Tumor Survival Research Articles

Differential effects of high-fiber and low-fiber diets on anti-tumor immunity and colon tumor progression in a murine model.

The role of dietary fiber in colon cancer prevention remains controversial. We investigated its impact on anti-tumor immunity and the gut microbiota in APCmin/+ mice infected with Enterotoxigenic Bacteroides fragilis. Mice were fed high-fiber, low-fiber, or chow diets, and tumor burden, survival, cytokines, microbiota, and metabolites were analyzed. Contrary to the belief that high fiber inhibits tumor progression, it had no significant impact compared to chow diet. However, the low-fiber diet significantly reduced tumor burden and improved survival. Mechanistically, high fiber increased pro-inflammatory cytokines and CD4+Foxp3+RORγt+IL-17A+ regulatory T cells, while low fiber enhanced anti-inflammatory cytokines and cytotoxic T-cells. High fiber enriched microbial taxa associated with IL-17A+RORγt+ Tregs and altered metabolites, including reduced tryptophan and increased short-chain fatty acids and bile acids. Low fiber produced opposite effects. These findings suggest that dietary fiber's effects on colon cancer depends on microbial infection and immune status, emphasizing the need for personalized dietary interventions in colon cancer management.

Nanocarrier-mediated modulation of cGAS-STING signaling pathway to disrupt tumor microenvironment.

The cGAS-STING signaling plays an important role in the immune response in a tumor microenvironment (TME) of triple-negative breast cancer (TNBC). The acute and controlled activation of cGAS-STING signaling results in tumor suppression, while chronic activation of cGAS-STING signaling results in immune-suppressive TME that could result in tumor survival. There is a need, therefore, to develop therapeutic strategies for harnessing tumor suppressive effects of cGAS-STING signaling while minimizing the risks associated with chronic activation. Combination therapies and nanocarriers-based delivery of cGAS-STING agonists have emerged as promising strategies in immunotherapy for controlled modulation of cGAS-STING signaling in cancer. These approaches aim to optimize the tumor suppressive effects of the cGAS-STING pathway while minimizing the challenges associated with modulators of cGAS-STING signaling. In the present review, we discuss recent advancements and strategies in combination therapies and nanocarrier-based delivery systems for effectively controlling cGAS-STING signaling in cancer immunotherapy. Further, we emphasized the significance of nanocarrier-based approaches for effective targeting of the cGAS-STING signaling, tackling resistance mechanisms, and overcoming key challenges like immune suppression, tumor heterogeneity, and off-target effects.

The relationship between tumour necrosis, systemic inflammation, body composition and survival in patients with colon cancer

BackgroundIn cancer cachexia the relationship between the tumour, its environment and the systemic inflammatory response is not clear. This study aims to examine this relationship in greater detail.MethodsHost characteristics included the presence of a Systemic Inflammatory Response (SIR) as measured by Systemic Inflammatory Grade (SIG), sarcopenia (SMI) and myosteatosis (SMD) were measured. Categorical variables were analysed using χ2 test for linear-by-linear association, or χ2 test for 2 by 2 tables. Survival analysis was carried out using univariate and multivariate Cox regression.ResultsA total of 473 patients were included. Of these, 70.4% were over 65 years of age, 54.8% were male and 49.8% had an ASA grade of 1 or 2. Pathological examination showed that the majority of patients had a T3 (53.7%) or a T4 (34.0%) cancer and 73.0% had evidence of necrosis. A SIG score of 0 or 1 was present in 57.7% of patients. Tumour necrosis was associated with age (p < 0.01), tumour location (p < 0.01), T-stage (p < 0.001), margin involvement (p < 0.05), SIG (p < 0.001), SMI (p < 0.01), SMD (p < 0.05) and 5-year survival (p < 0.001). On multivariate survival analysis in patients with T3 cancers age (HR: 1.45 95% CI 1.13–1.86 p < 0.01), ASA grade (HR: 1.50 95% CI 1.15–1.95 p < 0.01) and SIG (HR: 1.28 95% CI 1.11–1.48 p < 0.001) remained independently associated with survival.ConclusionThese results suggest that tumour necrosis and the subsequent SIR could result in profound changes in body composition and survival. Further pre-clinical and clinical work is required to prove causation.

Cancer cells avoid ferroptosis induced by immune cells via fatty acid binding proteins

BackgroundCancer creates an immunosuppressive environment that hampers immune responses, allowing tumors to grow and resist therapy. One way the immune system fights back is by inducing ferroptosis, a type of cell death, in tumor cells through CD8 + T cells. This involves lipid peroxidation and enzymes like lysophosphatidylcholine acyltransferase 3 (Lpcat3), which makes cells more prone to ferroptosis. However, the mechanisms by which cancer cells avoid immunotherapy-mediated ferroptosis are unclear. Our study reveals how cancer cells evade ferroptosis and anti-tumor immunity through the upregulation of fatty acid-binding protein 7 (Fabp7).MethodsTo explore how cancer cells resist immune cell-mediated ferroptosis, we used a comprehensive range of techniques. We worked with cell lines including PD1-sensitive, PD1-resistant, B16F10, and QPP7 glioblastoma cells, and conducted in vivo studies in syngeneic 129 Sv/Ev, C57BL/6, and conditional knockout mice with Rora deletion specifically in CD8+ T cells, Cd8 cre;Rorafl mice. Methods included mass spectrometry-based lipidomics, targeted lipidomics, Oil Red O staining, Seahorse analysis, quantitative PCR, immunohistochemistry, PPARγ transcription factor assays, ChIP-seq, untargeted lipidomic analysis, ROS assay, ex vivo co-culture of CD8+ T cells with cancer cells, ATAC-seq, RNA-seq, Western blotting, co-immunoprecipitation assay, flow cytometry and Imaging Mass Cytometry.ResultsPD1-resistant tumors upregulate Fabp7, driving protective metabolic changes that shield cells from ferroptosis and evade anti-tumor immunity. Fabp7 decreases the transcription of ferroptosis-inducing genes like Lpcat3 and increases the transcription of ferroptosis-protective genes such as Bmal1 through epigenetic reprogramming. Lipidomic profiling revealed that Fabp7 increases triglycerides and monounsaturated fatty acids (MUFAs), which impede lipid peroxidation and ROS generation. Fabp7 also improves mitochondrial function and fatty acid oxidation (FAO), enhancing cancer cell survival. Furthermore, cancer cells increase Fabp7 expression in CD8+ T cells, disrupting circadian clock gene expression and triggering apoptosis through p53 stabilization. Clinical trial data revealed that higher FABP7 expression correlates with poorer overall survival and progression-free survival in patients undergoing immunotherapy.ConclusionsOur study uncovers a novel mechanism by which cancer cells evade immune-mediated ferroptosis through Fabp7 upregulation. This protein reprograms lipid metabolism and disrupts circadian regulation in immune cells, promoting tumor survival and resistance to immunotherapy. Targeting Fabp7 could enhance immunotherapy effectiveness by re-sensitizing resistant tumors to ferroptosis.

Autophagy and Cancer: Insights into Molecular Mechanisms and Therapeutic Approaches for Chronic Myeloid Leukemia

Autophagy is a critical cellular process that maintains homeostasis by recycling damaged or aberrant components. This process is orchestrated by a network of proteins that form autophagosomes, which engulf and degrade intracellular material. In cancer, autophagy plays a dual role: it suppresses tumor initiation in the early stages but supports tumor growth and survival in advanced stages. Chronic myeloid leukemia (CML), a hematological malignancy, is characterized by the Philadelphia chromosome, a chromosomal abnormality resulting from a translocation between chromosomes 9 and 22. Autophagy has emerged as a key factor in CML pathogenesis, promoting cancer cell survival and contributing to resistance against tyrosine kinase inhibitors (TKIs), the primary treatment for CML. Targeting autophagic pathways is being actively explored as a therapeutic approach to overcome drug resistance and enhance cancer cell death. Recent research highlights the intricate interplay between autophagy and CML progression, underscoring its role in disease biology and treatment outcomes. This review aims to provide a comprehensive analysis of the molecular and cellular mechanisms underlying CML, with a focus on the therapeutic potential of targeting autophagy.

Clinicopathological factors related to survival in gastroenteropancreatic neuroendocrine tumors (GEP-NET): 20 years experience in the American British Cowdray Medical Center.

656 Background: Neuroendocrine neoplasms (NEN) are a diverse group of tumors originating from neuroendocrine cells found throughout the body. Their “rarity”, heterogeneity, and non-specific presentation contribute to limited reliable epidemiological data, especially in developing countries such as Mexico. This study aims to analyze the clinical and pathological features of gastroenteropancreatic neuroendocrine tumors (GEP-NET) and their association with survival in a third-level center in Mexico. Methods: A retrospective cohort study at the American British Cowdray Medical Center, in Mexico City, was conducted. We included all histopathological confirmed GEP-NET from 2004 to 2024. Clinical, biochemical, and radiological features at diagnosis were analyzed. Survival was estimated using Kaplan-Meier and Log-Rank test. Results: We identified 110 NENs, of which 89% were GEP-NET, 56.1% were female, and the median age was 57.7 (SD 13.8) years. The clinical stage was metastatic (50%), localized (37.7%), and locally advanced (6.1%). The primary sites were the pancreas (49%), small bowel (23.5%), gastric (10.2%), colon (7.1%), rectum (5.1%), appendix (3.1%), and unknown (2%). ECOG performance status were 0-1 in 96.9%. In the metastatic setting, liver involvement was 96.2%, mainly high hepatic burden (59.6%). Symptoms were abdominal pain (34.6%), diarrhea (16.3%), and bowel obstruction (6.1%). Functioning tumors were 26.8%, and carcinoid syndrome was found in 9.2%. Grades 1, 2, and 3 were 62.9%, 34%, and 3.1% respectively. The median of Ki-67 was 6.4%. At diagnosis, Ga-68 PET/CT scan, serum CgA, and urinary 5-HIIA were performed in 98.2%, 39.7%, and 16.3% of patients. Among metastatic patients, 87.1% received at least one line of systemic treatment, primarily with somatostatin analogs (62.9%). In all population, the median follow-up was 42.5 months and the median overall survival (OS) was 164.9 (SD 12.2) months. Univariate analyses showed that primary site (p=0.02), Ki-67 &lt;5% (p=0.02), CgA &lt;700 ng/ml (p=0.03), and low hepatic burden (p=0.01) were statistically significantly associated with OS. Conclusions: This study provides critical insights into GEP-NET characteristics in a Mexican population, highlighting clinical, biochemical, and radiological factors associated with better survival.

Evaluation of event-free survival (EFS) as a surrogate for overall survival (OS) in patients with locally advanced esophageal carcinoma (LA EC) receiving definitive chemoradiotherapy (dCRT).

412 Background: Drug development in esophageal cancer is rapidly evolving, and identifying surrogates for patient outcomes to accelerate clinical drug development remains an important unmet medical need. Although early clinical endpoints such as EFS, disease free survival (DFS) are proven to be valid surrogates for overall survival (OS) in early esophageal (Ajani JA et al. 2022), gastric (Oba K et al. 2013; Wainberg ZA et al. 2023), and gastroesophageal junction tumors (Ronellenfitsch U. et al. 2013) after disease resection, there are no such surrogacy data evaluating patients who underwent non-operative management. Specifically, there has been no prior systemic evaluation of the predictive value of EFS as a surrogate for OS among LA EC patients treated with dCRT. This study evaluated the trial-level correlation between EFS and OS in unresectable LA EC patients receiving dCRT. Methods: A systematic literature review was conducted to identify randomized controlled trials (RCTs) of dCRT interventions in unresectable LA EC (search cutoff date: April 2023). Studies reporting EFS (or similar outcomes such as progression free survival (PFS), defined as time from randomization to local, regional, or distant recurrence, or death) and OS were included. EFS and OS hazard ratios (HRs) of each treatment comparison were extracted. Correlation between the log(HR) of EFS and OS was assessed using weighted linear regression (WLR). The coefficient of determination (R 2 ) was used to evaluate the strength of the correlation. A good surrogate was defined as an R 2 ≥ 0.65 (Ciani et al . 2017) or an R 2 ≥ 0.75 (Lassere et al . 2008). Leave-one-out cross-validations and sensitivity analyses were conducted to assess the robustness of the WLR model and correlation analyses, respectively. Results: The final analysis included 14 between-treatment comparisons from 11 RCTs (total number of patients = 2,812). We found a strong statistical correlation between EFS and OS, with an estimated slope coefficient of 0.91 ( p &lt; 0.001) and R 2 of 0.80 (95% confidence interval [CI]: 0.38, 0.96). In the leave-one-out cross validation, 71.4% of observed OS HRs fell within the predicted 95% CIs. Sensitivity analyses showed R 2 of 0.75 among studies conducted in China and R 2 of 0.73 after including studies that did not report EFS definition. Conclusions: In a pooled analysis of 11 clinical trials corresponding to over 2800 patients, we observed a strong statistical correlation between EFS and OS outcomes. This analysis supports the utility of EFS as a valid surrogate of OS in patients with unresectable LA EC receiving dCRT.

Evaluating polyethylene, polyether-ether-ketone, and metal-on-metal locking mechanism survival in Modular Universal Tumour and Revision System knee reconstructions for oncological indications : insights from the MUTARS Orthopedic Registry Europe.

Over time, the locking mechanism of Modular Universal Tumour and Revision System (MUTARS) knee arthroplasties changed from polyethylene (PE) to polyether-ether-ketone Optima (PEEK) and metal-on-metal (MoM) in an attempt to reduce the risk of mechanical failure. In this study, we aimed to assess the cumulative incidence of locking mechanism revision for symptomatic instability by type of material, and assess potential associated risk factors. The MUTARS Orthopaedic Registry Europe was used for a retrospective review of 316 patients (54% male (n = 170), median age 44 years (IQR 23 to 61)) who underwent a MUTARS knee arthroplasty for oncological indications between December 1995 and January 2023. The minimum follow-up was 12 months, and the median follow-up was 7.9 years (IQR 3.3 to 13.0). A competing risk model was used to estimate the cumulative incidence of first locking mechanism revision with death and revision for any other reason as competing events. Possible risk factors were assessed employing a univariate cause-specific hazards regression model. Symptomatic instability of the hinge or locking mechanism due to wear (n = 20) or breakage (n = 14) occurred in 34 patients (11%): 9% of PE (n = 4/45), 20% of PEEK (n = 9/44), and 9% of MoM locking mechanisms (n = 21/227). The cumulative incidences of revision for instability due to wear or locking mechanism breakage at two, five, and ten years were 0%, 5% (95% CI 1 to 15), and 5% (95% CI 1 to 15) for PE, 5% (95% CI 1 to 14), 14% (95% CI 5 to 26), and 16% (95% CI 7 to 29) for PEEK, and 0%, 3% (95% CI 1 to 6), and 10% (95% CI 5 to 16) for MoM. With PE as the reference category, the cause-specific hazard ratio for PEEK and MoM were 3.6 (95% CI 1.1 to 11.9; p = 0.036) and 3.2 (95% CI 1.1 to 9.5; p = 0.043), respectively. Age, BMI, resection length, and extra-articular resections were not associated with the time to locking mechanism revision. Alterations in prosthetic materials have not decreased the revision risk for locking mechanism failure. Besides locking mechanism material, no other patient- or prosthesis-related risk factors for locking mechanism failure were identified. Improvement of the locking mechanism is warranted since revision exposes patients to the risk of serious secondary complications.

A phase II open-label study of sacituzumab govitecan in patients with previously treated locally advanced, recurrent, or metastatic cholangiocarcinoma (SIGNA).

TPS651 Background: Cholangiocarcinoma (CCA) is a highly aggressive cancer with limited treatment options. Trop-2, a transmembrane calcium signal transducer, plays a key role in cellular self-renewal, proliferation, and transformation, thereby promoting tumorigenesis. Its overexpression has been associated with disease progression and shorter survival in several epithelial tumors, including CCA. Sacituzumab govitecan (SG) is an antibody-drug conjugate composed of a humanized anti-trophoblast cell-surface antigen 2 (Trop-2) monoclonal antibody coupled to SN-38, the active metabolite of the topoisomerase inhibitor, irinotecan. Based on the results from the Phase III ASCENT trial, SG was approved by the FDA for treating relapsed or refractory triple-negative breast cancer and hormone receptor-positive breast cancer, regardless of Trop-2 expression. Given Trop-2's expression in CCA, SG is being investigated as a potential treatment option in this setting. Methods: This Phase II, non-randomized, open-label, single-arm study is being conducted at the University of Kansas Cancer Center and its affiliated sites. Eligibility : Key inclusion criteria include patients with locally advanced, recurrent, or metastatic CCA who have undergone at least one line of prior therapy, have adequate archival tissue for biomarker evaluation or are willing to undergo a biopsy, and have an ECOG performance status of 0-1. Key exclusion criteria include known homozygosity for the UGT1A1*28 allele, which is associated with irinotecan toxicity, and prior treatment with topoisomerase I inhibitors. Treatment Plan : SG is administered at 10 mg/kg intravenously on Days 1 and 8 of every 21-day cycle. Imaging will be performed every 6 weeks. Biopsies will be required both prior to treatment and on-treatment (between Days 15-21 of Cycle 1). Objectives : Primary objective: To determine the anti-tumor activity of SG as measured by the overall response rate (ORR) according to RECIST 1.1. Secondary objectives: To assess treatment safety in participants who have received at least one dose of SG, and to evaluate anti-tumor activity based on progression-free survival (PFS), disease control rate (DCR), and overall survival (OS). Statistical Plan : The sample size (n=22) was calculated using a modified Simon two-stage design, hypothesizing an improvement in ORR to 25%, compared to a baseline value of 8%. In the first stage, 14 patients will be enrolled. If ≤1 participant demonstrates an ORR, the study will be stopped for futility. If ≥2 participants show ORR, an additional 8 patients will be enrolled (total n=22). The study will be deemed successful if ≥4 participants achieve an ORR. This design provides 80.9% power with an 8.5% type I error rate. Stopping rules include halting the trial if the grade 4-5 treatment-related toxicity rate reaches 10%. Enrollment is ongoing. Clinical trial information: NCT06178588 .

Tumor mutational burden and survival on immune checkpoint inhibition in &gt;8000 patients across 24 cancer types

BackgroundThere is uncertainty around clinical applicability of tumor mutational burden (TMB) across cancer types, in part because of inconsistency between TMB measurements from different platforms. The KEYNOTE 158 trial supported United States Food and Drug Administration (FDA) approval of the Foundation Medicine test (FoundationOneCDx) at TMB≥10 mut/Mb as a companion diagnostic (CDx) for single-agent pembrolizumab in second+line. Using a large real-world dataset with validated survival endpoint data, we evaluated clinical validity of TMB measurement by the test in over 8000 patients across 24 cancer types who received single-agent immune checkpoint inhibitor (ICI).MethodsPatients with advanced-stage cancers from 24 cancer types treated with single-agent anti-PD(L)1 therapy in standard-of-care settings were included. Deidentified data from electronic health records from approximately 280 cancer treatment facilities were captured into a clinico-genomic database. This study used the TMB algorithm from the FDA-approved test supporting solid tumor CDx and composite mortality variable validated against the national death index: real-world overall survival (rwOS). Following a prespecified analysis plan, rwOS by TMB level was assessed using Cox PH models adjusted for Eastern Cooperative Oncology Group performance status, prior treatment, microsatellite instability, sex, age, opioid rx pretherapy, and socioeconomic assessment.Results8440 patients met inclusion criteria. Adjusting for aforementioned factors, increasing TMB was significantly associated with rwOS across tumor types; HRs (95% CIs) relative to TMB&lt;5: TMB 5 to &lt;10: 0.95 (0.89 to 1.02), TMB 10 to &lt;20: 0.79 (0.73 to 0.85), TMB≥20: 0.52 (0.47 to 0.58). For individual cancer types with prespecified statistical power, adjusted rwOS comparing TMB≥10 vs TMB&lt;10 significantly favored TMB≥10 in 9 of 10 cancer types. In microsatellite stable subcohorts (except colorectal cancer), TMB≥10 remained associated with enriched ICI benefit. Exploratory assessments of patients receiving ICI+chemotherapy (n=4369) observed more favorable rwOS only in TMB≥20.ConclusionsAcross &gt;8000 patients treated with single-agent ICI, and within individual cancer types with sufficient power, elevated TMB based on the FDA-approved CDx was associated with more favorable rwOS compared with similar patients with lower TMB levels. This biomarker deserves further clinical investigation to potentially guide the use of immunotherapy in expanded clinical contexts.

Systematic literature review (SLR) of prognostic factors (PFs) in locally advanced rectal cancer (LARC) and mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) rectal cancer (RC).

303 Background: Innovative immunotherapies arebeing developed to improve clinical outcomes in patients (pts) withdMMR/MSI-H LARC who respond poorly to the current standard of care. A comprehensive overview of PFs in dMMR/MSI-H LARC may provide insight into the natural history of this disease to inform clinical study design and pt risk stratification. Methods: Systematic searches of bibliographic databases (EMBASE, MEDLINE, Cochrane; 2013–2023) and congress websites (2021–2023) were conducted to identify PFs for tumor response and survival outcomes in adult pts with LARC (SLR1) and dMMR/MSI-H RC (SLR2). Given the expected high volume of evidence, SLR1 was limited to large observational studies (≥1000 pts) and clinical trials (≥100 pts); SLR2 had no such limits. Results: 95 of 2307 publications met the inclusion criteria for SLR1. Of the PFs reported in ≥20 studies, older age, more lymph node involvement or fewer nodes assessed, higher T-stage or larger tumor size, higher histologic grade, and more comorbidities were most frequently significantly associated with poorer patient prognosis (Table). 3 of 289 publications met the inclusion criteria for SLR2. Neoadjuvant chemoradiation therapy (CRT) compared to chemotherapy (CT) was associated with statistically significant worse disease-free survival (DFS) and distant metastasis-free survival (DMFS), while T- or N-stage, age, and sex did not significantly impact these outcomes. Low vs middle tumor localization was also associated with worse DMFS. Stage III and IV disease were associated with worse RC-specific survival, while surgical procedure (segmental vs extended) showed no difference in overall survival (OS). The addition of neoadjuvant CRT or adjuvant CRT/CT to surgery alone had no impact on OS but was associated with worse DFS. Conclusions: Evidence regarding PFs in dMMR/MSI-H RC is scarce and may limit its interpretability, highlighting the need for further research that may be informed by the PFs identified from SLR1. The results from these SLRs may be helpful for optimizing patient management and treatment decision making, and to further contextualize RC clinical trials. PFs reported in ≥20 studies with ≥75% of studies reporting significant results in pts with LARC. PF Studies reporting PF (n) Studies reporting significant* impact of PF on prognosis (%) Poorer prognosis group Top 2 most frequently reported outcomes Age 59 81.4 Older OS, DFS Lymph node involvement/assessment 55 78.2 Yes or higher N stage OS, DFS T-stage or tumor size 53 79.2 Higher or larger OS, DFS Histologic grade 37 75.7 Higher OS, pathological complete response (pCR) Comorbidities 23 87.0 More OS, pCR *p-value &lt;0.05 was considered significant as reported in the identified studies.

Phosphatidic acid as a cofactor of mTORC1 in platinum-based chemoresistance: Mechanisms and therapeutic potential.

Platinum-based chemotherapeutics, such as cisplatin and carboplatin, are widely used to treat various malignancies. However, the development of chemoresistance remains a significant challenge, limiting their efficacy. This review explores the multifaceted mechanisms of platinum-based chemoresistance, with a particular focus on the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway, which plays a critical role in promoting tumor survival and resistance to platinum compounds. Additionally, we examined the role of phosphatidic acid (PA) and its synthesizing enzymes, phospholipase D (PLD) and lysophosphatidic acid acyltransferase (LPAAT), in the regulation of mTORC1 activity. Given the involvement of mTORC1 in chemoresistance, we evaluated the potential of mTOR inhibitors as a therapeutic strategy to overcome platinum resistance. Finally, we discuss combination therapies targeting the mTOR pathway alongside conventional chemotherapy to improve treatment outcomes. This review highlights the potential of targeting mTORC1 and related pathways to improve therapeutic strategies for chemoresistant cancers.

NRF-mediated autophagy and UPR: Exploring new avenues to overcome cancer chemo-resistance.

The development of chemo-resistance remains a significant hurdle in effective cancer therapy. NRF1 and NRF2, key regulators of redox homeostasis, play crucial roles in the cellular response to oxidative stress, with implications for both tumor growth and resistance to chemotherapy. This study delves into the dualistic role of NRF2, exploring its protective functions in normal cells and its paradoxical support of tumor survival and drug resistance in cancerous cells. We investigate the interplay between the PERK/NRF signaling pathway, ER stress, autophagy, and the unfolded protein response, offering a mechanistic perspective on how these processes contribute to chemoresistance. Our findings suggest that targeting NRF signaling pathways may offer new avenues for overcoming resistance to chemotherapeutic agents, highlighting the importance of a nuanced approach to redox regulation in cancer treatment. This research provides a molecular basis for the development of NRF-targeted therapies, potentially enhancing the efficacy of existing cancer treatments and offering hope for more effective management of resistant tumors.

Discovery of a sushi domain-containing protein 2-positive phenotype in circulating tumor cells of metastatic breast cancer patients

Cell lines derived from circulating tumor cells (CTCs) in the blood provide important biological information on cancer metastasis. CTC-ITB-01 is a CTC cell line derived from a patient with metastatic estrogen receptor-alpha (ER-alpha) positive breast cancer two months before the death of the patient. After a LC-MC/MS based proteomics analysis of CTC-ITB-01, we found extraordinary high levels of the poorly characterized protein SUSD2 (sushi domain-containing protein 2) in CTC-ITB-01. Expression of SUSD2 on subsets of CTCs was validated on clinical blood samples of patients with metastatic breast cancer. SUSD2-positive CTCs could be captured specifically by a MACS-based approach. We overexpressed SUSD2 in the poorly-metastatic cell line MCF-7. This resulted in upregulation of ER-alpha, the tumor progression protein GRP78 (78-kDa glucose-regulated protein) and downregulation of the tumor suppressor protein PDCD4 (programmed cell death protein 4). We observed downregulation of SUSD2 and PDCD4 after hypoxia and simulation of re-oxygenation in the blood in MCF-7 and MDA-MB-468, while in CTC-ITB-01 SUSD2 levels remained unchanged, and only PDCD4 was downregulated under hypoxia. In conclusion, we show, for the first time, that SUSD2 is expressed in CTCs and appears to affect key proteins in tumor progression and survival.

Targeting PCSK9, through an innovative cVLP-based vaccine, enhanced the therapeutic activity of a cVLP-HER2 vaccine in a preclinical model of HER2-positive mammary carcinoma.

HER2-targeted therapies have revolutionized the treatment of HER2-positive breast cancer patients, leading to significant improvements in tumor response rates and survival. However, resistance and incomplete response remain considerable challenges. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition is a novel therapeutic strategy for the management of dyslipidemia by enhancing the clearance of low-density lipoprotein cholesterol receptors, however recent evidence also shows links between PCSK9 and cancer cells. We present an innovative immunization approach combining capsid virus-like particle (cVLP)-based vaccines against HER2 and PCSK9. The therapeutic activity of the combined vaccine was evaluated in female mice challenged with HER2-positive mammary carcinoma cells. Controls included untreated mice and mice treated with cVLP-PCSK9 and cVLP-HER2 as standalone therapies. Antibodies elicited by vaccinations were detected through ELISA immunoassay. The functional activity of the antibodies was tested in 3D-soft agar assay on human HER2 + + + trastuzumab sensitive and resistant cells. Mice vaccinated with cVLP-HER2 + cVLP-PCSK9 displayed tumor regression from the 40th day after cell challenge in 100% of mice remaining tumor-free even 4months later. In contrast, 83% of mice treated with cVLP-HER2 vaccine alone experienced an initial tumor regression, followed by tumor relapse in 60% of subjects. Untreated mice and mice treated with the cVLP-PCSK9 vaccine alone developed progressive tumors within 1-2months after cell injection. The combined vaccine approach elicited strong anti-human HER2 antibody responses (reaching 1-2mg/ml range) comprising multiple immunoglobulins isotypes. cVLP-PCSK9 vaccine elicited anti-PCSK9 antibody responses, resulting in a marked reduction in PCSK9 serum levels. Although the anti-PCSK9 response was reduced when co-administered with cVLP-HER2, it remained significant. Moreover, both cVLP-HER2 + cVLP-PCSK9 and cVLP-HER2 alone induced anti-HER2 antibodies able to inhibit the 3D growth of human HER2 + + + BT-474 and trastuzumab-resistant BT-474 C5 cells. Strikingly, antibodies elicited by the combined vaccination were more effective than those elicited by the cVLP-HER2 vaccine alone in the inhibition of trastuzumab-resistant C5 cells. The results indicate that cVLP-PCSK9 vaccination shows adjuvant activity when combined with cVLP-HER2 vaccine, enhancing its therapeutic efficacy against HER2-positive breast cancer and holding promise in overcoming the challenges posed by resistance and incomplete responses to HER2-targeted therapy.

Yttrium-90 Radioembolization for Intrahepatic Cholangiocarcinoma: Non-University Tertiary Care Center Experience.

Intrahepatic cholangiocarcinoma (ICC) presents a significant clinical challenge due to its high fatality rate and limited surgical candidacy. With only 30-40% of patients eligible for surgery upon diagnosis, alternative therapies are imperative. This study assesses the efficacy of Yttrium-90 (Y-90) radioembolization for unresectable ICC patients in a non-university tertiary care center (NUTCC). A retrospective analysis of 15 unresectable ICC patients treated with Y-90 radioembolization was conducted. Tumor response, survival, and adverse events were evaluated using RECIST criteria. 60% of patients exhibited partial response, and 20% showed stable disease, with notable tumor size reduction and a median survival of 14 months. Minimal adverse effects were observed, indicating Y-90's favorable safety profile. Y-90 radioembolization shows potential in reducing tumor burden and enhancing survival rates with minimal adverse effects for unresectable ICC. Larger prospective studies are needed to confirm its efficacy and define its role in ICC treatment protocols.

Decoding oral cancer: insights from miRNA expression profiles and their regulatory targets

Oral cancer (OC) is a prevalent malignancy with high mortality rates, largely attributed to late diagnosis and limited therapeutic advancements. MicroRNAs (miRNAs), as critical regulators of gene expression, have emerged as key players in modulating plethora of cellular mechanisms. This study analyzed miRNA and gene expression profiles in OC using publicly available datasets from the Gene Expression Omnibus (GEO) to explore their roles in tumorigenesis. A total of 23 differentially expressed miRNAs (DEmiRs) and 1,233 differentially expressed genes (DEGs) were identified. Functional annotation and pathway enrichment analyses highlighted significant involvement of DEmiRs and their target genes in cell cycle-related processes, including enrichment in the nucleus, transcription factor activity, regulation of nucleosides, nucleotide and nucleic acids, cell growth and/or maintenance, mitotic cell cycle, mitotic M-M/G1 phases an DNA replication. Furthermore, different signaling cascades such as IGF signaling, PDGF signaling and LKB1 signaling and PLK1 signaling pathways were also found associated with DEmiR-related regulation of OC progression. Protein-protein interaction (PPI) network analysis identified key molecular hubs associated with DEmiR and DEGs in OC. Notably, most of these hub genes such as NEK2, NDC80, NUF2, PLK1, SMAD2, TP53, TPX2, TTK, UBE2C, WDHD1, WTAP, YWHAZ are directly or indirectly associated with cell cycle progression, underscoring the role of DEmiRs in driving tumor proliferation and survival in OC via dysregulating cell cycle. This study offers insights into the molecular mechanisms underlying OC and highlights miRNAs as potential biomarkers and therapeutic targets to disrupt the cancerous cell cycle and improve treatment outcomes.

Receptor CDCP1 is a potential target for personalized imaging and treatment of poor outcome HER2+, triple negative and metastatic ER+/HER2- breast cancers.

Receptor CUB-domain containing- protein 1 (CDCP1) was evaluated as a target for detection and treatment of breast cancer. CDCP1 expression was assessed immunohistochemically in tumors from 423 patients (119 triple-negative breast cancer (TNBC); 75 HER2+; 229 ER+/HER2- including 228 primary tumors, 229 lymph node and 47 distant metastases). Cell cytotoxicity induced in vitro by a CDCP1-targeting antibody-drug conjugate (ADC), consisting of the human/mouse chimeric antibody ch10D7 and the microtubule disruptor monomethyl auristatin E (MMAE), was quantified, including in combination with HER2-targeting ADC T-DM1. Detection of CDCP1-expressing primary and metastatic xenografts in mice was examined by PET-CT imaging using 89zirconium-labelled ch10D7 (89Zr-ch10D7). The impact of ch10D7-MMAE on tumor burden and survival in vivo, including in combination with T-DM1, was quantified in cell line and patient-derived xenograft mouse models. CDCP1 is expressed predominantly on the surface of malignant cells of 70% of TNBCs, 80% of HER2+ tumors, and increases in ER+/HER2- tumors from 44.9% in primary tumors to 56.4% in lymph node metastases and 74.3% in distant metastases. PET-CT imaging with 89Zr-ch10D7 is effective for the detection of primary and metastatic CDCP1-expressing TNBCs in mice. ADC ch10D7-MMAE kills CDCP1-expressing cells in vitro and controls primary and metastatic TNBC xenografts in mice, conferring significant survival advantages over chemotherapy. It compares favorably to T-DM1 in vivo, and ch10D7-MMAE combined with T-DM1 showed the most potent efficacy, markedly reducing tumor burden of CDCP1+/HER2+ xenografts and prolonging mouse survival, compared with T-DM1 or ch10D7. CDCP1-directed molecular imaging has potential to identify aggressive breast cancers for CDCP1-targeted treatment.

TNIP1 Impacts Prognosis by Modulating the Immune Microenvironment in BRCA.

Breast invasive carcinoma (BRCA) affects women worldwide, and despite advancements in diagnosis, prevention, and treatment, outcomes remain suboptimal. TNIP1, a novel target involved in multiple immune signaling pathways, influences tumor development and survival. However, the connection between BRCA and TNIP1 remains unclear. Analysis of data from the TCGA, GEO, Sangerbox, and Ualcan databases revealed that TNIP1 is underexpressed in BRCA tissues. This finding was corroborated by RT-PCR and immunohistochemistry. Furthermore, data from the TCGA and GEPIA2 databases, along with Sangerbox, identified TNIP1 as a marker of poor prognosis in BRCA patients. TNIP1 expression shows significant positive correlations with the BRCA Tumor Microenvironment (TME) StromalScore (R = 0.22), ImmuneScore (R = 0.25), and ESTIMATEScore (R = 0.27). Various algorithms have demonstrated a strong association between TNIP1 expression and BRCA tumor-infiltrating immune cells (TIICs). Further analysis using EPIC, TIMER, MCPCounter, QUANTISEQ, xCell, and other computational tools revealed that elevated TNIP1 expression is significantly associated with increased immune cell scores. TNIP1 expression in BRCA tumor tissues also shows a strong correlation with immune checkpoint markers. Data from the HAP database indicate that TNIP1 expression is predominantly involved in the normal skin microenvironment. Subsequent analysis using the TISCH platform with the BRCA single-cell dataset demonstrated that TNIP1 exhibits higher expression levels in immune cells compared to non-immune cells in BRCA patients. This expression is significantly positively correlated with inflammation (R = 0.25) and differentiation (R = 0.28) within the TME, while showing negative correlations with BRCA stemness (R = -0.34) and invasion (R = -0.22). Consequently, TNIP1 is proposed as a potential prognostic marker and therapeutic target for BRCA.

Liposomal encapsulation of cholecalciferol mitigates in vivo toxicity and delays tumor growth

IntroductionVitamin D3 (cholecalciferol) has demonstrated potential anticancer properties, but its clinical application is limited by associated toxicity at effective doses. This study investigated the use of liposomal encapsulation to increase the therapeutic efficacy of vitamin D3 while mitigating its toxicity.MethodsLiposomal vitamin D3 (VD-LP) was prepared via the film-hydration method and characterized for particle size, polydispersity index, encapsulation efficiency, and long-term stability. In vitro gene expression modulation was evaluated in monocytic THP-1 cells, and antiproliferative effects were assessed in HT29 (colorectal), BT474 (breast), and TRAMP-C1 (prostate) cancer cell lines. In vivo antitumor efficacy and toxicity were tested in a mouse model with subcutaneously implanted MC38 tumors. Tumor growth, survival rates, and serum calcium and phosphate levels were analyzed.ResultsVD-LP demonstrated high encapsulation efficiency and stability over 90 days, with a consistent particle size of approximately 83 nm. VD-LP modulated immune-related and metabolic gene expression in THP-1 cells, including upregulation of antimicrobial peptides and vitamin D receptor genes. VD-LP showed superior antiproliferative effects compared to free vitamin D3 in all tested cancer cell lines. In vivo, VD-LP delayed tumor growth and improved survival without causing hypercalcemia, highlighting its favorable toxicity profile.DiscussionLiposomal encapsulation of vitamin D3 significantly improves its anticancer efficacy while mitigating toxicity, making it a promising strategy for future cancer therapies. VD-LP shows potential for enhanced therapeutic applications with reduced adverse effects, warranting further clinical exploration.