Cancer research communications最新文献

Use of glucagon-like peptide-1 receptor agonists (GLP1-RA) for weight loss is increasing; implications in breast cancer (BC) survivors remain unclear.This retrospective cohort study evaluated treatment patterns, weight loss, and outcomes in BC survivors at an academic institution receiving GLP1-RA. We evaluated patients with non-metastatic (ductal carcinoma in situ (DCIS), stage 1-3) BC who received GLP1-RA (2005 - 2024). Linear regression models estimated associations between weight change and clinical factors. After excluding DCIS, propensity score matching (1:2) was used to match patients who received GLP1-RA with patients who did not, based on confounding covariates. Kaplan-Meier estimates and log-rank tests compared disease-free survival (DFS) and overall survival (OS) between GLP1-RA users versus non-users in the subgroup with invasive disease. We identified 1,022 patients; 79% had DM2. Median weight and body mass index at GLP1-RA initiation were 86.8 kg (47.2-175.0 kg) and 33.5 kg/m2 (18.9-61.8 kg/m2). In semaglutide or tirzepatide users (442, 43.2%), median weight change at 3, 6, and 12 months after GLP1-RA initiation was -1.9% (-13.2%-14.9%), -3.1% (-20.2%-19.0%), and -2.6% (-27.8%-11.5%), respectively. Endocrine therapy and metformin use were associated with weight gain and loss, respectively; invasive disease stage was linked to greater weight loss. GLP1-RA was not associated with DFS, but OS significantly differed between GLP1-RA users (n=810) and non-users (n=1620) (HR 0.37, 95% CI: 0.27-0.53, p<0.0001). In conclusion, in this real-world study in BC survivors, GLP1-RA was associated with modest weight loss and improved all-cause survival. Clinical trials are warranted to study GLP1-RA in this population.

Immunotherapy often fails in solid tumors due to an immunosuppressive tumor microenvironment, driven in part by dysfunctional dendritic cells impairing antigen presentation, and suppressive neutrophils. Recent studies revealed a non-canonical role for neutrophils in antigen presentation (nAPC), whose frequency in tumors correlates with improved prognosis in several human cancers. Here, we show that an intravenously delivered antibody-antigen-conjugate (AAC) targeting neutrophil FcγRIIIB reprograms neutrophils into nAPCs that drive robust CD8⁺ T cell activation. This response requires neutrophils and their expression of MHC-I and occurs independently of conventional type-1 dendritic cells (cDC1), demonstrating that nAPCs can compensate for cDC1 deficiencies. In a mouse melanoma model, AAC therapy promotes durable immunity limiting metastases of Ova-negative tumors in the lung and contralateral skin, with tumor burden inversely correlating with intratumoral nAPC frequency. AAC treatment efficacy is attributed to tumor infiltration by antigen-specific CD8⁺ T cells, NK cells, and memory TSCM and TRM cells recognizing both the target antigen and melanocyte-lineage antigens, consistent with effective epitope spreading, which could overcome tumor heterogeneity and antigen loss. Mechanistically, the spleen is required for T cell priming and tumor infiltration, suggesting AAC engages a cancer-spleen axis that bypasses the dysfunctional tumor-draining lymph node (LN). Both CD8⁺ T cells and NK cells are essential for tumor control. Co-treatment with anti-PD-1 enhances tumor regression and metastasis control, while anti-PD-1 alone is ineffective. In summary, AAC therapy reprograms neutrophils to initiate potent T cell immunity, offering a novel strategy to break immune exclusion and enhance anti-PD1 therapy in solid tumors.

INAFM2, the human homolog of the Drosophila inaF, is a predicted membrane protein with no known function in vertebrates. Through an in vivo genome-wide transcriptional activation screen, we uncovered INAFM2 as a potent driver of metastasis, leading us to propose naming the vertebrate gene and its protein product ROME (Regulator of Metastasis). We discovered ROME's subcellular localization, posttranslational modifications, and transcriptional profiles related to its expression. ROME negatively regulates the canonical Wnt pathway by directly binding to beta-catenin. Blocking ROME expression in zebrafish embryos results in severe developmental defects and early mortality, which can be reversed by inhibiting the canonical Wnt pathway. Notably, we demonstrate that ROME expression regulates human cancer cell motility and invasion in vitro and metastasis in vivo in both zebrafish and immunodeficient mice via tail vein and orthotopic injection models. ROME-mediated increase in cancer cell intravasation is dependent on its direct interaction with vimentin. Further, we show that elevated ROME expression correlates with poorer patient survival in multiple human cancers. Taken together, this is the first report of the vertebrate ROME gene producing a biologically active plasma membrane glycoprotein that is critical for normal development and metastasis.

Patient-derived tumoroids have emerged as promising models for evaluating patient-specific responses to anti-cancer therapies, yet their clinical adoption remains limited. While the reasons for this limited implementation are not fully elucidated, several are known and can be addressed: (1) lack of standardized protocols for tumoroid cultivation and drug exposure complicating cross-lab comparisons, (2) labor- and time-intensive cultivation procedures conflicting with clinical guidelines for timely therapy initiation, (3) prevalent use of destructive endpoint assays restricting subsequent analyses and proper growth-rate correction, and (4) poorly defined criteria for classifying tumoroid drug sensitivity that are not linked to clinical outcomes, leading to suboptimal treatment allocation in prospective studies. In this study, we developed two classifiers for assessing colorectal tumoroid sensitivity to oxaliplatin and SN-38 based on historical response rates for patients with colorectal cancer. Utilizing longitudinal, label-free confocal imaging, these classifiers offer a non-destructive method that corrects for growth-rate variations and preserves patient-derived material for further analysis. Currently, these classifiers are undergoing evaluation in a prospective clinical trial to determine the feasibility of incorporating tumoroid-based drug screening into clinical decision-making. This approach lays the groundwork for next-generation molecular tumor boards, enabling anti-cancer treatment decisions informed by integrated functional assays and biomarkers.

Lymphedema is a chronic complication of breast cancer treatment, and early intervention is crucial to reduce morbidity. This study evaluated the role of blood-based cytokine biomarkers in the prognostication of breast cancer-related lymphedema (BCRL) to improve risk prediction. A secondary analysis of inflammatory biomarkers for BCRL was performed using a previously published cohort of 147 breast cancer patients who had undergone serum cytokine profiling during their treatment at the Princess Margaret Cancer Centre from 2010-2014. Prognostic cytokine variables for lymphedema were selected by regression analysis and independence from known clinical risk factors. Regression-based modeling was employed to integrate prognostic variables for the prediction of lymphedema occurrence. We identified the immunostimulatory cytokine IFN-α2A as a potential biomarker for lymphedema development (OR 3.10, 95% CI 1.05-9.51, p=0.042), independent from known clinical risk factors. Furthermore, Kaplan-Meier analysis demonstrated 3-year lymphedema-free survival of 95% (90-100%) vs. 85% (77-94%) for below vs. above median concentrations of IFN-α2A (p=0.026). In combination with an established clinical risk regression-based model, patients identified as high risk based on clinical factors alone were able to be correctly reclassified as low risk by IFN-α2A in 31% (8/26) of cases. Our combined logistic regression model using both IFN-α2A and clinical risk score achieved an AUC of 0.895 (95% CI: 0.796 - 0.971) and Brier Score of 0.101 (95% CI: 0.061 - 0.149), representing a favourable improvement compared to the logistic regression model using clinical risk factors alone. IFN-α2A in combination with established clinical risk factors may be useful for improving BCRL prognostication.

Immune cells in the tumor microenvironment (TME) are attractive therapeutic targets, however their responses to immunotherapy and targeted therapy remain incompletely understood. We developed a patient-derived ex vivo system to profile baseline immune characteristics and model treatment-induced activation at the single-cell level. The model was utilized to study T cell responses to PD-1 blockade and VEGFR inhibition (VEGFRi) in renal cell carcinoma (RCC) patients. The baseline RCC TME was highly infiltrated by T cells, characterized by diverse cytotoxic, memory, exhausted, or regulatory phenotypes. T cells were activated by direct CD3/CD28/CD2 stimulation, upregulating the IFN-gamma, TNF, and IL-2 signaling pathways. However, activation capacity varied noticeably depending on the baseline phenotype. PD-1 blockade induced modest T cell activation, whereas VEGFRi downregulated several immune markers, including signaling pathways and immune activation-related cytokines. Our study reveals the suppressive features of the RCC TME and the challenge of fully overcoming it with PD-1 blockade and VEGFRi.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by a poor prognosis owing to the lack of therapeutic targets, including hormone receptors and HER2. Systemic chemotherapy remains the primary treatment option; however, its efficacy is limited by chemotherapy resistance, a substantial challenge in clinical management. The present study aimed to develop a novel anticancer drug that overcomes chemotherapy resistance in TNBC. First, chemotherapy-resistant MDA-MB-468 cells derived from TNBC were developed via long-term exposure to adriamycin or paclitaxel. Compared with parental cells, these resistant cells exhibited reduced sensitivity to paclitaxel, adriamycin, and eribulin in the viability assays. Various compounds were screened for their cell growth-inhibitory activity against these resistant cells to identify novel therapeutic agents; ZSTK3744 was a promising candidate and showed significant antitumor activity in vitro and in vivo. ZSTK3744 upregulated CYP1A1, CYP1B1, and TIPARP expression in MDA-MB-468 cells but exhibited no cell growth-inhibitory activity in aryl hydrocarbon receptor (AhR) knockout cells, indicating that ZSTK3744 acts as an AhR agonist. Notably, ZSTK3744 demonstrated superior tumor inhibition and lower pulmonary toxicity in ex vivo and in vivo models than other AhR agonists. These results suggest that ZSTK3744 combines robust cell growth-inhibitory activity with a favorable safety profile. In conclusion, ZSTK3744 is a promising candidate for overcoming chemotherapy resistance in TNBC, addressing the urgent need for more effective treatment options for this aggressive cancer subtype.

Plasma cell-free DNA (cfDNA) analysis holds potential to improve the detection of naturally occurring cancer in dogs, which can also serve as important model organisms for human cancer. However, there are limited comparative data on the characteristics of canine and human cfDNA. We characterized cfDNA fragmentation in 254 plasma samples from 54 healthy dogs and 54 dogs with naturally occurring sarcomas and compared them with 35 samples of human cfDNA. Using electrophoresis, whole-genome sequencing with both short and long reads, and multiplexed quantitative PCR, we assessed both fragment size distribution and fragment end sequences. We then trained a random forest classifier to distinguish healthy dogs from those with sarcomas based on cfDNA fragmentation features. Canine cfDNA fragment size distributions showed a striking deviation from humans, including a median of only 39% of fragments between 50 and 700 base pairs versus 84% in human samples. Fragment end nucleotides were more random in dogs than in humans at multiple size ranges. Similar to human patients with cancer, dogs with sarcomas had detectable copy-number changes and characteristically shorter cfDNA fragments relative to healthy dogs, enabling classification of cancer samples with 91% accuracy. Our results demonstrate key differences in cfDNA fragmentation between dogs and humans and highlight the potential for comparative translational research to advance blood-based early cancer detection in both species.

Significance: cfDNA analysis in dogs with naturally occurring cancers can enable precise detection of canine cancer and serve as a model system for human oncology. In this study, we observed differences in cfDNA fragmentation patterns between humans, healthy dogs, and dogs with sarcomas. Our results highlight the opportunity for comparative oncology research, the development of canine cfDNA diagnostics, and the investigation of biological mechanisms driving differences between humans and dogs.

Low-dose computed tomography (LDCT) plays a critical role in screening individuals for lung cancer. To better understand why its utilization remains poor, we analyzed the geospatial distribution of lung cancer screening programs in Florida to determine whether the distribution of these programs aligns with populations at greatest risk. Accredited programs offering LDCT were identified from public databases maintained by the American College of Radiology (ACR). Age-adjusted incidence and mortality for lung cancer were retrieved from the Florida Cancer Data System and Florida Department of Health. County-level demographic features were retrieved from the 2022 U.S. Census and Florida Department of Health. Univariate Pearson correlations and Kruskal-Wallis analyses revealed that screening programs in Florida are more likely to be located in counties with greater population density and a greater proportion of college-educated residents, physicians per capita, and residents with private insurance. In contrast, the number of facilities correlated inversely with the proportion of current smokers, White residents, and lung cancer incidence and mortality. In multivariate analyses, only smoking remained significantly associated with disease-specific incidence or mortality. No association between outcomes and the number of facilities in each county was identified. In conclusion, these findings indicate that the geographic distribution of certified screening programs in Florida does not align with lung cancer burden. Moving forward, strategies to address this mismatch may be helpful for improving the early detection of lung cancer.

Significance: Our findings indicate that there is a significant misalignment between the distribution of ACR-accredited facilities offering LDCT for screening and the regions of Florida where the incidence and mortality of lung cancer are greatest. In contrast to previous reports examining national data, our data suggest that these geographic disparities limit the ability of populations most vulnerable to lung cancer to ACR-certified screening.

Purpose: Whole-body hyperthermia (WBHT) is a promising therapy for advanced malignancies, including metastatic pancreatic ductal adenocarcinoma (PDAC). This first-in-human study evaluated the safety and tolerability of repeated WBHT sessions at 41.50°C for various treatment durations and in combination with standard-of-care chemotherapy regimens.

Patients and methods: Twelve patients with advanced solid tumors, primarily metastatic PDAC, completed the study. WBHT was administered using an innovative medical device (TempoCure, ElmediX) as monotherapy or with standard-of-care chemotherapy in escalating durations of 2, 4, and 6 hours, in four cohorts. Safety was assessed through adverse event (AE) monitoring, serious AE (SAE) reporting, and comprehensive clinical and laboratory evaluations up to a 10-week follow-up. Tolerability was evaluated according to whether patients were able to complete all planned WBHT cycles, with or without concomitant chemotherapy, without the need for dose modifications or treatment interruptions.

Results: The WBHT treatment was well tolerated, with most patients completing scheduled treatments despite advanced disease. The most frequent AEs were fatigue, hypokalemia, nausea, and diarrhea. Initial decubitus ulcers led to improved patient handling protocols. No clear increase in AE or SAE incidence was associated with longer WBHT durations or chemotherapy combination. The trend toward fewer AEs in later treatments likely reflects a procedural learning curve.

Conclusions: WBHT administered with the TempoCure system at 41.50°C for 2, 4, and 6 hours is safe and tolerable alone or in combination with chemotherapy, in patients with advanced cancer refractory to prior treatments. These findings support further investigation in upcoming randomized trials designed to evaluate efficacy in metastatic PDAC.

Significance: The MATTERS trial demonstrates that WBHT at 41.50°C, delivered with the TempoCure device, is a safe and well-tolerated treatment for advanced malignancies, particularly in patients with refractory metastatic PDAC. These findings support the integration of WBHT with standard chemotherapy regimens, paving the way for future efficacy trials aimed at improving therapeutic outcomes in challenging cancer populations.