Cancer Models Research Articles

Research on Prediction Model of Benign and Malignant Breast Cancer Based on Machine Learning

This study uses three machine learning models to perform classification analysis on breast cancer data, aiming to improve diagnostic accuracy. After data preprocessing and standardization, the performance of each model was comprehensively evaluated using classification and regression metrics. The results showed that the logistic regression model performed the best, with an accuracy of 0.9825, while SVM and random forest also showed good performance. The classification effects of each model were visualized through ROC curves and confusion matrices, demonstrating that logistic regression has high application value in breast cancer diagnosis.

Prognostic model for second progression-free survival and overall survival in patients with high-risk metastatic hormone-sensitive prostate cancer treated with abiraterone acetate and androgen deprivation therapy.

To develop and validate a prognostic risk model for high-risk metastatic hormone-sensitive prostate cancer (mHSPC) patients treated with upfront abiraterone acetate (ABI). This retrospective multicenter study involved 233 high-risk mHSPC patients who received upfront ABI, developed by three academic centers. The model was externally validated with an independent cohort of 282 patients. To identify independent prognostic factors for second progression-free survival (PFS2) and develop the best-fitted model, Cox proportional hazards regression, followed by the Akaike information criterion, was used. Patients were categorized into three groups based on their risk scores. PFS2 and overall survival (OS) were evaluated according to the risk groups in the discovery and validation cohorts. The median age was 72 (range 51-89) years, with a median follow-up duration of 27 months. Independent factors linked to PFS2 included an Eastern Cooperative Oncology Group performance status ≥2, a primary Gleason score of 5, an extent of disease score of ≥3 or liver metastasis, and lactate dehydrogenase >220 U/L. Median PFS2 for favorable-, intermediate-, and poor-risk groups were not reached, 43 months, and 16 months, respectively. The median OS was 29 months in the poor-risk group, whereas it was not reached in the favorable- and intermediate-risk groups. The 2-year OS rates in the favorable-, intermediate- and poor-risk groups were 94.5%, 80.1%, and 60.3%, respectively. The validation cohort confirmed the risk model's relationship with PFS2 and OS. The median PFS2 and OS in the high-risk group were 21 months and 32 months, respectively. Our prognostic model, including five clinical factors, is useful for patient care and treatment selection in high-risk mHSPC patients treated with ADT plus ABI. The developed model could provide more accurate information, guide treatment decisions, or classify patients in future clinical trials.

Hyaluronan-based Hydrogels for 3D Modelling of Tumour Tissues.

Although routine 2D cell culture techniques have advanced basic cancer research owing to their simplicity, cost-effectiveness, and reproducibility, they have limitations that necessitate the development of advanced 3D tumour models that better recapitulate the tumour microenvironment. Various biomaterials have been used to establish these 3D models, enabling the study of cancer cell behaviour within different matrices. Hyaluronic acid (HA), a key component of the extracellular matrix in tumour tissues, has been widely studied and employed in the development of multiple cancer models. This review first examines the role of HA in tumours, including its function as an extracellular matrix (ECM) component and regulator of signalling pathways that affect tumour progression. It then explores HA-based models for various cancers, focusing on HA as a central component of the 3D matrix and its mobilization within the matrix for targeted studies of cell behaviour and drug testing. The tumour models discussed included those for breast cancer, glioblastoma, fibrosarcoma, gastric cancer, hepatocellular carcinoma, and melanoma. The review concludes with a discussion of future prospects for developing more robust and high-throughput HA-based models to more accurately mimic the tumour microenvironment and improve drug testing.

Hypoxia-induced TIMAP Upregulation in Endothelial Cells and TIMAP-dependent Tumour Angiogenesis.

TIMAP, the endothelial cell-predominant protein phosphatase 1β regulatory subunit also known as PPP1R16B, promotes in vitro endothelial cell proliferation and angiogenic sprouting. TIMAP was first identified as a target of TGF-β1 mediated repression, but the molecular pathways regulating its expression in endothelial cells are not well-defined. This study examined the role of BMP9, hypoxia and angiogenic growth factors in the regulation of TIMAP expression and determined whether TIMAP plays a role in tumor angiogenesis and growth in vivo. BMP9, which potently activated the SMAD1/5/8 pathway in endothelial cells, significantly reduced TIMAP mRNA and protein expression. Conversely, hypoxia and the prolyl hydroxylase inhibitor Roxadustat raised TIMAP mRNA and protein levels by inhibiting the BMP9 pathway. Angiogenic growth factors, most prominent among them VEGFA and IGF-I, raised endothelial TIMAP levels partly by attenuating BMP9 pathway activation, but also through BMP pathway-independent mechanisms. Cultured breast cancer E0771 cells released mediators that raised TIMAP expression in endothelial cells, effects that were inhibited by the VEGF inhibitor Sunitinib in conjunction with the IGF-1 inhibitor Picropodophyllin. In the mouse E0771 breast cancer model in vivo, tumor growth and tumor angiogenesis were markedly attenuated in TIMAP deficient, compared to wild-type littermates. These findings indicate that TIMAP plays a critical pro-angiogenic function during tumor angiogenesis in vivo, likely through hypoxia-driven inhibition of the BMP9 pathway and through elaboration of angiogenic growth factors by tumor cells.

The Inhibitory Effects of Anti-GPC3 Antibody on Wnt/β-Catenin Signaling Pathway as a Biological Therapy in Liver Cancer.

To investigate the effects of anti-GPC3 antibody on the Wnt/catenin pathway in liver cancer biology, thus providing a new target for the biological treatment of the disease. A total of 12 BALB/C experimental nude mice were selected as experimental objects. The mice were all male, weighed 15-20g and aged 4-5weeks. First, mouse liver cancer models were constructed. Then, the HepG2 liver cancer cells in logarithmic growth period were inoculated into the caudal veins of mouse models. On the 3rd day after inoculation, the tumor formations of nude mice were observed. Second, the anti-GPC3 antibody was designed and constructed, and the activity of anti-GPC3 antibody was detected. The mouse models were divided into the experimental group (EG) and the control group (CG), with 6 mice in each group. In the EG, mice were injected with 3mg/kg of anti-GPC3 antibody in the caudal veins once a day for three consecutive days, while in the CG mice were injected with the same amount of saline as the control. Mice in both groups received 3 injections in total. After the last administration, all mice were euthanized using the decapitation method following anesthesia with ethyl ether. The liver cancer cells of nude mice were extracted and cultured in DMEM medium. The effects of anti-GPC3 antibody on Wnt/β-catenin in liver cancer nude mice and the effects of anti-GPC3 antibody on epithelial-mesenchymal transition (EMT) in mouse liver cancer cells were observed. The bodyweight, liver weight and index of mice in the EG increased significantly (P < 0.05). The serum alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP) levels of mice in the EG were reduced than those in the CG (P < 0.05). Compared with the CG, the superoxide dismutase (SOD) concentration increased, while the malonaldehyde (MDA) concentration decreased in the liver tissues of mice in the EG (P < 0.05). There was binding activity between GPC3 recombinant protein and the antibody; the affinity constant was KD = 1.4 × 10-6 M, compared with the commercial anti-GPC3 antibody, the affinity constant was lower. The interference effects of siRNA on anti-GPC3 antibody were detected by Western Blot. After the injection of anti-GPC3 antibody, the expression of β-catenin siRNA in liver cancer cells decreased significantly. The optical microscope images of mouse liver cancer cells in groups were compared. Through down-regulating the Wnt/β-catenin by anti-GPC3 antibody, the morphology of epithelial cells was maintained, the cells were arranged orderly, the cubic structure was kept stable, and the occurrence of EMT was reduced. However, in the CG, the structure of mouse liver cancer cells was disordered, the obvious EMT occurred (P < 0.05). Through down-regulating the expression of Wnt/β-catenin by anti-GPC3 antibody, the invasiveness, and metastasis of liver cancer cells could be effectively inhibited. Compared with the CG, the number of cells passing through the chamber was significantly reduced (P < 0.05). The anti-GPC3 antibody had inhibitory effect on Wnt/β-catenin signaling pathway. The occurrence of EMT and the invasiveness of liver cancer cells were inhibited effectively. Therefore, the anti-GPC3 antibody could be used as a reference for clinical molecular targeted therapy of liver cancer.

Excessive autophagy-inducing and highly penetrable biomineralized bacteria for multimodal imaging-guided and mild hyperthermia-enhanced immunogenic cell death

The tumor microenvironment, characterized by hypoxia, supports the efficacy of anaerobic bacteria like attenuated S. typhimurium in cancer therapies. These bacteria target and penetrate deep tumor regions, significantly reducing tumor size but often lead to tumor regrowth due to limited long-term efficacy. To enhance the therapeutic impact, a novel biohybrid system, S@UIL, has been developed by coating S. typhimurium with a zirconium-based nanoscale metal–organic framework (UiO-66-NH2) loaded with indocyanine green (ICG) and luteolin (LUT). This system maintains the bacteria’s tumor-targeting ability while increasing the penetration and therapeutic effectiveness through excessive autophagy and mild hyperthermia. In a subcutaneous colon cancer model, the integration of LUT and ICG promotes autophagic cell death and photothermal sensitization, leading to the release of damage-associated molecular patterns (DAMPs). These DAMPs activate immune responses through dendritic cells and T-cells, enhancing immunogenic cell death (ICD) and potentially reducing immune evasion by tumors. This single-administration approach also integrates multimodal imaging capabilities, providing a promising strategy for improved tumor ICD induction and cancer progression inhibition.

Multifunctional Sensors for Successive Detection of Endogenous ONOO- and Mitochondrial Viscosity: Discriminating Normal to Cancer Models.

Diagnosing cancer in its early stages can play an important role in prolonging the lifespan of patients, which demands the use of powerful tools to detect biomarkers accurately. However, since most fluorescent probes described for cancer diagnosis are limited to recognizing a single molecule, achieving the high accuracy criteria remains difficult. Here, sensor 1 is constructed for the sequential detection of D, ONOO-, and viscosity. Initially, sensor 1 detected D and underwent an intramolecular charge transfer mechanism, resulting in the formation of 2 and fluorescence quenching at 587 nm. Subsequently, the intermediate (2) monitored ONOO- and reproduced sensor 1 reversibly with fluorescence enhancement at 496 nm, showing concentration-related quantitative analysis. Similar sensing processes were observed in monitoring ONOO- and viscosity by synthetically developed sensor 2. The proposed mechanisms of sensors 1 and 2 are verified through various characterizations (1H NMR, HR-MS, and HPLC) and DFT calculations. Investigations on endogenous ONOO- and mitochondrial viscosity in cancer (HeLa) and normal (NCM460) cells were conducted to distinguish cancerous cells from normal cells. We anticipated that sensor 2 could effectively serve as a reliable bioanalytical reagent for cancer diagnosis at an earlier stage through sequential detection of two cancer markers, ONOO- and mitochondrial viscosity, in living cells. Importantly, sensor 2 has been employed for imaging ONOO- in normal and liver injury mouse models and tissues, achieving outstanding results.

Accurate Co-Localization of Luciferase Expression and Fluorescent Anti-CEA Antibody Targeting of Liver Metastases in an Orthotopic Mouse Model of Colon Cancer

Background: The present study aimed to validate the accuracy of a tumor-specific antibody to target liver metastases of colorectal cancer. Methods: A humanized anti-CEA antibody conjugated to a fluorescent dye (M5A-IR800) was tested for targeting human colorectal cancer liver metastases (CRLMs) expressing luciferase in an orthotopic mouse model. Orthotopic mouse models of CRLMs were established by implanting fragments of a luciferase-expressing human colorectal cancer cell line, LS174T, in the liver of nude mice. Mice received 50 µg M5A-IR800 72 h prior to imaging. To test co-localization, bioluminescence imaging was performed using D-luciferin, which was given via intraperitoneal injection just prior to imaging. Results: Tumors were able to be visualized non-invasively through the skin with the luciferase–luciferin signal. Intra-abdominal imaging showed accurate labeling of CRLMs with M5A-IR800, which co-localized with the luciferase–luciferin signal. Conclusions: The present results validate the accuracy of a tumor-specific anti-CEA antibody in targeting liver metastases of colorectal cancer.

MRI detection of free-contrast agent nanoparticles.

The integration of nanotechnology into biomedical imaging has significantly advanced diagnostic and theranostic capabilities. However, nanoparticle detection in imaging relies on functionalization with appropriate probes. In this work, a new approach to visualize free-label nanoparticles using MRI and MRS techniques is described, consisting of detecting by 1H CSI specific proton signals belonging to the components naturally present in most of the nanosystems used in preclinical and clinical research. Three different nanosystems, namely lipid-based micelles, liposomes, and perfluorocarbon-based nanoemulsions, were synthesized, characterized by high resolution NMR and then visualized by 1H CSI at 300 MHz. Subsequently the best 1H CSI performing system was administered to murine models of cancer to evaluate the possibility of tracking the nanosystem by looking at its proton associated signal. Furthermore, an in vitro comparison between 1H CSI and 19F MRI was carried out. The study successfully demonstrates the feasibility of detecting nanoparticles using MRI/MRS without probe functionalization, employing 1H CSI. Among the nanosystems tested, the perfluorocarbon-based nanoemulsion exhibited the highest SNR. Consequently, it was evaluated in vivo, where its detection was achievable within tumors and inflamed regions via 1H CSI, and in lymph nodes via PRESS. These findings present a promising avenue for nanoparticle imaging in biomedical applications, offering potential enhancements to diagnostic and theranostic procedures. This non-invasive approach has the capacity to advance imaging techniques and expand the scope of nanoparticle-based biomedical research. Further exploration is necessary to fully explore the implications and applications of this method.

Substrate stiffness modulates extracellular vesicles’ release in a triple-negative breast cancer model

Aim: The microenvironment effect on the tumoral-derived Extracellular Vesicle release, which is of significant interest for biomedical applications, still represents a rather unexplored field. The aim of the present work is to investigate the interrelation between extracellular matrix (ECM) stiffness and the release of small EVs from cancer cells. Here, we focus on the interrelation between the ECM and small extracellular vesicles (sEVs), specifically investigating the unexplored aspect of the influence of ECM stiffness on the release of sEVs. Methods: We used a well-studied metastatic Triple-Negative Breast Cancer (TNBC) cell line, MDA-MB-231, as a model to study the release of sEVs by cells cultured on substrates of different stiffness. We have grown MDA-MB-231 cells on two collagen-coated polydimethylsiloxane (PDMS) substrates at different stiffness (0.2 and 3.6 MPa), comparing them with a hard glass substrate as control, and then we isolated the respective sEVs by differential ultracentrifugation. After checking the cell growth conditions [vitality, morphology by immunofluorescence microscopy, stiffness by atomic force microscopy (AFM)], we took advantage of a multi-parametric approach based on complementary techniques (AFM, Nanoparticle Tracking Analysis, and asymmetric flow field flow fractionation with a multi-angle light scattering detector) to characterize the TNBC-derived sEV obtained in the different substrate conditions. Results: We observe that soft substrates induce TNBC cell softening and rounding. This effect promotes the release of a high number of larger sEVs. Conclusion: Here, we show the role of ECM physical properties in the regulation of sEV release in a TNBC model. While the molecular mechanisms regulating this effect need further investigation, our report represents a step toward an improved understanding of ECM-cell-sEVs crosstalk.

Blockade of Crk eliminates Yki/YAP-activated tumors via JNK-mediated apoptosis in Drosophila

Selective elimination of cancer cells without causing deleterious effects on normal cells is an ideal anti-cancer strategy. Here, using Drosophila cancer model, we performed an in vivo RNAi screen for anti-cancer targets that selectively eliminate tumors without affecting normal tissue growth. In Drosophila imaginal epithelium, clones of cells expressing oncogenic Ras with simultaneous mutations in the cell polarity gene scribble (RasV12/scrib−/−) develop into malignant tumors. We found that knockdown of Crk, the Drosophila ortholog of human CRK (CT10 regulatory kinase) and CRKL (Crk-like) adapter proteins, significantly suppresses growth of RasV12/scrib−/− tumors by inducing c-Jun N-terminal kinase (JNK)-mediated apoptosis, while it does not affect growth of normal epithelium. Mechanistically, Crk inhibition blocks Yorkie (Yki)/YAP activity by impairing F-actin accumulation, an upstream event of Yki/YAP activation in tumors. Inhibition of Yki/YAP in tumors causes intracellular JNK signaling to be used for apoptosis induction. Given that molecules and signaling pathways identified in Drosophila are highly conserved and activated in human cancers, our findings would provide a novel, to the best of our knowledge, anti-cancer strategy against YAP-activated cancers.

Estrogen signaling suppresses tumor-associated tissue eosinophilia to promote breast tumor growth.

Estrogens regulate eosinophilia in asthma and other inflammatory diseases. Further, peripheral eosinophilia and tumor-associated tissue eosinophilia (TATE) predicts a better response to immune checkpoint blockade (ICB) in breast cancer. However, how and if estrogens affect eosinophil biology in tumors and how this influences ICB efficacy has not been determined. Here, we report that estrogens decrease the number of peripheral eosinophils and TATE, and this contributes to increased tumor growth in validated murine models of breast cancer and melanoma. Moreover, estrogen signaling in healthy female mice also suppressed peripheral eosinophil prevalence by decreasing the proliferation and survival of maturing eosinophils. Inhibiting estrogen receptor (ER) signaling decreased tumor growth in an eosinophil-dependent manner. Further, the efficacy of ICBs was increased when administered in combination with anti-estrogens. These findings highlight the importance of ER signaling as a regulator of eosinophil biology and TATE and highlight the potential near-term clinical application of ER modulators to increase ICB efficacy in multiple tumor types.

Remodeling the tumor immune microenvironment through hydrogel encapsulated G-Rh2 in situ vaccine and systemic immunotherapy

Ginsenoside Rh2 (G-Rh2) is a vital bioactive compound in Traditional Chinese Medicine, celebrated for its strong pharmacological properties, particularly its potent antitumor effects. However, its poor water solubility and limited bioavailability have necessitated the development of a novel drug delivery method. In this study, we utilized an indocyanine green carboxylic acid-hydroxypropyl cellulose-abietic acid-bovine serum albumin hydrogel (ICG-HPC-AA/BSA hydrogel) as a tumor in situ vaccine to enhance the permeability, retention, and tumor-targeted therapeutic efficacy of G-Rh2. We examined the therapeutic impact of a G-Rh2-loaded hydrogel combined with systemic PD-1 antibody treatment in murine models of H22 liver cancer and CT26 colon cancer. Additionally, we explored the immune microenvironment of the tumors influenced by this in situ vaccination strategy.

Establishment of Translational Luciferase-Based Cancer Models to Evaluate Antitumoral Therapies

Establishment of Translational Luciferase-Based Cancer Models to Evaluate Antitumoral Therapies

Decorin, an exercise-induced secretory protein, is associated with improved prognosis in breast cancer patients but does not mediate anti-tumorigenic tissue crosstalk in mice

BackgroundRegular exercise can reduce incidence and progression of breast cancer, but the mechanisms for such effects are not fully understood. MethodsWe used a variety of rodent and human experimental model systems to determine whether exercise training can reduce tumor burden in breast cancer and to identify mechanism associated with any exercise training effects on tumor burden. ResultsWe show that voluntary wheel running slows tumor development in the mammary specific polyomavirus middle T antigen overexpression (MMTV-PyMT) mouse model of breast cancer but only when mice are not housed alone. We identify the proteoglycan decorin as a contraction-induced secretory factor that systemically increases in patients with breast cancer immediately following exercise. Moreover, high expression of decorin in tumors is associated with improved prognosis in patients, while treatment of breast cancer cells in vitro with decorin reduces cell proliferation. Notwithstanding, when we overexpressed decorin in murine muscle or injected recombinant decorin systemically into mouse models of breast cancer, elevated plasma decorin concentrations did not result in higher tumor decorin levels and tumor burden was not improved. ConclusionExercise training is anti-tumorigenic in a mouse model of luminal breast cancer, but the effect is abrogated by social isolation. The proteoglycan decorin is an exercise-induced secretory protein, and tumor decorin levels are positively associated with improved prognosis in patients. The hypothesis that elevated plasma decorin is a mechanism by which exercise training improves breast cancer progression in humans is not, however, supported by our pre-clinical data since elevated circulating decorin did not increase tumor decorin levels in these models.

Cancer cell membrane-coated siRNA-Decorated Au/MnO2 nanosensitizers for synergistically enhanced radio-immunotherapy of breast cancer

Radiotherapy plays a critical role in the clinical treatment of breast cancer. However, the efficacy of traditional X-ray radiotherapy is greatly limited by its low tumor specificity and treatment tolerance mediated by the tumor microenvironment. Herein, we proposed a novel nano-radiotherapy sensitization strategy to design and construct a cancer cell membrane-coated siRNA-decorated Au/MnO2 nanosensitizer (R&F@Au/MnO2-CM) to synergistically enhance radio-immunotherapy for breast cancer. In the integrated nanosensitizer, the cancer cell membrane (CM) derived from 4T1 breast cancer cells is utilized for targeted functionality, while Au/MnO2 is designed to improve X-ray absorption and alleviate tumor hypoxia. Additionally, PD-L1 siRNA (R) is used to downregulate PD-L1 expression in tumor cells. In an in situ mouse model of 4T1 breast cancer, R&F@Au/MnO2-CM demonstrated accurate tumor identification via CM-mediated homologous targeting after intravenous injection, which was monitored in real-time through NIR-II fluorescence imaging of NIR-935 (F). Subsequently, the radiotherapy sensitivity was achieved due to the strong radiation absorption properties and oxygen generation through catalysis of Au/MnO2 upon X-ray irradiation. Furthermore, the immunosuppressive microenvironment of the tumor is improved by downregulating PD-L1, enhancing synergistic anti-tumor effect. Our findings demonstrate a promising approach for tumor treatment by combining targeted enhanced radiotherapy with immune activation.

Symptom severity reported by older adults with cancer and its impact on survival prognostication

Introduction: Symptom burden is a crucial factor for survival prognostication, but older adults may report fewer and less severe symptoms than younger patients. We investigated the impact of age on symptom severity and its prognostic implications in the prognostic model for advanced cancer (PRO-MAC).Materials and Methods: Eight hundred forty subjects with incurable cancer, who were reviewed by palliative medicine at a tertiary university hospital, were categorized into four groups based on age: < 65 (young), 65–74 (young-old), 75–84 (old-old), and ≥ 85 (oldest-old) for comparison. The study compared individual symptoms reported on the Edmonton Symptom Assessment System-revised (ESAS-r) and analyzed the significance of each prognostic variable in the PRO-MAC model using multivariate Cox proportional hazards regression analysis for all age categories. We generated the log-rank test for each age group to evaluate the effectiveness of PRO-MAC across age groups.Results: The older adults had significantly lower unadjusted mean scores in pain, tiredness, anxiety, wellbeing, and ESAS-r summative score compared to young adults. There was a higher proportion of older adults with no symptoms. The ESAS-r summative score remained a significant prognostic factor only in the young and young-old groups. More participants in the older age groups had dementia, which may impact reporting of symptom severity. Despite these findings, the PRO-MAC model remains applicable across all age groups as a multi-domain 90-day survival prognostication tool.Discussion: Symptom burden, including pain, tiredness, anxiety, wellbeing, as well as summative ESASr scores, are lower in older adults with cancer. This could affect the prognostication of survival using symptom burden. However, a multi-dimensional prognostic model like PRO-MAC remains effective for older adults with advanced cancer. Further research is needed to explore tools that can help older adults express the severity of their symptoms and incorporate this into survival prognostication.

Anti-tissue factor antibody conjugated with monomethyl auristatin E or deruxtecan in pancreatic cancer models.

Antibody-drug conjugates (ADCs) have been recognized as a promising class of cancer therapeutics. Tissue factor (TF), an initiator of the blood coagulation pathway, has been investigated regarding its relationship with cancer, and several preclinical and clinical studies have presented data on anti-TF ADCs, including tisotumab vedotin, which was approved in 2021. However, the feasibility of other payloads in the design of anti-TF ADCs is still unclear because no reports have compared payloads with different cytotoxic mechanisms. For ADCs targeting other antigens, such as Her2, optimizing the payload is also an important issue in order to improve invivo efficacy. In this study, we prepared humanized anti-TF Ab (clone.1084) conjugated with monomethyl auristatin E (MMAE) or deruxtecan (DXd), and evaluated the efficacy in several cell line- and patient-derived xenograft models of pancreatic cancer. As a result, optimizing the drug / Ab ratio was necessary for each payload in order to prevent pharmacokinetic deterioration and maximize delivery efficiency. In addition, MMAE-conjugated anti-TF ADC showed higher antitumor effects in tumors with strong and homogeneous TF expression, while DXd-conjugated anti-TF ADC was more effective in tumors with weak and heterogeneous TF expression. Analysis of a pancreatic cancer tissue array showed weak and heterogeneous TF expression in most TF-positive specimens, indicating that the response rate to pancreatic cancer might be higher for DXd- than MMAE-conjugated anti-TF ADC. Nevertheless, our findings indicated that optimizing the ADC payloads individually in each patient could maximize the potential of ADC therapeutics.

Host ANGPTL2 establishes an immunosuppressive tumor microenvironment and resistance to immune checkpoint therapy.

Use of immune checkpoint inhibitors (ICIs) as cancer immunotherapy has advanced rapidly in the clinic; however, mechanisms underlying resistance to ICI therapy, including impaired T cell infiltration, low immunogenicity, and tumor "immunophenotypes" governed by the host, remain unclear. We previously reported that in some cancer contexts, tumor cell-derived angiopoietin-like protein 2 (ANGPTL2) has tumor-promoting functions. Here, we asked whether ANGPTL2 deficiency could enhance antitumor ICI activity in two inflammatory contexts: a murine syngeneic model of colorectal cancer and a mouse model of high-fat diet (HFD)-induced obesity. Systemic ANGPTL2 deficiency potentiated ICI efficacy in the syngeneic model, supporting an immunosuppressive role for host ANGPTL2. Relevant to the mechanism, we found that ANGPTL2 induces pro-inflammatory cytokine production in adipose tissues, driving generation of myeloid-derived suppressor cells (MDSCs) in bone marrow and contributing to an immunosuppressive tumor microenvironment and resistance to ICI therapy. Moreover, HFD-induced obese mice showed impaired responsiveness to ICI treatment, suggesting that obesity-induced chronic inflammation facilitated by high ANGPTL2 expression blocks ICI antitumor effects. Our findings overall provide novel insight into protumor ANGPTL2 functions and illustrate the essential role of the host system in ICI responsiveness.

Gastrin-releasing peptide receptor as theranostic target in estrogen-receptor positive breast cancer: A preclinical study of the theranostic pair [55Co]Co- and [177Lu]Lu-DOTA-RM26

BackgroundPatients with advanced metastatic estrogen receptor-positive breast cancer often develop resistance to standard treatments, leading to uncontrolled progression. Thus, innovative therapies are urgently needed. The gastrin-releasing peptide receptor (GRPR) is overexpressed in various cancers, including breast cancer, making it an interesting theranostic target. RM26, a GRPR-targeting antagonist, has demonstrated promising in vivo kinetics in prostate cancer models. This study evaluated the theranostic capabilities of [55Co]Co−/[177Lu]Lu-DOTA-RM26 in vitro in estrogen receptor-positive breast cancer cells and assessed the diagnostic potential of [55Co]Co-DOTA-RM26 in vivo in a breast cancer mouse model. MethodsWe analyzed the binding specificity of [57Co]Co-/[177Lu]Lu-DOTA-RM26 in T47D breast cancer cells, using [57Co]Co-DOTA-RM26 as a surrogate for [55Co]Co-DOTA-RM26. The therapeutic efficacy of increasing [177Lu]Lu-DOTA-RM26 concentrations was determined via viability assay in vitro. Ex vivo biodistribution of [57Co]Co-DOTA-RM26 (17.2 ± 2.7 kBq, 33 ± 5.2 pmol/mouse) was investigated in 12 mice (n= 4/group) with orthotopic breast cancer tumors. The mice were sacrificed at 4 and 24 h post-injection (pi), including a blocking group (20 nmol of unlabeled [Tyr4]-Bombesin) at 4 h pi. For imaging, two tumor-bearing mice underwent [55Co]Co-DOTA-RM26 PET/CT, 4 and 24 h pi (2.8 ± 0.2 MBq, 167.5 ± 0.5 pmol/mouse), with or without GRPR blocking. ResultsIn vitro studies revealed high, specific binding of [57Co]Co-DOTA-RM26 (43 ± 1 % of total added activity per 106 cells (%IA/106)) and [177Lu]Lu-DOTA-RM26 (37 ± 4 %IA/106). The activity was predominantly localized at the cell surface: 71 ± 3 % and 80 ± 6 % for [57Co]Co-DOTA-RM26 and [177Lu]Lu-DOTA-RM26, respectively. [177Lu]Lu-DOTA-RM26 significantly reduced cell viability at all activity concentrations >0.625 MBq/mL (p < 0.0001), with cell viability below 1 % at concentrations ≥5 MBq/mL. Biodistribution data (n = 12) indicated a high, specific tumor uptake of [57Co]Co-DOTA-RM26, surpassing all other tissues significantly at both time points, 3.7 ± 0.6 % of the injected activity per gram (%IA/g) 4 h pi and 0.98 ± 0.05 %IA/g 24 h pi. The kidneys showed the second-highest uptake (2.0 ± 0.1 %IA/g 4 h pi), followed by the pancreas (1.4 ± 0.4 %IA/g 4 h pi). PET/CT imaging with [55Co]Co-DOTA-RM26 supported the biodistribution data and, distinctly visualized the tumor 24 h pi and showed an improved tumor-to-background compared to the earlier time points. Effective GRPR blocking significantly reduced tumor uptake in the PET images 24 h pi. ConclusionThese findings suggest that the theranostic pair [55Co]Co−/[177Lu]Lu-DOTA-RM26 holds significant promise as a theranostic agent for estrogen receptor-positive breast cancer.