Tumor Treatment Efficacy Research Articles

Effects of nutritional status on short-term prognosis after minimally invasive pancreaticoduodenectom

Minimally invasive pancreaticoduodenectomy (MIPD) has been routinely performed in major centers, and its feasibility and efficacy in tumor treatment have been highly recognized. Malnutrition has been associated with higher rates of morbidity, and increased mortality in surgical patients. The effect of the nutritional status on MIPD outcomes still remains unclear and controversial. The clinical data of 207 consecutive patients who had MIPD between June 2017 and December 2022 were retrospectively analyzed. A multidimensional nutrition assessment was performed before surgery. Multivariable analysis and propensity score matching (PSM) was performed to identify the association of preoperative nutritional status on postoperative short-term prognosis(Morbidity–Mortality, Clavien-Dindo classification ≥ IIIa, postoperative pancreatic fistulas and biliary fistula). In the multivariable analysis, sarcopenia (OR 9.74, 95% CI 3.34–43.03) was associated with postoperative morbidity and sarcopenia (OR 6.74, 95% CI 2.24–30.24) was associated with major complications. In the cohort after PSM, sarcopenia remained independently associated with morbidity (OR 12.44, 95% CI 3.72- 59.16) and major complications (OR 8.14, 95% CI 2.13- 43.83). Sarcopenia before MIPD has an impact on postoperative outcomes. Nutritional status assessment, especially sarcopenia, should be part of the routine preoperative procedures to provide early and appropriate nutritional support for MIPD patients.

Enhancing localized chemotherapy with anti-angiogenesis and nanomedicine synergy for improved tumor penetration in well-vascularized tumors

Intratumoral delivery and localized chemotherapy have demonstrated promise in tumor treatment; however, the rapid drainage of therapeutic agents from well-vascularized tumors limits their ability to achieve maximum therapeutic efficacy. Therefore, innovative approaches are needed to enhance treatment efficacy in such tumors. This study utilizes a mathematical modeling platform to assess the efficacy of combination therapy using anti-angiogenic drugs and drug-loaded nanoparticles. Anti-angiogenic drugs are included to reduce blood microvascular density and facilitate drug retention in the extracellular space. In addition, incorporating negatively charged nanoparticles aims to enhance diffusion and distribution of therapeutic agents within well-vascularized tumors. The findings indicate that, in the case of direct injection of free drugs, using compounds with lower drainage rates and higher diffusion coefficients is beneficial for achieving broader diffusion. Otherwise, drugs tend to accumulate primarily around the injection site. For instance, the drug doxorubicin, known for its rapid drainage, requires the prior direct injection of an anti-angiogenic drug with a high diffusion rate to reduce microvascular density and facilitate broader distribution, enhancing penetration depth by 200%. Moreover, the results demonstrate that negatively charged nanoparticles effectively disperse throughout the tissue due to their high diffusion coefficient. In addition, a faster drug release rate from nanoparticles further enhance treatment efficacy, achieving the necessary concentration for complete eradication of tumor compared to slower drug release rates. This study demonstrates the potential of utilizing negatively charged nanoparticles loaded with chemotherapy drugs exhibiting high release rates for localized chemotherapy through intratumoral injection in well-vascularized tumors.

Abstract B033: Towards magnetic resonance microscopy for liquid biopsy in cancer therapy monitoring

Abstract The advancement of liquid biopsy techniques promises to revolutionize cancer diagnostics and therapy monitoring, by offering a minimally invasive approach to track tumor progression and treatment efficacy. One central issue preventing advancements are innovations in sensor technology, necessary to enable the detection of molecular and cellular biomarkers with sufficient precision. Over the past decade, atomic-scale quantum sensors have emerged as powerful detectors, offering the ability to perform precise measurements of temperature, pressure, and magnetic fields on the single cell scale. These sensors, based on the interaction of spin qubits with their environment, have the unique capability to amplify and exploit environmental interactions for highly accurate detection, making them ideal for complex biological applications. In this context, we present an advanced quantum sensing platform specifically tailored for liquid biopsy applications in cancer therapy monitoring. This platform integrates the capabilities of optical microscopy with magnetic resonance imaging (MRI) techniques, utilizing nitrogen-vacancy (NV) centers in diamond as quantum sensors by converting magnetic resonance signals into optical signals, which are subsequently captured by a high-speed camera. Our platform offers a novel approach, promising quantitative analysis of single cancer cells from liquid samples with unprecedented accuracy. Unlike traditional MRI, our method captures signals over a wide field of view directly in real space. Each camera pixel records a magnetic resonance spectrum, providing detailed multicomponent information about the sample, such as molecular concentration, diffusion, and relaxation behavior, which are critical for understanding the tumor’s microenvironment. Our quantum sensing technology holds significant potential for enhancing the sensitivity of liquid biopsies. By capturing detailed molecular information from blood or other body fluids, it will enable in-depth analysis of Circulating Tumor Cells (CTCs), circulating tumor DNA (ctDNA), exosomes, and other biomarkers. Citation Format: Karl D. Briegel, Robin D. Allert, Dominik B. Bucher, Julia D. Draeger, Nick R v. Grafenstein, Linyan Nie. Towards magnetic resonance microscopy for liquid biopsy in cancer therapy monitoring [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr B033.

KRAS mutations promote the intratumoral colonization of enterotoxigenic bacteroides fragilis in colorectal cancer through the regulation of the miRNA3655/SURF6/IRF7/IFNβ axis

ABSTRACT KRAS mutations are associated with poor prognosis in colorectal cancer (CRC). Although the association between the gut microbiota and CRC has been extensively documented, it is unclear whether KRAS mutations can regulate the gut microbiota. Metagenomics has identified changes in the diversity of the gut microbiota in CRC due to KRAS mutations. Specifically, KRAS mutations positively correlate with the abundance of the bacteroides. Understanding how to regulate the classic carcinogenic bacterium within the bacteroides, such as enterotoxigenic bacteroides fragilis (ETBF), to enhance treatment efficacy of tumors is a key focus of research. Mechanistically, we found that the reduction of miR3655 is indispensable for KRAS mutation-promoted proliferation of CRC and the abundance of ETBF. miR3655 targets SURF6 to inhibit its transcription. Further transcriptomic sequencing revealed that SURF6 promotes intratumoral colonization of ETBF in CRC by inhibiting the nuclear translocation and transcription levels of the IRF7, affecting the activation of the IFNβ promoter. Regulating miR3655 and SURF6 can promote IFNβ secretion in CRC, directly killing ETBF. These data indicate that KRAS mutations affect the intratumoral colonization of ETBF in CRC through the miR3655/SURF6/IRF7/IFNβ axis. This provides new potential strategies for treating CRC associated with KRAS mutations or high levels of ETBF.

CD38 as theranostic target in oncology.

CD38 is a multifunctional transmembrane glycoprotein found in multiple tissues and overexpressed in many cancer cells, notably in hematological malignancies such as leukemia and multiple myeloma (MM). Therefore, targeting CD38 remains an attractive strategy for cancer treatment in hematological malignancies as well as in solid tumors. It plays a critical role in the progression of these diseases through its ADP-ribosyl cyclase and cADPR-hydrolase activities. Its importance has led to the development of various anti-CD38 monoclonal antibodies (mAbs), including daratumumab and isatuximab, approved for MM treatment. These mAbs exert their anti-tumor effects through Fc-dependent immune mechanisms and immunomodulation, enhancing T-cell and NK-cell-mediated responses. However, resistance mechanisms arise during the treatment with daratumumab, creating the necessity for new therapies. This review explains current knowledge about the role of CD38 as a target in oncology and aims to delineate the use of single domain antibodies (sdAbs) as innovative theranostic tools in nuclear medicine. For diagnostic purposes, PET radionuclides like 68Ga, 64Cu, and SPECT radionuclides like 99mTc and 111In, are commonly used. Significant progress has been made in anti-CD38 radioligand therapy (RLT), with anti-CD38 antibodies providing insights into tumor biology and treatment efficacy. In terms of therapy, RLT is a promising approach that offers precise targeting of malignant cells while minimizing exposure to healthy tissue. This involves the use of radionuclides emitting α particles, like 225Ac, 212Pb or 211At, and β--particles like 90Y, 131I, or 177Lu, to exert cytotoxic effects. Derived from Camelidae heavy chain antibodies, sdAbs offer advantages over conventional mAbs such as small size, high stability, specificity, and ability to recognize hidden epitopes. CD38-specific sdAbs, such as sdAb 2F8, characterized by our laboratory, showing excellent tumor targeting and their engineered constructs, such as biparatopic antibodies and chimeric antibodies, represent a new generation of theranostic agents for diagnosis and treatment CD38-expressing malignancies.

A Cardiac-Targeting and Anchoring Bimetallic Cluster Nanozyme Alleviates Chemotherapy-Induced Cardiac Ferroptosis and PANoptosis.

Doxorubicin (DOX), a potent antineoplastic agent, is commonly associated with cardiotoxicity, necessitating the development of strategies to reduce its adverse effects on cardiac function. Previous research has demonstrated a strong correlation between DOX-induced cardiotoxicity and the activation of oxidative stress pathways. This work introduces a novel antioxidant therapeutic approach, utilizing libraries of tannic acid and N-acetyl-L-cysteine-protected bimetallic cluster nanozymes. Through extensive screening for antioxidative enzyme-like activity, an optimal bimetallic nanozyme (AuRu) is identified that possess remarkable antioxidant characteristics, mimicking catalase-like enzymes. Theoretical calculations reveal the surface interactions of the prepared nanozymes that simulate the hydrogen peroxide decomposition process, showing that these bimetallic nanozymes readily undergo OH⁻ adsorption and O₂ desorption. To enhance cardiac targeting, the atrial natriuretic peptide is conjugated to the AuRu nanozyme. These cardiac-targeted bimetallic cluster nanozymes, with their anchoring capability, effectively reduce DOX-induced cardiomyocyte ferroptosis and PANoptosis without compromising tumor treatment efficacy. Thus, the therapeutic approach demonstrates significant reductions in chemotherapy-induced cardiac cell death and improvements in cardiac function, accompanied by exceptional in vivo biocompatibility and stability. This study presents a promising avenue for preventing chemotherapy-induced cardiotoxicity, offering potential clinical benefits for cancer patients.

Biomimetic Modification of siRNA/Chemo Drug Nanoassemblies for Targeted Combination Therapy in Breast Cancer.

The development and progression of tumors are characterized by intricate biological processes. Monotherapy not only struggles to achieve effective treatment but also tends to precipitate a series of issues, including multidrug resistance and limited antitumor effect. Consequently, it is imperative to adopt a synergistic multitherapy approach to enhance the efficacy of tumor treatment. The integration of chemotherapy drug with oligonucleotide drug for combinational treatment has shown significant promise in improving tumor therapeutic efficiency. However, the effective in vivo codelivery of oligonucleotide drugs and chemotherapy drugs faces substantial challenges such as poor stability of oligonucleotide drugs during the circulation time, limited tumor accumulation, and uncertain delivery ratios of different payloads. To overcome these obstacles, we have engineered cyclic Arg-Gly-Asp (cRGD)-modified red blood cell membrane (RBCm)-coated multidrug nanocomplexes, which were self-assembled from the Polo-like kinase 1 siRNA (siPlk1) and an irreversible tyrosine kinase inhibitor neratinib targeted to human epidermal growth factor receptor 2 (HER2) overexpressed in breast cancer. Through electrostatic and amphiphilic interactions between the positively charged neratinib and negatively charged siPlk1, we have successfully fabricated uniform multidrug nanoparticles. The cRGD-modified red blood cell membranes coated on the surface of the multidrug nanoparticles could enhance drug stability in circulation and tumor accumulation. This targeted combinational therapy significantly enhanced the antitumor efficiency in HER2-positive breast cancer in vitro and in vivo.

Near-infrared photoimmunotherapy in cancer treatment: a bibliometric and visual analysis.

Near-infrared photoimmunotherapy (NIR-PIT) is an emerging cancer treatment technology that combines the advantages of optical technology and immunotherapy to provide a highly effective, precise, and low side-effect treatment approach. The aim of this study is to visualize the scientific results and research trends of NIR-PIT based on bibliometric analysis methods. The Web of Science Core Collection (WoSCC) database was searched in August 2024 for relevant publications in the field of NIR-PIT. Data were analyzed using mainly CiteSpace and R software for bibliometric and visual analysis of the country/region, authors, journals, references and keywords of the publications in the field. A total of 245 publications were retrieved, including articles (n = 173, 70.61%) and reviews (n = 72, 29.39%). The annual and cumulative number of publications increased every year. The highest number of publications was from the United States (149, 60.82%), followed by Japan (70, 28.57%) and China (33, 13.47%). The research institution with the highest number of publications was National Institutes of Health (NIH)-USA (114, 46.53%). Kobayashi H (109) was involved in the highest number of publications, Mitsunaga M (211) was the most frequently cited in total. CANCERS (17) was the most frequently published journal, and NAT MED (220) was the most frequently co-cited journal. The top 10 keywords include near-infrared photoimmunotherapy (166), photodynamic therapy (61), monoclonal antibody (58), in vivo (50), cancer (46), expression (31), breast cancer (27), enhanced permeability (24), antibody (23), growth factor receptor (16). Cluster analysis based on the co-occurrence of keywords resulted in 13 clusters, which identified the current research hotspots and future trends of NIR-PIT in cancer treatment. This study systematically investigated the research hotspots and development trends of NIR-PIT in cancer treatment through bibliometric and visual analysis. As an emerging strategy, the research on the application of NIR-PIT in cancer treatment has significantly increased in recent years, mainly focusing on the targeting, immune activation mechanism, and treatment efficacy in solid tumors has received extensive attention. Future studies may focus on improving the efficacy and safety of NIR-PIT in cancer treatment, as well as developing novel photosensitizers and combination therapeutic regimens, and exploring the efficacy of its application in a wide range of solid tumors, which will provide an important reference and guidance for the application of NIR-PIT in clinical translation.

Mitochondria in tumor immune surveillance and tumor therapies targeting mitochondria.

Mitochondria play a central role in cellular energy production and metabolic regulation, and their function has been identified as a key factor influencing tumor immune responses. This review provides a comprehensive overview of the latest advancements in understanding the role of mitochondria in tumor immune surveillance, covering both innate and adaptive immune responses. Specifically, it outlines how mitochondria influence the function of the tumor immune system, underscoring their crucial role in modulating immune cell behavior to either promote or inhibit tumor development and progression. Additionally, this review highlights emerging drug interventions targeting mitochondria, including novel small molecules with significant potential in cancer therapy. Through an in-depth analysis, it explores how these innovative strategies could improve the efficacy and outlook of tumor treatment.

CXCL12+ tumor-associated endothelial cells promote immune resistance in hepatocellular carcinoma

The tumor microenvironment (TME) plays a crucial role in the limited efficacy of existing treatments for hepatocellular carcinoma (HCC), with tumor-associated endothelial cells (TECs) serving as fundamental TME components that substantially influence tumor progression and treatment efficacy. However, the precise roles and mechanisms of TECs in HCC remain inadequately understood. We employed a multi-omics profiling strategy to investigate the single-cell and spatiotemporal evolution of TECs within the microenvironment of HCC tumors showcasing varied responses to immunotherapy. Through an analysis of a clinical cohort of HCC patients, we explored the correlation between TEC subpopulations and immunotherapy outcomes. The influence of TEC subsets on the immune microenvironment was confirmed through comprehensive in vitro and in vivo studies. To further explore the mechanisms of distinct TEC subpopulations in microenvironmental modulation and their impact on immunotherapy, we utilized TEC subset-specific knockout mouse models as well as humanized mouse models. In this research, we identified a new subset of CXCL12+ TECs that exert a crucial role in immune suppression within the HCC TME. Functionally, CXCL12+ TECs impede the differentiation of CD8+ naïve T cells into CD8+ cytotoxic T cells by secreting CXCL12. Furthermore, they attract myeloid-derived suppressor cells (MDSCs). A bispecific antibody was developed to target both CXCL12 and PD1 specifically, showing significant promise in bolstering anti-tumor immune responses and advancing HCC therapy. CXCL12+ TECs are pivotal in mediating immunosuppression within HCC microenvironment and targeting CXCL12+ TECs presents a promising approach to augment the efficacy of immunotherapies in HCC patients. This investigation reveals a pivotal mechanism in the HCC TME, where CXCL12+ TECs emerge as crucial modulators of immune suppression. The discovery of CXCL12+ TECs as inhibitors of CD8+ naïve T cell activation and recruiters of MDSCs significantly advances our grasp of the dynamic between HCC and immune regulation. Moreover, the development and application of a bispecific antibody precisely targeting CXCL12 and PD1 has proven to enhance immune responses in a humanized mouse HCC model. This finding underscores a promising therapeutic direction for HCC, offering the potential to amplify the impact of current immunotherapies.

Therapeutic Effect of Boron Neutron Capture Therapy on Boronophenylalanine Administration via Cerebrospinal Fluid Circulation in Glioma Rat Models.

In recent years, various drug delivery systems circumventing the blood-brain barrier have emerged for treating brain tumors. This study aimed to improve the efficacy of brain tumor treatment in boron neutron capture therapy (BNCT) using cerebrospinal fluid (CSF) circulation to deliver boronophenylalanine (BPA) to targeted tumors. Previous experiments have demonstrated that boron accumulation in the brain cells of normal rats remains comparable to that after intravenous (IV) administration, despite BPA being administered via CSF at significantly lower doses (approximately 1/90 of IV doses). Based on these findings, BNCT was conducted on glioma model rats at the Kyoto University Research Reactor Institute (KUR), with BPA administered via CSF. This method involved implanting C6 cells into the brains of 8-week-old Wistar rats, followed by administering BPA and neutron irradiation after a 10-day period. In this study, the rats were divided into four groups: one receiving CSF administration, another receiving IV administration, and two control groups without BPA administration, with one subjected to neutron irradiation and the other not. In the CSF administration group, BPA was infused from the cisterna magna at 8 mg/kg/h for 2 h, while in the IV administration group, BPA was intravenously administered at 350 mg/kg via the tail vein over 1.5 h. Thermal neutron irradiation (5 MW) for 20 min, with an average fluence of 3.8 × 1012/cm2, was conducted at KUR's heavy water neutron irradiation facility. Subsequently, all of the rats were monitored under identical conditions for 7 days, with pre- and post-irradiation tumor size assessed through MRI and pathological examination. The results indicate a remarkable therapeutic efficacy in both BPA-administered groups (CSF and IV). Notably, the rats treated with CSF administration exhibited diminished BPA accumulation in normal tissue compared to those treated with IV administration, alongside maintaining excellent overall health. Thus, CSF-based BPA administration holds promise as a novel drug delivery mechanism in BNCT.

Miniaturized protein profiling permits targeted signaling pathway analysis in individual circulating tumor cells to improve personalized treatment

BackgroundTraditional genomic profiling and mutation analysis of single cells like Circulating Tumor Cells (CTCs) fails to capture post-translational and functional alterations of proteins, often leading to limited treatment efficacy. To overcome this gap, we developed a miniaturized ‘protein analysis on the single cell level’ workflow—baptized ZeptoCTC. It integrates established technologies for single-cell isolation with sensitive Reverse Phase Protein Array (RPPA) analysis, thus enabling the comprehensive assessment of multiple protein expression and activation in individual CTCs.MethodsThe ZeptoCTC workflow involves several critical steps. Firstly, individual cells are labeled and isolated. This is followed by cell lysis and the printing of true single cell lysate preparations onto a ZeptoChip using a modified micromanipulator, CellCelector™. The printed lysates then undergo fluorescence immunoassay RPPA protein detection using a ZeptoReader. Finally, signal quantification is carried out with Image J software, ensuring precise measurement of multiple protein levels.ResultsThe efficacy of ZeptoCTC was demonstrated through various applications. Initially, it was used for measuring EpCAM protein expression, a standard marker for CTC detection, revealing higher levels in single MCF-7 over MDA-MB-231 tumor cells. Furthermore, in Capivasertib (Akt-inhibitor)-treated MCF-7 single cells, ZeptoCTC detected a 2-fold increase in the pAkt/Akt ratio compared to control cells, and confirmed co-performed bulk-cell western blot analysis results. Notably, when applied to individual CTCs from metastasized breast cancer patients, ZeptoCTC revealed significant differences in protein activation levels, particularly in measured pAkt and pErk levels, compared to patient-matched WBCs. Moreover, it successfully differentiated between CTCs from patients with different Akt1 genotypes, highlighting its potential to determine the activation status of druggable cancer driving proteins for individual and targeted treatment decision making.ConclusionsThe ZeptoCTC workflow represents a valuable tool in single cell cancer research, crucial for personalized medicine. It permits detailed analysis of key proteins and their activation status of targeted, cancer-driven signaling pathways in single cell samples, aiding in understanding tumor response, progression, and treatment efficacy beyond bulk analysis. The method significantly advances clinical investigations in cancer, improving treatment precision and effectiveness. The workflow will be applicable to protein analysis on other types of single cells like relevant in stem cell, neuropathology and hemopoietic cell research.

CD38 symmetric dimethyl site R58 promotes malignant tumor cell immune escape by regulating the cAMP-GSK3β-PD-L1 axis

In recent years, immunotherapy has emerged as an effective approach for treating tumors, with programmed cell death ligand 1 (PD-L1)/programmed cell death protein-1 (PD-1) immune checkpoint blockade (ICB) being a promising strategy. However, suboptimal therapeutic efficacy limits its clinical benefit. Understanding the regulation mechanism of PD-L1 expression is crucial for improving anti-PD-L1/PD-1 therapy and developing more effective tumor immunotherapy. Previous studies have revealed that resistance to PD-L1/PD-1 blockade therapy arises from the upregulation of CD38 on tumor cells induced by ATRA and IFN-β, which mediates the inhibition of CD8+ T cell function through adenosine receptor signaling, thereby promoting immune evasion.Yet, the precise role of CD38 in regulating PD-L1 on malignant tumor cells and its impact on CD8+ T cells through PD-L1 remain unclear. Here, we demonstrate that CD38 is highly expressed in malignant tumors (lung cancer, nasopharyngeal carcinoma, cervical cancer) and upregulates PD-L1 protein expression, impairing CD8+ T cell function. Mechanistically, CD38 phosphorylates GSK3β via the adenosine-activated cAMP-PKA signaling pathway, leading to GSK3β inactivation and enhanced PD-L1 stability and expression, facilitating tumor immune escape. Furthermore, we identify PRMT5 as a novel CD38-interacting molecule that symmetrically dimethylates CD38 arginine position 58, augmenting PD-L1 stability and expression through the ADO-cAMP-GSK3β signaling axis. This inhibits CD8+ T cell-mediated tumor cell killing, enabling tumor cells to evade immune surveillance. Our findings suggest that targeting the CD38 R58 site offers a new avenue for enhancing anti-PD-L1/PD-1 therapy efficacy in tumor treatment.

The synergistic effects of anoikis-related genes and EMT-related genes in the prognostic prediction of Wilms tumor.

Wilms tumor (WT) is the most common type of malignant abdominal tumor in children; it exhibits a high degree of malignancy, grow rapidly, and is prone to metastasis. This study aimed to construct a prognosis model based on anoikis-related genes (ARGs) and epithelial-mesenchymal transition (EMT)-related genes (ERGs) for WT patients; we assessed the characteristics of the tumor microenvironment and treatment efficacy, as well as identifying potential therapeutic targets. To this end, we downloaded transcriptome sequencing data and clinical data for WT and normal renal cortices and used R to construct and validate the prognostic model based on ARGs and ERGs. Additionally, we performed clinical feature analysis, nomogram construction, mutation analysis, drug sensitivity analysis, Connectivity Map (cMAP) analysis, functional enrichment analysis, and immune infiltration analysis. Finally, we screened the hub gene using the STRING database and validated it via experiments. In this way, we constructed a model with good accuracy and robustness, which was composed of seven anoikis- and EMT-related genes. Paclitaxel and mesna were selected as potential chemotherapeutic drugs and adjuvant chemotherapeutic drugs for the WT high-risk group by using the Genomics of Drug Sensitivity in Cancer (GDSC) and cMAP compound libraries, respectively. We proved the existence of a strong correlation between invasive immune cells and prognostic genes and risk scores. Next, we selected NTRK2 as the hub gene, and in vitro experiments confirmed that its inhibition can significantly inhibit the proliferation and migration of tumor cells and promote late apoptosis. In summary, we screened out the potential biomarkers and chemotherapeutic drugs that can improve the prognosis of patients with WT.

Hyaluronic acid-covered ferric ion-rich nanobullets with high zoledronic acid payload for breast tumor-targeted chemo/chemodynamic therapy

Due to the heterogeneity of the tumor microenvironment, the clinical efficacy of tumor treatment is not satisfied, highlighting the necessity for new strategies to tackle this issue. To effectively treat breast tumors by tumor-targeted chemo/chemodynamic therapy, herein, the Fe3+-rich MIL-88B nanobullets (MNs) covered with hyaluronic acid (HA) were fabricated as vehicles of zoledronic acid (ZA). The attained ZA@HMNs showed a high ZA payload (ca 29.6 %), outstanding colloidal stability in the serum-containing milieu, and accelerated ZA as well as Fe3+ release under weakly acidic and glutathione (GSH)-rich conditions. Also, the ZA@HMNs consumed GSH by GSH-mediated Fe3+ reduction and converted H2O2 into OH via Fenton or Fenton-like reaction with pH reduction. After being internalized by 4T1 cells upon CD44-mediated endocytosis, the ZA@HMNs depleted intracellular GSH and degraded H2O2 into OH, thus eliciting lipid peroxidation and mitochondria damage to suppress cell proliferation. Also, the ZA@HMNs remarkably killed macrophage-like RAW 264.7 cells. Importantly, the in vivo studies and ki67 and GPX4 staining of tumor sections demonstrated that the ZA@HMNs efficiently accumulated in 4T1 tumors to hinder tumor growth via ZA chemotherapy combined with OH-mediated ferroptosis. This work presents a practicable strategy to fabricate ZA@HMNs for breast tumor-targeted chemo/chemodynamic therapy with potential clinical translation.

Virtual screening reveals fluorescent probes for detecting Pan-Zinc center activity in serum MMPs: A potential biomarker for early tumor screening

Early tumor screening is pivotal for enhancing tumor treatment efficacy and patient survival rates, yet identifying reliable biomarkers for early detection remains a challenge. Previous studies have explored different isoforms of matrix metalloproteinases (MMPs) in serum for their predictive value in tumor, but their results have been inconsistent. Herein, we introduce a novel fluorescent probe, C9 (N-oxide-8-hydroxyquinoline-5-sulfonic acid), designed to specifically label the pan zinc center activity of MMPs (PZCA-MMPs), which in a sense represents the overall MMPs activity in serum. The rational design of fluorescent probe C9 is based on its ability to bind the zinc ions in the structure of MMPs, facilitated by the oxides on hydroxyl (–OH) and nitro oxide (N→O) groups present in C9, as supported by theoretical calculations such as Gaussian and Schrödinger. Experimental validation confirmed its efficacy for detecting PZCA-MMPs in vitro and for fluorescence imaging of MMPs’ zinc ions in cellular contexts, validated through absolute integrated fluorescence intensity measurements at 510 nm. We also demonstrated through in vitro fluorescent analysis that neither metal ions nor abundant serum proteins such as albumin (BSA) and other metalloproteins interfere with the signal response of C9. Notably, in comparative analysis of serum samples from healthy controls and breast tumor patients, PZCA-MMPs showed a highly discriminatory area under the ROC curve (AUC) of 0.9377, surpassing established tumor biomarkers such as CA125, CA15-3, CA19-9, and CA72-4. In particular, for tumor patients, PZCA-MMPs can effectively distinguish between metastatic and non-metastatic patients (*P<0.05). Therefore, this provides a potential alternative biomarker for tumor screening. Future studies aim to further elucidate the clinical utility of PZCA-MMPs using a broader spectrum of clinical samples.

Role and functional mechanisms of IL‑17/IL‑17R signaling in pancreatic cancer (Review).

Interleukin‑17 (IL‑17), an inflammatory cytokine primarily secreted by T helper 17 cells, serves a crucial role in numerous inflammatory diseases and malignancies via its receptor, IL‑17R. In addition to stimulating inflammatory responses, IL‑17 exhibits dual functions in tumors, exerting both pro‑ and antitumor effects. Pancreatic ductal adenocarcinoma (PDAC) is the most common pancreatic malignancy and accounts for >90% of pancreatic cancer cases. PDAC is characterized by a prominent stromal microenvironment with significant heterogeneity, which contributes to treatment resistance. IL‑17/IL‑17R signaling has a notable effect on tumorigenesis, the tumor microenvironment and treatment efficacy in various cancer types, including PDAC. However, the specific mechanisms of IL‑17/IL‑17R signaling in pancreatic cancer remain uncertain. This review presents a brief overview of the current knowledge and recent advances in the role and functional mechanisms of IL‑17/IL‑17R signaling in pancreatic cancer. Furthermore, the potential of IL‑17‑targeted therapeutic strategies for PDAC treatment is also discussed.

A Novel Nanocatalyst for Combined Chemodynamic and Starvation Therapy in Cancer Treatment

Cancer remains a significant challenge due to the limitations and side effects of tra- ditional treatments. Novel minimally invasive therapies are essential to enhance patient outcomes. This study introduces MIL-101(Fe)@MnO2 @Gox/HA, a nanocatalyst that com- bines glucose oxidase and manganese dioxide in an iron-based metal-organic framework (MOF) coated with hyaluronic acid. This nanoplatform demonstrates strong water affin- ity, tumor targeting, and durability. MIL-101(Fe)@MnO2 @Gox/HA presents a promis- ing anti-cancer strategy, warranting further investigation to enhance tumor targeting and treatment efficacy.

Assessing olaparib efficacy in U.S. Veterans with metastatic prostate cancer utilizing a time-indifferent g-rate method ideal for real-world analyses

We aimed to assess real-world efficacy of the PARP inhibitor, olaparib, in US Veterans with metastatic prostate cancer (mPC) by leveraging the national data repository and evaluate a novel approach to assess treatment efficacy in tumors considered rare or harboring rare mutations. Included Veterans had 1) mPC with somatic or germline alterations/mutations in genes involved in homologous recombination repair (HRR), 2) received olaparib monotherapy as well as a novel hormonal therapy/androgen receptor pathway inhibitors (NHT/ARPI), and/or chemotherapy, and 3) estimable rates of tumor growth (g-rate) using PSA values obtained while receiving treatment. Previous work has shown an excellent inverse correlation of g-rate with survival. Using g-rate, we determined tumor doubling time (DT) and DT ratios (DT on olaparib/DT on prior medication). We postulated that a DT ratio≥ 1 was associated with benefit. We identified 139 Veterans, including 42 Black males with tumors harboring mutations/alterations in HRR genes who received olaparib: BRCA2 (50), ATM (32), BRCA1 (10), other mutations (47). 62/139 (45%) of all and 21/42 (50%) of Black Veterans had DT ratios ≥1, including 31, 10, 2, and 19 with BRCA2, ATM, BRCA1, and other mutations, respectively (p=0.006). Median survival with DT ratios ≥1 was superior, being 24.5 vs. 11.4 months for DT ratio <1 (p=0.01, HR 0.50, 95% CI 0.29-0.85). Benefit from olaparib, defined as DT ratio ≥1, was not observed for germline status, starting PSA value, number of prior therapies, or immediate prior therapy. Compared to matched cohorts, tumors in the olaparib cohort had shorter DTs with enzalutamide in first line (367 vs. 884 days; p=0.0043). Using equations indifferent to timing of assessments ideal for real-world efficacy analyses, we showed DT ratio ≥1 representing slower tumor growth on olaparib relative to the prior therapy correlates with improved survival. Olaparib efficacy in Veterans with mPC harboring mutations/alterations in HRR genes emulates clinical trial results. Black men had comparable results. Compared to matched cohorts, in first line, enzalutamide was less efficacious in tumors harboring mutations/alterations in HRR genes. American Society of Clinical Oncology Conquer Cancer Foundation (ASCO CCF), the Blavatnik Family Foundation and the Prostate Cancer Foundation (PCF).

Nanomedicines in diagnosis and treatment of prostate cancers: an updated review.

Prostate cancer (PC) is the third most common male cancer in the world, which occurs due to various mutations leading to the loss of chromatin structure. There are multiple treatments for this type of cancer, of which chemotherapy is one of the most important. Sometimes, a combination of different treatments, such as chemotherapy, radiotherapy, and surgery, are used to prevent tumor recurrence. Among other treatments, androgen deprivation therapy (ADT) can be mentioned, which has had promising results. One of the drawbacks of chemotherapy and ADT treatments is that they are not targeted to the tumor tissue. For this reason, their use can cause extensive side effects. Treatments based on nanomaterials, known as nanomedicine, have attracted much attention today. Nanoparticles (NPs) are one of the main branches of nanomedicine, and they can be made of different materials such as polymer, metal, and carbon, each of which has distinct characteristics. In addition to NPs, nanovesicles (NVs) also have therapeutic applications in PC. In treating PC, synthetic NVs (liposomes, micelles, and nanobubbles) or produced from cells (exosomes) can be used. In addition to the role that NPs and NVs have in treating PC, due to being targeted, they can be used to diagnose PC and check the treatment process. Knowing the characteristics of nanomedicine-based treatments can help design new treatments and improve researchers' understanding of tumor biology and its rapid diagnosis. In this study, we will discuss conventional and nanomedicine-based treatments. The results of these studies show that the use of NPs and NVs in combination with conventional treatments has higher efficacy in tumor treatment than the individual use of each of them.