5µL injections at a 1mL/min flow rate on a reversed-phase Zorbax® Eclipse Plus 3.5µm C18 column (150×4.6mm) with isocratic acetonitrile/water (85/15, by volume) elution. Detection was performed with 505nm excitation and 510nm emission wavelengths. Validation studies were designed and performed according to the International Council for Harmonization (ICH) guidelines for bioanalytical method validation. The limit of quantification (LOQ) and limit of detection (LOD) were determined to be 0.5 and 0.2nmol/L, respectively. The linearity range was demonstrated between 10 and 500nmol/L, and the trueness and precision of the method were validated. Good stability was shown in three relevant analytical conditions. The greenness of the developed method was also demonstrated with the AGREE, AGREEprep and MoGAPI tools. Finally, the rapid, precise and sensitive validated analytical method was successfully applied to determine the difference in P-gp expression in three cancer cell lines: DU4475, CCRF-CEM and KG-1a.

BE-43547A2 exerts hypoxia-selective inhibition on human pancreatic cancer cells through targeting eEF1A1 and disrupting its association with FoxO1.

Hypoxia is a key feature of the tumor microenvironment that leads to the failure of many chemotherapies and induces more aggressive and resistant cancer phenotypes. Up to date, there are very few compounds and treatments that can target hypoxia. BE-43547A2 from Streptomyces sp. was one of the most hypoxia-selective compounds against PANC-1, MCF-7, and K562 cell lines. In this study, we investigated the molecular mechanism underlying the hypoxia selectivity of BE-43547A2 in human pancreatic cancer cells. We showed that BE-43547A2 displayed hypoxia-selective cytotoxicity in five pancreatic cancer cells (PANC-1, Capan-2, MIA PaCa-2, AsPC-1, and PaTu8988T) with IC50 values under hypoxia considerably lower than those under normoxia. We demonstrated that BE-43547A2 is directly bound to eEF1A1 protein in PaTu8988T cells under hypoxia. Furthermore, we revealed that hypoxia significantly elevated the expression levels of HIF1α, FoxO1, and eEF1A1 in the five pancreatic cancer cells; eEF1A1 interacted with FoxO1 in the cytoplasm, which was disrupted by BE-43547A2 followed by the nuclear translocation of FoxO1 and ultimate inhibition of JAK/STAT3 signaling pathway under hypoxia. This study reveals that BE-43547A2, targeting eEF1A1, disrupts its interaction with FoxO1 in human pancreatic cancer cells under hypoxia. This compound could serve as a potential hypoxia-selective therapy.

Treatment Options for Advanced Non-Small Cell Lung Cancer After Failure of Previous Immune Checkpoint Inhibitors and Chemotherapy: Meta-Analysis of Five Randomized Controlled Trials.

Immune checkpoint inhibitors (ICIs), either alone or in combination with platinum-based chemotherapy, are effective in the first-line treatment of metastatic, non-oncogene-addicted, non-small cell lung cancer (NSCLC). However, when NSCLC patients progress, the efficacy of available treatment options is limited. We undertook a meta-analysis that compared combination regimens with the current standard of care. Only randomized controlled trials (RCTs) were included (endpoint, overall survival [OS]). Our analysis used an artificial intelligence software program that reconstructs individual patient data from Kaplan-Meier curves. Hazard ratio (HR) with 95% confidence interval (CI) was the main parameter. Heterogeneity was based on Wald's test and likelihood ratio test. Five RCTs were included, whose experimental arms included five different combinations. In our analysis, these combination regimes showed no OS benefit compared to chemotherapy (HR = 1.066, 95%CI, 0.9311 to 1.221; p = 0.35). Among the five control arms, cross-trial heterogeneity was remarkably low (likelihood ratio test = 3.76 on 4 df, p = 0.40; Wald test = 3.83 on 4 df, p = 0.40. In conclusion, five new second-line combination treatments for patients with NSCLC were not found to determine any benefit in terms of OS in comparison with the current standard of care.

Core-Shell Nanoparticles with Sequential Drug Release Depleting Cholesterol for Reverse Tumor Multidrug Resistance.

Multidrug resistance (MDR) facilitates tumor recurrence and metastasis, which has become a main cause of chemotherapy failure in clinical. However, the current therapeutic effects against MDR remain unsatisfactory, mainly hampered by the rigid structure of drug-resistant cell membranes and the uncontrolled drug release. In this study, based on a sequential drug release strategy, we engineered a core-shell nanoparticle (DOX-M@CaP@ATV@HA) depleting cholesterol for reverse tumor MDR. DOX-M@CaP@ATV@HA could accurately target tumor cells due to the active targetability of hyaluronic acid (HA) toward CD44 receptors. The calcium phosphate (CaP) shell was cleaved in the lysosomal acidic environment so that the cholesterol-lowering drug atorvastatin (ATV) was rapidly released to diminish cholesterol and P-glycoprotein (P-gp) level on the membrane, thereby boosting tumor cell drug uptake. Next, doxorubicin (DOX) was gradually released from the hydrophobic core of the mPEG-DSPE micelle, inflicting irreversible DNA damage and triggering apoptosis. The nanosystem was proven both in vitro and in vivo to reverse MDR effectively and exhibited a remarkable therapeutic efficacy on drug-resistant tumors with high biosafety. In conclusion, DOX-M@CaP@ATV@HA effectively reverses MDR via cholesterol depletion, which provides an innovative strategy for tumor MDR treatment.

Second-Line Treatment Options for Patients with Metastatic Triple-Negative Breast Cancer: A Review of the Clinical Evidence.

Metastatic triple-negative breast cancer has a poor prognosis and poses significant therapeutic challenges. Until recently, limited therapeutic options have been available for patients with advanced disease after failure of first-line chemotherapy. The aim of this review is to assess the current evidence supporting second-line treatment options in patients with metastatic triple-negative breast cancer. Evidence was reviewed from controlled clinical trials in which eribulin, vinorelbine, capecitabine, gemcitabine, gemcitabine plus carboplatin, fam-trastuzumab-deruxtecan, sacituzumab govitecan, olaparib, and talazoparib were used in the second-line treatment for metastatic breast cancer, either as study drugs or as comparators. The benefit of treatment was evaluated using the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale. Based on the evidence review, sacituzumab govitecan was identified as the preferred second-line treatment option for patients with metastatic triple-negative breast cancer, supported by clinical evidence and consensus across international clinical guidelines. Olaparib and talazoparib are of use in patients with human epidermal growth factor receptor 2-negative metastatic breast cancer and germline BRCA1/2 mutations. Exploratory data for fam-trastuzumab-deruxtecan suggest a survival benefit in human epidermal growth factor receptor 2-low, hormone-receptor-negative patients, but further solid evidence is required. Other chemotherapies with lower European Society for Medical Oncology-Magnitude of Clinical Benefit Scale scores may continue to be useful in highly selected patients.

RNF138 contributes to cisplatin resistance in nasopharyngeal carcinoma cells

Resistance to chemotherapy is a significant concern in the treatment of nasopharyngeal carcinoma (NPC), and occurs due to various mechanisms. This study is aimed to evaluate the effects of RING finger protein 138 (RNF138) in the development of cisplatin resistance to NPC. After gene overexpression and silencing, the expression levels of RNF138 were evaluated. The impacts of RNF138 on the proliferation and apoptosis rate of NPC cells were then assessed. γ-H2AX-mediated DNA damage was determined via immunofluorescence assay. Moreover, a tumor xenograft mouse model was developed to investigate the role of RNF138 on NPC progression in vivo. Additionally, transcriptome analysis was performed in 5–8 F cells transfection with OE-RNF1138 or OE-NC.Cisplatin significantly inhibited the proliferation, and promoted apoptosis and DNA damage in NPC cells; however, overexpression of RNF138 reversed the aforementioned regulatory role of cisplatin on NPC cells. Knockdown of RNF138 resulted in contrasting phenotypic outcomes. Additionally, in nude mice, RNF138 overexpression attenuated the suppressive effects of cisplatin on the growth of xenograft tumor, while RNF138 silencing further enhanced the inhibiting role of cisplatin. We further indicated that in 5–8 F cells following RNF138 overexpression, some pathways such as PI3K-Akt signaling pathway, human papillomavirus infection and ErbB signaling pathway that have been reported to be associated with NPC progression and cisplatin resistance were significantly enriched. These findings indicate that the modulation of RNF138 could potentially address the issue of chemotherapy failure by overcoming cisplatin resistance in NPC cells, making it a promising candidate for targeted drug therapy.

Curcumin-Loaded Maltodextrin-Based Proniosomes Potentially Effective against Gemcitabine-Resistant Cholangiocarcinoma.

Cholangiocarcinoma (CCA) or bile-duct cancer is most prevalent in Southeast Asian counties including Thailand. Patients present at an advanced stage when the cancer is often drug resistant, leading to chemotherapy failure. Curcumin has therapeutic potential with various anticancer properties. However, its effectiveness is limited by its low bioavailability, poor solubility, and instability. This study aimed to synthesize, characterize and evaluate the efficacy of curcumin-loaded maltodextrin-based proniosomes (CMPNs) to overcome the limitations of curcumin for treating gemcitabine-resistant CCA cells (KKU-213BGemR) in vitro and in vivo. Various proniosome formulations were developed and tested for their efficacy against KKU-213BGemR cells using cytotoxicity, clonogenic, migration, and invasion assays. The potential mechanism involving in cell cycle arrest, apoptosis, expression of C/EBP homologous protein (CHOP), a pro-apoptotic transcription factor, and other apoptotic markers were investigated. The results showed that nanoscale CMPNs exhibited a good curcumin loading capacity and an entrapment efficiency of over 97%, as well as good stability and permeability through porcine esophageal mucosa. CMPNs inhibited proliferation, colony formation, migration/invasion and induced apoptosis in KKU-213BGemR cells. Western blot analysis revealed CMPNs significantly increased CHOP, the cleavage products of poly(ADP-ribose) polymerase-1 (PARP-1), apoptosis-inducing factor, and caspase-3 expression in KKU-213BGemR cells. A xenograft model revealed that 62.5 mg/kg BW CMPNs significantly suppressed proliferating cell nuclear antigen and increased CHOP-mediated apoptosis, leading to significantly reduced tumor volume. In conclusion, CMPNs effectively overcome limitations of curcumin and offer an effective strategy against gemcitabine-resistant CCA via CHOP-mediated pathways. These proniosomes are promising as an alternative treatment approach for CCA.

Microsomal glutathione transferase 1 confers cisplatin resistance of non-small cell lung cancer via interaction with arachidonate lipoxygenase 5 to repress ferroptosis.

Cisplatin (DDP) resistance remains a primary cause of chemotherapy failure and recurrence of non-small cell lung cancer (NSCLC). Abnormal high microsomal glutathione transferase 1 (MGST1) expression has been found in DDP-resistant NSCLC cells. This study aimed to explore the function and mechanism of MGST1 in DDP resistance of NSCLC cells. The expression levels of target molecules were assessed by quantitative real-time polymerase chain reaction (RT-qPCR) and western blotting. Cell proliferation was evaluated by cell counting kit-8 (CCK-8) and colony formation assays. Ferroptosis was determined by malondialdehyde (MDA), glutathione (GSH), Fe2+, and reactive oxygen species (ROS) levels. The interaction between proteins was confirmed by Co-immunoprecipitation (Co-IP). The effect of MGST1 on DDP resistance was evaluated using the tumor xenograft assay in vivo. Immunohistochemical staining was performed to measure Ki-67 and p-H2A.X expression in tumor tissues. MGST1 expression was higher, while arachidonate lipoxygenase 5 (ALOX5) expression was lower in DDP-resistant NSCLC patients and cells. MGST1 ablation sensitized NSCLC cells to DDP therapy through inducing ferroptosis. MGST1 protein directly interacted with ALOX5 protein to restrain ALOX5-triggered ferroptosis. Ferroptosis inhibitor or sh-ALOX5 reversed the promotive effect of MGST1 silencing on the DDP sensitivity of NSCLC cells. Finally, MGST1 depletion sensitized NSCLC cells to DDP therapy in nude mice in vivo. MGST1 high expression contributed to DDP resistance of NSCLC cells by inhibiting ALOX5-induced ferroptosis. Our results provide a potential therapeutic target for overcoming DDP resistance in NSCLC patients.

A Novel Competing Endogenous RNA Network Reveals Potential Mechanisms and Biomarkers of Chemoresistance in Lung Adenocarcinoma.

Platinum resistance is a common cause of chemotherapy failure in lung adenocarcinoma (LUAD). Competing endogenous RNAs (ceRNAs), which function by competitively binding to miRNAs, can influence drug response. However, the regulatory mechanisms of ceRNAs underlying chemoresistance in LUAD remain largely unknown. Here, we proposed an integrated pipeline combining limma algorithm, miRNA binding prediction algorithm, expression correlation model and experimental support to identify functional lncRNA-miRNA-mRNA competing triplets associated with resistance, which showed variable competing patterns between resistant and sensitive cells. We found that a minority of altered ceRNAs overlapped in multiple types of cisplatin-resistant LUAD cell lines and were involved in biological processes known to mediate cancer drug response. We identified them as core resistance factors, forming a novel lncRNA-mediated resistance-related ceRNA network, which indicated a potential mechanism. Single-cell analysis revealed that these resistance-related ceRNAs regulated the functional states of LUAD cells, and survival analysis showed that they contributed to the prognosis of LUAD patients. The lncRNA regulators H19 and MIR193BHG were found to correlate with cisplatin activity in LUAD cell lines, and dysregulation of their expression triggered disorders of cisplatin response-related functions through multiple ceRNA regulatory axes in this network, suggesting them as potential resistance biomarkers and therapeutic targets. In summary, the integrated pipeline and the resulting data serve as a valuable resource for understanding the ceRNA mechanisms of chemoresistance and improving chemotherapy response.

Prognostic importance of direct assignment of parent-of-origin via long-read genome and epigenome sequencing in retinoblastoma.

Current clinical sequencing methods cannot effectively detect DNA methylation and allele-specific variation to provide parent-of-origin information from the proband alone. Parent-of-origin effects can lead to differential disease and the inability to assign this in de novo cases limits prognostication in the majority of affected individuals with retinoblastoma, a hereditary cancer with suspected parent-of-origin effects. To directly assign parent-of-origin in retinoblastoma patients, genomic DNA was extracted from blood samples for sequencing using a programmable, targeted single-molecule long-read DNA genomic and epigenomic approach. This allowed germline variant calling and simultaneous haplotype-resolved CpG methylation in subjects with familial (n=7) and de novo (n=9) retinoblastoma. Targeted long-read sequencing allowed phasing genomic variation with a differentially methylated region in intron 2 of the RB1 gene to confirm parent-of-origin in known familial samples. Leveraging this approach allowed us to directly assign parent-of-origin rapidly in simple and complex de novo cases from the proband alone. The ability to assign parent-of-origin in all cases of retinoblastoma showed that harboring disease-causing variants on the paternally inherited allele, whether arising familial or de novo, is associated with more advanced cancer staging at presentation and significantly greater risk of chemotherapy failure (P=0.002). This study demonstrates the diagnostic potential of multi-omic long-read profiling to unveil the parent-of-origin effect in hereditary cancer. The approach in this work will be instrumental in assigning parent-of-origin to other genetic diseases using local and distant imprinting signals in the genome. National Eye Institute, NIH (K08EY033789); Gerber Foundation; Research to Prevent Blindness.

Molecular docking and ADMET profiling of Carbazole-rhodanine hybrid as anticancer agent

Drug resistance and lack of specificity of currently available chemotherapeutics for cancer cells contribute to the failure of cancer chemotherapy. This highlights the pressing need to develop novel anticancer agents. This research aims to investigate the inhibiting potential of Carbazole and rhodanine derivatives against Human papillomaviruses (HPVs) and Breakpoint Cluster Region (BCR), with Abelson murine leukemia (ABL) tyrosine kinase to manage human cervical cancer and human chronic myeloid leukemia (CML), respectively. Some carbazole-rhodanine hybrids were evaluated in silico against human cervical cancer (Hela) and human CML (K562) cells. In this study, Molecular docking was used to determine binding affinity, bonding, and nonbonding interaction between the studied compounds and the target. Additionally, in-silico ADMET (adsorption, distribution, metabolism, excretion, and toxicity) screening was performed to explore the bioavailability, pharmacokinetic properties, and toxicity of the carbazole-rhodanine hybrids. The structure of the compounds was also discussed relative to their bioactivity. The molecular docking revealed that the test compounds except D, E, and L demonstrated better binding affinity, hence better inhibition efficiency towards Hela and K562 cell lines than the reference drug (etoposide). Compound G with a cyano substituent showed the highest binding affinity with the two receptors used, with a binding energy of -7.9 kcal mol-1 against hela (6HKS) and -10.0 against K562 (5HU9). This was in accordance with the experimental result. The SAR illustrated that a strong electron-withdrawing substituent attached to the para-position of the phenyl ring increased the activity. The ADMET profiling showed that compounds E, G, and J had superior drug-likeness, pharmacokinetic, and toxicity properties. Based on the results, compound G may be a good candidate to be developed further into a therapeutic agent to treat chronic myeloid leukemia and cervical cancer.

Triptolide exhibits dual anti-tumor effects through inhibiting autophagy and extracellular matrix activation in pancreatic cancer.

The tumor microenvironment in pancreatic cancer, characterized by abundant desmoplastic stroma, has been implicated in the failure of chemotherapy. Therefore, developing therapeutic strategies targeting tumor and stromal cells is essential. Triptolide, a natural compound derived from the plant Tripterygium wilfordii, has shown antitumor activity in various cancers, including pancreatic cancer. However, its effects on pancreatic cancer cells and the microenvironment remain unclear. This study aimed to explore the effect of triptolide on tumor cells and the tumor microenvironment in pancreatic cancer. Cell Counting Kit-8, colony formation, apoptosis, and cell cycle assays were performed to determine the effect of triptolide on tumor cells. Additionally, co-culture assays were performed to explore the effects of the compound on cancer-associated fibroblasts (CAFs) in vitro. Orthotopic xenograft and subcutaneous tumor models were used to explore the antitumor and antistromal activation effects of triptolide in vivo. RNA sequencing was performed to identify the pathways involved in these processes in pancreatic cancer cells. Triptolide inhibited the proliferation of pancreatic cancer cells and attenuated stromal activation in vitro and in vivo. Furthermore, it suppressed autophagy and induced apoptosis in pancreatic cancer cells by inhibiting the secretion of CXCL1. Extracellular matrix formation in CAFs was disrupted by suppressing the paracrine secretion of TGF-β from tumor cells. These findings indicate that triptolide plays a dual antitumor role against tumor cells and CAFs, thus providing new insights into treating pancreatic cancer in the future.

A French multicenter real-life study on the biological and clinical parameters associated with response to immune checkpoint inhibitors (ICIs) in second-line treatment of advanced urothelial carcinoma: Impact of antibiotics administration at the time of ICIs initiation.

BackgroundAfter failure of first-line chemotherapy, standard of care for advanced urothelial cancer (aUC) is immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 pathway. Several prognostic models (Bajorin and Bellmunt scores) have been evaluated, but only in the context of chemotherapy. ObjectiveTo study whether the variables in these scores and new emerging clinical and biological criteria have an impact on the probability of objective response in aUC treated with ICIs in 2nd-line setting and beyond. Materials and methodsBetween October 2016 and March 2023, we included 168 patients treated with ICIs in 2nd-line setting or more in two French centers. Variables of interest were selected after a literature review and collected retrospectively. Analyses used log-rank test and multivariate models (binary logistic and Cox regressions). Results and limitationsMedian age at diagnosis was 68 years. Patients presented with bladder tumors in 73.8% and upper urinary tract tumors in 26.2%. 63.7% of patients had received only one line of chemotherapy before ICIs. Median follow-up after starting ICIs was 8.9 months.The variables statistically associated with objective response were:− The presence of locally advanced or lymph node-only disease compared with visceral involvement (adjusted Odds Ratio 0.19, 95% confidence interval [0.06 – 0.55], p = 0,002) and bone-only involvement (aOR 0.22 [0.08 – 0.64], p = 0.005)− The absence of antibiotic therapy the month before/after ICIs initiation (aOR 0.31 [0.12 - 0.84], p = 0.021).Limitations included retrospective design and small number of patients included. ConclusionThis real-life study from two French centers found a higher likelihood of objective response:In the absence of antibiotic therapy at ICIs initiation.In locally advanced or lymph node-only disease, in contrast to visceral or bone-only disease.Our results suggest that negative impact of antibiotic therapy on the response to ICIs needs to be further investigated to optimize the management of these patients. Micro AbstractIn this study, we investigated the effect of clinical and biological criteria on response to immunotherapy in advanced urothelial cancer. We found that patients who received antibiotics had a lower probability of achieving a response to immunotherapy, while those with locally advanced or lymph node-only disease appeared to have better chance of response to immunotherapy than those with bone or visceral involvement.

Innovative Nanomaterials for Targeting Hypoxia to Improve Treatment for Triple-negative Breast Cancer.

Triple-negative breast cancer (TNBC) is an aggressive breast cancer with a high rate of metastases, a short overall survival time, and a poor response to targeted therapy. Improving tumor hypoxia by lowering the oxygen consumption rate of breast tumor cells is a powerful strategy. A viable way to address this issue is to improve therapeutic efficacy by improving the effectiveness of radiation and overcoming drug resistance in TNBC treatment by controlling hypoxia in the tumor microenvironment. The failure of radiation and chemotherapy in TNBC is frequently caused by hypoxia. In TNBC therapy, novel nanomaterials are used for oxygen delivery or generation to affect the tumor microenvironment to improve the effects of ionizing radiation using nanoplatforms. One of the growing fields is novel nano-based drug delivery devices for hypoxic regions and hypoxia- inducible factor-1 (HIF1) targeted therapeutics. Biocompatible nanoparticles may be used in the treatment of TNBC patients in the clinic. Because of the rising market and competition, intellectual property rights (IPR), patents, and tactics may be critically considered. To better comprehend the current state of IPR and patents in cancer nanotechnology, this overview examines recent advances and sophisticated protection measures in this area.

Understanding Bacterial Roles in Cancer Chemo-resistance: A Signaling Pathway Mapping Study

Introduction: Chemoresistance is one of the leading causes of chemotherapy failure among cancer patients. Out of several hypotheses proposed for chemoresistance, bacteria-mediated chemoresistance to cancer drugs has not been well established. Thus, the aim of this review is to map the pathways by which bacteria exhibit chemoresistance in specific cancers. Material and Methods: Relevant articles on bacteria-mediated chemoresistance in cancer were retrieved by conducting a systematic search across PubMed, Scopus and Web of Science databases. The search was limited to English original articles published until 15th December 2023. Results: A total of nine articles were included to map the pathways involved in chemoresistance. Numerous pathways have been connected to various forms of cancer, such as autophagy pathway in colorectal and esophageal cancers by Fusobacterium nucleatum causing oxaliplatin and 5-FU resistance; DNA damage response pathway also by Fusobacterium nucleatum promoting CDDP resistance in esophageal cancer; Porphyromonas gingivalis led to oral and esophageal cancer resistance to paclitaxel via JAK/STAT pathway. NF-κB pathway involved in gastric cancer in the presence of Helicobacter pylori towards cisplatin, and also 5-FU resistance via the apoptotic pathway. Cellular metabolism modulation by Lactobacillus iners was also implicated in cervical cancer chemoresistance. Conclusion: We conclude that bacteria can mediate chemoresistance not merely to antibiotics but also to anticancer drugs. Thus, a detailed understanding of the pathways associated with chemoresistance mediated via bacteria might help in targeting these pathways or antibiotics to prevent bacterial growth could help overcome resistance.

Targeting breast cancer resistance protein (BCRP/ABCG2) in cancer.

Breast cancer is one of the most common cancers among women. Nowadays postoperative adjuvant chemotherapy is the mainstay for clinical treatment of breast cancer. However, the emergence of multidrug resistance (MDR) in breast cancer has become a main reason for the failure of clinical chemotherapy. Multiple studies have demonstrated that the formation of MDR in breast cancer is combined with ATP-binding transporters, which are the proteins that can lead to the drug resistance by pumping out chemotherapeutic drugs to reduce their intracellular accumulation. This kind of protein mainly includes P-glycoprotein (Pgp, ABCB1, MDR1), multidrug resistance-associated protein (MRP-1, ABCC1) and breast cancer resistance protein (BCRP, ABCG2). The former two transporters have been investigated deeply and widely, while the molecular mechanism of BCRP regulation of breast cancer drug resistance has relatively not much been explored in the area of breast cancer. How to design a novel, effective and non-toxic BCRP inhibitor to reverse the MDR of breast cancer, and boost the success rate of chemotherapy is a serious challenge at present. A detailed overview of the molecular role of BCRP-mediated breast cancer MDR and its inhibitors reported in recent years is provided in this article. The expectation is to provide ideas for clinically addressing MDR in breast cancer, and further guide the direction for the development of new anti-breast cancer drugs and reversal of breast cancer MDR drugs.

Prolonged clinical response is possible with regorafenib in refractory osteosarcoma: A case report

&lt;b&gt;Background:&lt;/b&gt; Treatment options for metastatic unresectable osteosarcoma are limited, and there is no standard approach after the failure of first-line chemotherapy. Conventional chemotherapy in the second and subsequent lines typically yield a median progression-free survival (PFS) of less than 4 months, with objective response rates ranging from 3 to 29%. The activity of anti-vascular endothelial growth factor receptor multi-tyrosine kinase inhibitors (TKIs) in bone sarcomas has been demonstrated. We present a case of metastatic osteosarcoma exhibiting a durable response to regorafenib treatment.&lt;br /&gt; &lt;b&gt;Case: &lt;/b&gt;We discuss a 30-year-old male with metastatic osteosarcoma who had extensive bone and lung metastases and was ineligible for metastasectomy. The patient had received all active chemotherapy regimens in the early and metastatic stages except ifosfamide. Next generation sequencing analysis of resected tumor tissue revealed a possibly pathogenic missense mutation (P.G472E) in NOTCH1 gene. Due to the presence of heart failure with a reduced ejection fraction, chemotherapy was not considered, and regorafenib was initiated. After four cycles of regorafenib, a partial metabolic response was achieved. The patient was followed up without progression under regorafenib for 15 months, without requiring dose reduction. Unfortunately, the treatment had to be interrupted for an extended period due to challenges with recurrent tumor infection and the necessity for repeated surgeries. Following successful wound site control, we restarted full-dose regorafenib and achieved a metabolic partial response again.&lt;br /&gt; &lt;b&gt;Conclusion: &lt;/b&gt;To our knowledge, this case represents the longest achieved PFS with regorafenib in metastatic osteosarcoma. TKIs can provide a durable clinical response in metastatic osteosarcoma patients. Clinical and molecular biomarkers are required to determine which patients are most likely to benefit from these treatments.

IRE1α inhibitor reduces cisplatin resistance in ovarian cancer by modulating IRE1α/XBP1 pathway.

Ovarian cancer, a leading cause of gynecological cancer deaths globally, poses significant treatment challenges. Cisplatin (CDDP) is the first treatment choice for ovarian cancer and it is initially effective. However, 80% of ovarian cancer patients eventually relapse and develop resistance, resulting in chemotherapy failure. Therefore, finding new treatment combinations to overcome ovarian cancer resistance can provide a new tactic to improve the ovarian cancer patients' survival rate. We first identified activation of the Unfolded Protein Response (UPR) in CDDP-resistant ovarian cancer cells, implicating the IRE1α/XBP1 pathway in promoting resistance. Our findings demonstrate that inhibiting IRE1α signaling can re-sensitizes resistant cells to CDDP in vivo and in vitro, suggesting that IRE1α inhibitor used in conjunction with CDDP presumably could merge as a novel therapeutic strategy. Here, our research highlights the critical role of IRE1α signaling in mediating CDDP resistance, and paves the way for improved treatment options through combinatorial therapy.