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Marriage is consistently associated with earlier cancer diagnosis and improved survival, but its relationship to cancer incidence is less understood. We examined cancer risk by marital status across cancer sites, sex, race/ethnicity, and age using large-scale, population-based US data. We analyzed Surveillance, Epidemiology, and End Results data from 12 states for adults ages ≥30 years, with denominators from the American Community Survey (2015-2022). Age-adjusted incidence rates were calculated, and negative binomial regression estimated incidence rate ratios (IRR) comparing never-married with ever-married adults, stratified by sex, age group, and cancer site. Never-married adults had higher cancer incidence [IRR = 1.68; 95% confidence interval (CI), 1.53-1.84 in men; 1.85; 95% CI, 1.68-2.03 in women] across nearly all major cancer sites and racial/ethnic groups (IRR range: 1.62 in White men to 1.96 in Black men). Never-married Black men had the highest incidence; among ever-married men, Black men had lower rates than White men. Among men, site-specific IRRs reached 5.04 for anal cancer; among women, 2.64 for cervical cancer. Pronounced marital disparities were observed for gynecologic cancers and for cancers linked to infections, tobacco, and alcohol, whereas differences were smaller for breast, thyroid, and prostate cancers. Ever-married adults consistently showed lower cancer risk. Whereas some variation may reflect selection into marriage, the magnitude and site-specific patterns of association suggest that marital status stratifies cancer risk through cumulative social and behavioral pathways, including those relevant to infection-related and lifestyle-associated cancers. Ever-married status may serve as a useful social indicator for cancer risk stratification and prevention.
Asbestos remains a leading occupational carcinogen, particularly in countries where its use persists despite known health risks. This study provides a systematic analysis of the burden of cancer attributable to occupational asbestos exposure in the Americas from 1990 to 2023, using estimates from the Global Burden of Disease (GBD) Study 2023. Age-standardised mortality and disability-adjusted life-years (DALYs) attributable to asbestos were analysed for mesothelioma, lung, laryngeal, and ovarian cancers, stratified by sex and region. We conducted a descriptive analysis to assess spatiotemporal trends in the burden of cancer attributable to occupational asbestos in the Americas from 1990 to 2023. We analysed trends in age-standardized mortality and DALY rates using segmented joinpoint regression. Age-period-cohort analyses were performed for age-specific mortality and DALY rates. All analyses were stratified by cancer type, sex and GBD regions, with estimated 95% uncertainty intervals (95% UI). In 2023, High-income North America had the highest burden of cancer attributable to occupational asbestos, with 5·1 deaths (95% UI 3·9; 6·4) and 84·9 DALYs (65·6; 108·5) per 100,000 population for both sexes. However, the region also experienced the most pronounced decline, with average annual reductions of 2·0% (-2·0; -1·9) in mortality and 2·5% (-2·5; -2·4) in DALYs. Southern Latin America had the second highest rates for cancer attributable to occupational asbestos, with 2·7 deaths (2·1; 3·5) and 53·1 DALYs (40·4; 69·3) for both sexes in 2023, and showed the strongest increase in women with 2·3% (2·2; 2·4) both in mortality and DALYs annually. Age-period-cohort modelling revealed marked increases in burden of cancer attributable to occupational asbestos among women, with mortality and DALY rate ratios (RR) for lung cancer rising to 1·31 (1·20; 1·44) in Tropical and Southern Latin America, and RR for mesothelioma rising to 1·22 (1·06; 1·40) in Southern Latin America. Our study revealed inequalities in the burden of cancer attributable to occupational asbestos exposure among regions in the Americas, as well as remarkable sex disparities. Although rates were declining in North America, there is growing concern over rising rates of lung cancer and mesothelioma among women in Tropical and Southern Latin America regions, especially in Argentina and Brazil. These disparities likely reflect differences in environmental and industrial regulatory practices, as well as gendered occupational exposure patterns. Also, upward trends in female lung cancer rates may reflect increased smoking among women, while mesothelioma is much more specific to asbestos exposure. Despite regulatory advances, legacy exposures and ongoing asbestos use persist in parts of Latin America, reinforcing the need for stricter occupational health policies and asbestos bans. The findings underscore the shifting epidemiology of asbestos-related cancers and call for targeted prevention efforts, improved surveillance, and gender-responsive occupational protections. This study was partially funded by the Bill & Melinda Gates Foundation and "Coordenação de Aperfeiçoamento de Pessoal de Nível Superior-Brasil (CAPES)".
What is this summary about?There are only a few current treatment options for people with newly diagnosed advanced or recurrent endometrial cancer (cancer that has returned). The DUO-E study is testing an immunotherapy, durvalumab, and a targeted therapy, olaparib, in people with newly diagnosed advanced endometrial cancer or recurrent endometrial cancer. Durvalumab blocks the activity of a protein called PD-L1 (programmed death-ligand 1). This makes cancer cells more susceptible to being killed by immune cells. Olaparib inhibits a protein called PARP (poly [ADP-ribose] polymerase), thereby stopping cancer cells from being able to repair their DNA. This can cause cancer cells to die or make them more visible to the immune system.Mismatch repair (MMR) is a DNA repair mechanism, and patients with endometrial cancer can be defined as having tumors that are able to carry out mismatch repair (mismatch repair proficient [pMMR]) or are not able to carry out mismatch repair (mismatch repair deficient [dMMR]). DUO-E enrolled people with either mismatch repair proficient (pMMR) or mismatch repair deficient (dMMR) tumors. DUO-E investigated whether chemotherapy + durvalumab followed by either durvalumab or durvalumab + olaparib can improve outcomes compared with chemotherapy alone.What are the key takeaways?For all the people in DUO-E, the risk of disease progression (the cancer growing, spreading, or getting worse) or death was reduced with chemotherapy + durvalumab followed by either durvalumab or durvalumab + olaparib, compared with chemotherapy alone. In terms of reducing the risk of disease progression or death, the greatest benefit for chemotherapy + durvalumab compared with chemotherapy alone was seen in people with tumors that were mismatch repair deficient (dMMR); for people with tumors that were mismatch repair proficient (pMMR), the addition of olaparib further enhanced the benefit seen with durvalumab. Side effects of the treatments were manageable and generally consistent with the known side effects of the drugs when used alone.What were the main conclusions reported by the researchers?Chemotherapy + durvalumab followed by either durvalumab or durvalumab + olaparib represent new treatment options for people with newly diagnosed advanced or recurrent endometrial cancer.Clinical trial number: NCT04269200.
Early screening and targeted intervention can effectively reduce cancer burden. However, most studies have proposed polygenic score (PRS) to perform risk prediction and population risk stratification. We investigate the causal links and shared genetics between cancer and metabolic traits to map the onco-metabolic nexus. Using multivariable Cox models, we assessed 240 trait-cancer associations. Genomic analyses included genome-wide and local genetic correlations, and genomic structural equation modeling (gSEM) to identify pathways linking metabolic traits to cancer. We then used DBSLMM to build both single and integrative PRS models based on gSEM and compared their predictive performance. Most of the metabolic traits are risk factors to cancer, such as WHR-CRC (hazard ratio [HR] = 1.34, 95% confidence interval [CI]: 1.23-1.46, P = 1.59×10-11). In the genetic correlation analysis, we identified 41 significant pairs in onco-metabolic nexus and 405 significant genomic regions. MR analysis revealed 17 significant causal pairs. The integrative PRS model combining gSEM for metabolic traits improved prediction, with 13.95% variance explained in kidney cancer. The study highlights the intertwined genetic and clinical relationships between cancers and metabolic traits, improving cancer screening and intervention.
Relacorilant is a selective glucocorticoid receptor antagonist that increases the sensitivity of many cancer cell types to chemotherapy. The efficacy and safety of relacorilant plus nab-paclitaxel were assessed in the phase 3 ROSELLA (GOG-3073, ENGOT-ov72, APGOT-Ov10, and LACOG-0223) trial; the combination showed significant improvement in progression-free survival among patients with platinum-resistant ovarian cancer compared with nab-paclitaxel monotherapy. Results of the final overall survival analysis are reported here. In this open-label phase 3 trial, patients were randomly assigned 1:1 to receive relacorilant (150 mg orally the day before, day of, and day after nab-paclitaxel infusion) plus nab-paclitaxel (80 mg/m2 intravenously on days 1, 8, and 15 of each 28-day cycle) or nab-paclitaxel monotherapy (100 mg/m2 intravenously on the aforementioned schedule). Patients, aged 18 years or older, with one to three lines of previous anticancer therapy and platinum-resistant disease (progression <6 months from their last dose of platinum) were eligible. The trial was conducted at 117 hospitals and community oncology centres in 14 countries across Australia, Europe, Latin America, North America, and South Korea. Progression-free survival, assessed by blinded independent central review, and overall survival (time from randomisation to death from any cause) were dual primary endpoints. Additional prespecified endpoints included safety, second progression-free survival (time from randomisation to disease progression on subsequent anticancer therapy or death due to any cause, whichever occurred first), and patient-reported outcomes. This trial is registered at ClinicalTrials.gov, NCT05257408, and is ongoing. Between Jan 5, 2023, and April 8, 2024, 381 patients were randomly assigned to the relacorilant combination group (n=188) or the nab-paclitaxel monotherapy group (n=193). All patients had received bevacizumab; 167 (44%) had received three previous lines of therapy, and 234 (61%) had received a poly(ADP-ribose) polymerase inhibitor. At a median follow-up of 24·8 months (95% CI 23·6-25·7), the addition of relacorilant to nab-paclitaxel resulted in a statistically and clinically significant improvement in overall survival compared with nab-paclitaxel monotherapy (hazard ratio for death 0·65 [95% CI 0·51-0·83]; p=0·0004); 18-month overall survival was 46% and 27%, respectively. The median overall survival in the relacorilant combination group was extended by 4·1 months compared with the nab-paclitaxel monotherapy group (16·0 [95% CI 13·0-18·3] vs 11·9 months [10·0-13·8]). Subsequent anticancer treatments were similar across study groups. Adverse events were similar in both groups when adjusted for duration of study treatment. Neutropenia (121 [64%]), anaemia (115 [61%]), fatigue (101 [54%]), and nausea (82 [44%]) were the most common adverse events in the relacorilant combination group. No new safety signals were observed with additional follow-up since the primary analysis. The addition of relacorilant to nab-paclitaxel led to significantly longer overall survival in patients with platinum-resistant ovarian cancer, without the need for biomarker selection. The findings support relacorilant plus nab-paclitaxel as a potential new standard treatment option for patients with platinum-resistant ovarian cancer. Corcept Therapeutics.
Sporadic colorectal cancer remains a significant driver of worldwide morbidity and mortality. Environmental factors associated with colorectal cancer are increasingly well-described and now include generalized colonic dysbiosis and individual enteric bacteria. Clostridioides difficile is one such species, with recent mouse model work suggesting prolonged exposure to C. difficile toxin B is conducive to colonic tumorigenesis. However, there is a dearth of real-world human evidence linking C. difficile exposure and colorectal cancer. Herein, we analyzed a multicenter, longitudinal, electronic health record-based dataset to test the association between C. difficile test positivity and the risk of incident colorectal cancer utilizing unadjusted and multivariable (controlled for clinical conditions independently associated with colorectal cancer development) Cox proportional hazard modeling to compare C. difficile exposed and nonexposed cohorts. We found that individuals who tested recurrently positive for C. difficile had a significantly increased risk of incident colorectal cancer [adjusted HR (aHR) 2.05 (95% confidence interval, 1.27-3.29)] compared with those who tested positive only once [aHR 0.70 (0.45-1.10)] or never. Furthermore, we found potential trends that the effect of C. difficile test positivity on the risk of incident colorectal cancer was stronger amongst females compared with males. These findings help translate emerging mouse model work on C. difficile-influenced colorectal tumorigenesis and lay groundwork for more substantial human investigations into this connection. These findings also may begin to help guide the personalized deployment of novel fecal microbiota-based therapies designed to interrupt the life cycle of C. difficile within the gut of human hosts and, potentially, prevent long-term health sequelae of chronic C. difficile infection. These findings help translate emerging mouse model work on C. difficile-influenced colorectal tumorigenesis and lay groundwork for more substantial human investigations into this connection. These findings also may begin to help guide the personalized deployment of novel fecal microbiota-based therapies designed to interrupt the life cycle of C. difficile within the gut of human hosts and, potentially, prevent long-term health sequelae of chronic C. difficile infection.
Cancer is associated with many pre-existing health conditions (PHCs), but accurately quantifying these links remains challenging. Although some studies have examined these associations, large-scale analyses using diverse electronic health record (EHR) data remain limited and lack the ability to evaluate cancer risk when patients are stratified by interpersonal differences. Using a real-world EHR dataset from a large Louisiana health system comprising 8,283,236 records from 1,460,738 patients (2013-2022), we evaluated associations between pre-existing health conditions (PHCs) and subsequent cancer diagnoses within a fixed five-year risk window. We applied epidemiological, statistical, and artificial intelligence methods to the full dataset and to subgroups stratified by gender, race, and area deprivation index (ADI) for overall cancer and 20 cancer types. We identified nine ICD-10 chapters, including Chapter 4 (metabolic) and Chapter 14 (genitourinary), with 221 PHCs linked to increased cancer risk (RR > 1, 95% CI excluding 1.0, BH-FDR-adjusted p < 0.05). Key PHCs include systemic sclerosis, blood type, benign mammary dysplasia, immune mechanism disorders, disturbances of smell, lipoprotein metabolism disorders, HIV, vitamin D deficiency and diabetes. Chapter 12 (skin diseases) and Chapter 9 (circulatory diseases) showed strong associations with 10 and 13 cancer types, respectively. Age-, gender-, race-, and ADI-specific high-risk PHCs were also identified. However, these findings should be interpreted carefully, as ADI may not fully capture individual-level socioeconomic or environmental exposures, and the lack of tobacco data may introduce residual confounding.
Antibody-drug conjugate (ADC) represents an effective therapeutic strategy for cancer, leveraging a cancer-targeting monoclonal antibody (mAb) linked to a potent payload. In this study, we report novel dual-payload ADCs (DualADC), which harness one antibody to simultaneously deliver chemotherapy and immunotherapy for aggressive triple-negative breast cancer (TNBC). Specifically, we developed two-site, that is, cysteine and lysine, co-conjugation technologies to link a chemotherapeutic agent for direct tumor cell killing and a Toll-like receptor dual agonist for tumoral immunity enhancement to our humanized anti-CD276 (B7-H3) mAb. Our antibody binds to TNBC with high affinity and selectivity while exhibiting minimal off-target effects in normal human tissues. Three DualADCs were fully characterized by validating the conjugations and quantifying the drug-to-antibody ratios and drug-to-drug ratio using several analytic tools. In vitro evaluations revealed a high cancer cell binding rate via flow cytometry, efficient drug internalization with confocal microscopy, and high anticancer cytotoxicity in three TNBC cell lines. In vivo investigations in two TNBC xenograft mouse models demonstrated that DualADC carrying deruxtecan and imidazoquinoline has the best antitumor efficacy, that is, favorable biodistribution in TNBC, high tumor burden reduction, low systemic toxicity, and upregulation of immune pathways. Collectively, this study establishes advanced dual-payload antibody-drug conjugation technologies and identifies a good DualADC candidate for cancer therapy. Advanced dual-payload antibody-drug conjugation technologies were established, and a promising DualADC was developed for targeted cancer chemoimmunotherapy.
Patient-reported outcomes (PROs) are essential for understanding how cancer treatments affect individuals' symptoms, daily functioning and quality of life. This study examined how PRO data from pivotal clinical trials in breast cancer (BC), gastrointestinal (GI) cancers and non-small cell lung cancer (NSCLC) are reflected in regulatory drug labels and public-facing communications such as American Society of Clinical Oncology daily news. The goal was to identify gaps in the communication of these data, particularly in formats accessible to non-technical audiences and to highlight opportunities for improvement. We conducted a targeted review of oncology drugs approved between 2014 and 2024 by the US Food and Drug Administration and the European Medicines Agency. For each product, we assessed pivotal trials for PRO endpoints and reviewed regulatory labels for PRO claims. Public-facing materials-including sponsor websites, medical society platforms and patient advocacy content-were evaluated for the presence, clarity and visibility of PRO messaging. Messaging strength was internally rated as low, medium or high. Among 128 pivotal trials (28 BC, 34 GI, 66 NSCLC), 105 (82%) included PROs-84 as secondary and 40 as exploratory endpoints. The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item (EORTC QLQ-C30) was used in 83 trials (79.0%), and EuroQol Group in 72 (68.6%). Only 10 products included PRO content in their regulatory labelling. Of 16 BC drugs, all had PRO data, but only 4 had regulatory PRO claims. Most sponsor websites lacked PRO content; only seven products across all indications included healthcare professional-facing PRO narratives and only two on patient-facing websites. No product achieved a high messaging strength rating; 53 of 64 rated products were categorised as low (limited or no PRO communication). Despite widespread PRO data collection, integration into labelling and public communication remains limited. While label inclusion supports compliant dissemination, some PRO findings appear in public materials without formal claims. Advancing both methodological rigour and clear regulatory guidance is essential to promote balanced, patient-relevant communication in oncology.
Latinos face significant cancer health disparities and remain underrepresented in research. To address regional needs, the University of California Davis Comprehensive Cancer Center (UCDCCC) conducted its first Catchment Area Population Assessment (CAPA) to inform outreach and engagement strategies. Our purpose was to understand the best approaches for capturing Latino health need responses and to understand breast and cervical cancer screening rates and risk factors. This cross-sectional study compared two CAPA survey methodologies used from July 2019 to March 2020: a mail-based approach using random and unweighted probabilistic sampling of residential addresses versus a community-based approach using bilingual coordinators for in-person interviews. Comparisons were made on catchment population representativeness and breast and cervical cancer screening outcomes. The study included 361 Latino participants (255 community based and 106 mail based) across 16 of 19 UCDCCC catchment counties. Mail-based participants were significantly older, more educated, and had higher household incomes than community-based participants. Despite the differences in key demographics of participants in the two survey modalities, our results suggest that up-to-date breast and cervical cancer screening rates do not significantly differ. Time since the last routine checkup, primarily among community-based participants, emerged as a key predictor of screening adherence. Mail-based methods captured more affluent Latinos, whereas community-based methods reached more underserved populations. Each method introduced distinct sampling biases, but together they provided a more balanced representation of the catchment area. Mail- and community-based survey methods enhance the representativeness of Latino health data and support more equitable research recruitment strategies. Latinos remain underrepresented in cancer research, limiting effective outreach. This study demonstrates that combining mail- and community-based survey methods improves representation across socioeconomic groups, revealing key predictors of breast and cervical cancer screening adherence. These findings inform equitable data collection and engagement strategies, advancing inclusive cancer prevention efforts in underserved populations.
Cervical cancers (CaCx) remain a significant health burden. Limitations on CaCx chemotherapeutic intervention caused by toxic side effects are a persistent barrier to care. Here, we show that the human papillomavirus oncogenes that cause most CaCx also increase the levels of a cancer-associated isoform of PCNA known as caPCNA. The abundance of caPCNA is specifically elevated in CaCx. Similar to observations in other cancers, we found that a small molecule inhibitor of caPCNA (AOH1996) selectively killed cell line, organoid, and xenograft models of CaCx. Our subsequent molecular analysis identified a novel ability of AOH1996 to induce cell death by disrupting the interaction between PCNA and gamma tubulin, resulting in mitotic arrest. We show AOH1996 selectively induces mitotic death in transformed cells, because these cells attempt to progress through mitosis, rather than decondensing their chromosomes and reforming their nuclear membranes like untransformed control cells. Further, we show that these differences allow AOH1996 to specifically sensitize CaCx cells to cisplatin, a frontline chemotherapeutic used to treat CaCx. We found that subtherapeutic doses of AOH1996 and cisplatin could reduce CaCx xenograft growth and improve survival, similarly to a therapeutic dose of cisplatin without the cisplatin-induced toxicity that restricts care. To our knowledge, this study provides the first evidence that AOH1996 can function as a cisplatin-sensitizing agent in cervical cancer models.
Skin cancer is caused by aberrant cells that proliferate uncontrollably after unrepaired DNA damage results in mutations in the epidermis. The majority of skin cancer is caused by high UV exposure from the sun, tanning beds, or sunlamps. Due to sociocultural hurdles, limited access to specialized dermatological care, and low public knowledge, many nations, including India, have higher mortality rates and late-stage presentations. The unequal distribution of specialized dermatological treatments, particularly in rural and underdeveloped areas, makes detection and treatment more difficult. For skin cancer, one of the most prevalent malignancies with a high death rate, early detection is crucial. This study gathered 1200 dermoscopic images from two clinics in Himachal Pradesh in order to solve these problems. In order to automatically classify dermoscopic clinical images into melanoma and non-melanoma skin cancer categories, this study compares VGG16 with ResNet-50. Preprocessing, lesion segmentation, and classification are all part of the suggested approach. A collection of 1200 dermoscopic images with clinical annotations was used to improve the models. ResNet-50 outperformed VGG16 in tests, with 93% accuracy and 96% AUC-ROC as opposed to 89% and 94%, respectively. These results emphasize how crucial model selection and preprocessing are to diagnostic performance. Ensemble methods, multi-class classification, explainability integration, and clinical validation will be investigated in order to facilitate the implementation of AI-assisted dermatological diagnostic tools.
We present an update on the molecular pathology of prostate cancer, including its molecular classification, key driver gene and other somatic alterations, as well as current concepts around biomarker testing, with an emphasis on information pertinent to the surgical pathologist for their daily practice and communications with clinicians. For in depth coverage of the molecular and clinical features of potential prostate cancer precursors, including high grade prostatic intraepithelial neoplasia, the readers are directed to recent publications.
Two years of immunotherapy is the standard treatment for most patients with advanced non-small cell lung cancer. However, little is known about postimmunotherapy therapeutic strategies. To describe subsequent treatments and outcomes after pembrolizumab discontinuation following 2 years of therapy. This nationwide, population-based, retrospective cohort study used administrative health data from the French National Health Insurance database from patients who received a diagnosis of incident lung cancer between January 1, 2015, and December 31, 2022, who received pembrolizumab for 22 to 26 months and survived at least 29 months (landmark). The data cutoff was October 31, 2024. Data were analyzed in October 2025. Treatment with pembrolizumab for 22 to 26 months, followed by observation of subsequent therapeutic management after discontinuation. Overall survival (OS) was defined as the time between landmark and death of any cause. Time to next treatment or death was defined as the time between the last pembrolizumab infusion and new treatment or death. Among 41 498 patients who received frontline pembrolizumab for advanced disease, 5293 were alive at the landmark time and completed 2 years of treatment, and 1555 discontinued pembrolizumab at 2 years. The population of interest for this study included 1480 patients with at least 6 months of follow-up; the median (range) age was 63.0 (32.0-90.0) years, 537 (36.3%) were female, 943 (63.7%) were male, and 616 (41.6%) had received pembrolizumab monotherapy. After a median follow-up of 16 months (95% CI, 15.2-16.8) after the landmark, the OS rate at 48 months was 76.9% (95% CI, 72.7%-81.3%), and the time to next treatment or death rate at 48 months after pembrolizumab discontinuation was 49.9% (95% CI, 45.3%-55.0%). Overall, 387 patients (26.1%) received subsequent therapy. The first treatments after pembrolizumab discontinuation were chemotherapy (200 [51.7%]), radiotherapy (183 [47.3%]), and immunotherapy (4 [1.0%]). Considering all subsequent treatment lines, 19 patients (0.1%) received an immunotherapy rechallenge. Twelve months after initiation of the new treatment, the OS rates were 87.0% (95% CI, 81.6%-92.7%) for radiotherapy, 69.9% (95% CI, 61.1%-80.0%) for chemotherapy, and 61.4% (95% CI, 41.3%-91.4%) for immunotherapy. This cohort study found that, among long-term cancer survivors with advanced non-small cell lung cancer who were treated with pembrolizumab, survival outcomes were high and immunotherapy rechallenge was uncommon.
Colorectal cancer (CRC) progression is heavily influenced by the tumor microenvironment (TME), where cancer-associated fibroblasts (CAFs) are key players. However, the heterogeneity, plasticity, and functional roles of CAFs in CRC remain poorly understood. We integrated single-cell RNA sequencing (scRNA-seq) data from four public CRC datasets and spatial transcriptomics data. Using computational approaches such as Harmony, Monocle2, and CellChat algorithms, we analyzed cellular landscapes, CAF subtype identification, developmental trajectories, transcription factor networks, and cell-cell communications to reveal CAF heterogeneity and their crosstalk with other cell subtypes in CRC. We identified eight distinct CAF subtypes with unique gene expression profiles and developmental plasticity. The CTHRC1+ CAF subtype was significantly associated with T cell exclusion and upregulated expression of immune checkpoint genes. We uncovered a specific communication axis between CTHRC1+ CAFs and MMP7+ malignant epithelial (Malig-Epi) cells mediated by the thrombospondin (THBS)2-SDC4 ligand-receptor signaling. High infiltration of both cell types synergistically correlates with worse prognosis and unfavorable response to immunotherapy. Our study delineates CAF heterogeneity in CRC and highlights the CTHRC1+ CAF subtype as a critical organizer of an immunosuppressive niche. The THBS2-SDC4 signaling pathway between CTHRC1+ CAFs and MMP7+ epithelial cells acts as a potential therapeutic target to disrupt protumorigenic crosstalk and improve clinical outcomes for CRC patients.
Dietary macronutrient composition has emerged as a key modulator of pancreatic tumorigenesis, yet the impact of lipid-rich diets, particularly ketogenic diets (KD), on the earliest stages of pancreatic cancer development remains unclear. To investigate how dietary lipids shape the initiation and progression of Kras-driven neoplasia, we examined the effects of a low-fat diet (LFD), high-fat diet (HFD), and KD in the Ptf1aCreERT2;KrasG12V (AcinarKrasG12V) mouse model. KD-fed mice showed the shortest survival (median 26 ± 7 days) compared with the standard diet (SD, 87 ± 29; P = 0.02) and LFD (57 ± 27; P = 0.02), whereas HFD-fed mice also exhibited reduced survival relative to SD (35 ± 25; P = 0.05). KD feeding was associated with severe glucose intolerance and elevated circulating β-hydroxybutyrate levels. Histologically, KD-fed AcinarKrasG12V mice developed invasive, sarcomatoid-like pancreatic ductal adenocarcinoma (PDAC), whereas HFD-fed mice showed increased poorly differentiated PDAC; in both groups, these aggressive tumors were associated with extensive fibrosis and increased stromal CD39 expression relative to tumor compartments. Proteomic analysis demonstrated activation of the PI3K-Akt-mTOR and EGFR signaling pathways in tumors from KD- and HFD-fed AcinarKrasG12V mice. Serum cytokine/chemokine profiling revealed a proinflammatory and proangiogenic milieu in KD-fed AcinarKrasG12V mice. Collectively, these results suggest that dietary lipid enrichment prior to oncogenic Kras activation is associated with accelerated early pancreatic neoplasia and a microenvironment conducive to tumor progression. These findings underscore the need for careful consideration of KD use in individuals at elevated risk for pancreatic cancer. This article evaluates the impact of KDs and HFDs prior to oncogenic Kras activation in the AcinarKrasG12V model. These findings reveal that lipid-rich diets accelerate PDAC progression and have important implications for dietary recommendations in individuals at elevated pancreatic cancer risk.
BI 905711, a TRAILR2/CDH17 bispecific antibody, demonstrated preclinical apoptotic pathway activation and antitumor activity. Two phase Ia/Ib studies tested BI 905711 monotherapy (NCT04137289) or combination therapy (NCT05087992) in advanced, refractory gastrointestinal (GI) cancers. Both studies aimed to determine maximum tolerated dose (MTD) (phase Ia) and recommended phase II dose (RP2D)/recommended dose for expansion (RDE) (phase Ib). In phase Ia, patients received BI 905711 monotherapy (0.02-4.8 mg/kg), or 0.6-1.2 mg/kg plus biweekly FOLFIRI and bevacizumab. Phase Ib assessed selected doses and regimens given biweekly or weekly (three weeks on, one week off). Safety, efficacy, and pharmacokinetics/pharmacodynamics were evaluated. In NCT04137289, 110 patients [median age 61; 80% with colorectal cancer (CRC); median 3 prior therapies (range 1-6)] received monotherapy. No DLTs occurred, MTD was not reached, RP2D was not determined, and 48.2% of patients had treatment-related AEs (TRAEs); most commonly nausea (16.4%). In 104 response-evaluable patients, 22.1% achieved stable disease (SD). In NCT05087992, 12 patients with CRC [median age 54.5) received combination treatment. Two patients reported DLTs, MTD was not reached, and the selected RDE was 0.6 mg/kg plus biweekly FOLFIRI and bevacizumab. Most patients (91.7%) had TRAEs, including decreased appetite (33.3%), alanine transaminase increased, aspartate transaminase increased, and diarrhea (25.0% each). Eleven patients (91.7%) achieved SD. Pharmacokinetic/pharmacodynamic data indicated linear dose-exposure and ≥2-fold activation of plasma caspase 3/7. In heavily pretreated patients with GI tumors, BI 905711 monotherapy or with FOLFIRI plus bevacizumab displayed a manageable safety profile and limited clinical activity.
Excessive centrosome activation is detrimental to normal cells by hampering bipolar-spindle formation during mitosis and inducing cell death. In the highly aggressive anaplastic thyroid cancer (ATC), cells expressing the ALDH+ stem-cell trait are enriched in supernumerary centrosomes and tolerate centrosome amplification, which offers these cells a growth advantage. Our earlier work characterized the chromosomal instability within this cell population, which was due to dysfunctional centrosomes manifesting as a deficiency in pericentriolar material. Here, we report a novel 2-(4-morpholinoanilino-6-[(2-exo-norbornyl) amino)-purine (MEAP) that preferentially restores centrosome microtubule-nucleation activity in centrosome-deficient ALDH+ ATC cells. Exposure of these cells to MEAP induced pericentriolar accumulation and microtubule-nucleation activity of supernumerary centrosomes, resulting in spindle multipolarity. Consequently, MEAP was capable of preferentially eliminating ALDH+ ATC cell population, thus reducing cell spherogenesis and self-renewal capacity. In a preclinical ATC mouse model, MEAP preferentially eliminated ALDH+ cell clusters, increased the rate of spindle multipolarity, decreased chromosomal instability, and generated a robust antitumor response. Lastly, we identified that the selective activity of MEAP in ALDH+ cells involved the modulation of NEDD9-STAT3 signaling. Together, these findings support the potential of targeting centrosome amplification as an alternative therapeutic approach for aggressive ALDH+ cancers failing first line therapeutics.
Pancreatic ductal adenocarcinoma (PDAC) diagnoses are often accompanied by a number of physical and psychologic symptoms, including anxiety and depression. As a result, many patients are prescribed anxiolytics such as benzodiazepines (BZD) that have unintended effects on the tumor. Previous work from our lab has highlighted that structural differences between BZD compounds may be responsible for different clinical outcomes influenced by their effects on cancer-associated fibroblasts (CAF) within the PDAC tumor microenvironment (TME). In this study, we demonstrate that the commonly prescribed N-substituted triazolobenzodiazepine alprazolam (ALP) abrogates the production of proinflammatory cytokines, including CCL2, CXCL12, interleukin 6 (IL6), and IL8, in human CAFs. This phenotype is unique only to azole-containing BZDs, including midazolam. The ability of ALP to regulate proinflammatory cytokine production is maintained in vivo as ALP-treated mice bearing pancreatic tumors exhibited reductions in IL6 within the tumor interstitial fluid. Mechanistically, an unbiased phosphoproteomic approach revealed that ALP abrogates Toll-like receptor 4-mediated cytokine production in CAFs. These findings cumulatively support that ALP dampens CAF-mediated inflammatory signaling within the PDAC TME. The data in the present study focus on the characterization of the effects of ALP on CAF output and provide a compelling basis to suggest that ALP may have a broad impact on remodeling the pancreatic cancer immune landscape and therapeutic response.