Potential Biomarkers Of Response Research Articles

The tumor suppressor SALL2 opposes chemotherapeutic resistance in breast cancer.

Chemotherapy continues to be the primary treatment for certain types of breast cancer. However, despite an initial positive response to chemotherapeutic agents, the development of resistance is inevitable. The exact molecular mechanisms underlying this phenomenon remain unclear. In this research, a significant downregulation of SALL2 expression was observed in chemo-resistant breast cancer, which was attributed to promoter methylation. Decreased SALL2 expression correlated significantly with poorer relapse-free survival in chemotherapy-treated patients with breast cancer. Functionally, SALL2 silencing induced a stem cell-like phenotype in breast cancer cells, fostering resistance to cisplatin both in vitro and in vivo. This resistance was mediated, at least in part, through the transcriptional regulation of BTG2, a negative regulator of stemness, achieved by direct binding to its promoter regions. These findings underscore the critical role of SALL2 in modulating cisplatin response and propose SALL2 as a potential prognostic biomarker for chemotherapy response in breast cancer.

Potential Prognostic Protein Biomarkers in Tears From Noninfectious Uveitis Patients Under Biologic Treatment as a Prelude to Personalized Medicine.

Adalimumab (ADA) is a systemic biological treatment option approved for the treatment of noninfectious uveitis (NIU); however, up to 40% of patients do not respond to the drug, either in a primary or secondary manner. Here, we evaluated the proteomic profile of patients with NIU who fail to ADA to identify proteins implicated in intraocular inflammation, as well as potential biomarkers for treatment response and novel therapeutic targets. Cross-sectional observational study of patients with NIU under ADA treatment for six or more months. Tears were collected with microcapillary tubes and protein analyzed by data-independent acquisition/sequential window acquisition of all theoretical mass spectra. Differentially expressed proteins (DEPs) were defined based on the fold change between their expression in nonresponders (NR) and responders (R). Protein network and gene ontology analysis were performed. The χ2 test for trend and receiver operating characteristic (ROC) curves were used to evaluate potential biomarkers of treatment response. Twenty-nine DEPs, 14 upregulated and 15 downregulated, were detected in NR. These proteins were mainly related to enhanced neutrophil effector functions and redox imbalance. ROC analysis identified defensin-1,3 (DEF-1,3), biotinidase, and ATP-binding cassette transporter A1 as potential biomarkers for treatment response. This is the first study on a clinical cohort of patients with noninfectious uveitis that identifies tear proteins related to neutrophil hyperactivation as drivers of the persistent intraocular inflammation observed in NR to ADA and provides evidence that targeting interleukin 6, Janus kinases, or the complement cascade could be potential alternative therapeutic strategies in these patients. Our results indicate the potential of high-throughput proteomics to provide insights into the underlying pathological mechanisms of persistent intraocular inflammation observed in patients who do not adequately respond to anti-TNF treatment and the value of tear proteomics as a tool for personalized medicine.

CTIM-32. PHASE I/II STUDY OF STEREOTACTIC RADIOSURGERY WITH CONCURRENT OLAPARIB FOLLOWED BY ADJUVANT DURVALUMAB AND PHYSICIAN’S CHOICE SYSTEMIC THERAPY IN SUBJECTS WITH BREAST CANCER BRAIN METASTASES (SOLARA)

Abstract BACKGROUND Despite progress in the treatment of brain metastasis for HER2+ breast cancer, outcomes for patients with HER2-negative breast cancer brain metastases remain poor. Preclinical studies show inhibitors of poly(ADP-ribose) polymerase (PARP) are effective in combination with radiation therapy as a DNA damage response inhibitor. Triple-negative breast cancer (TNBC) has higher rates of homologous recombination deficiency compared to other subtypes, and together with HER2-negative, BRCA-mutated breast cancer would be particularly sensitive to PARP inhibition. PARP inhibition has also demonstrated promising efficacy combined with immunotherapy in patients with germline BRCA-mutant and metastatic TNBC in clinical trials. In addition, immunotherapy with stereotactic radiosurgery (SRS) is associated with favorable intracranial control and survival in patients with brain metastases. We hypothesize that this biologically-driven combination will enhance local control of SRS-treated brain metastases through synergy with PARP inhibition, while controlling micrometastatic disease via potentiation of the immune response. METHODS We are conducting a multi-institution, Phase I/II trial of SRS plus olaparib, followed by durvalumab (with physician’s choice systemic therapy), for patients with TNBC (any BRCA status) or HER2-negative with BRCA-mutated (germline or somatic) breast cancer brain metastases [NCT04711824]. A total of 41 patients are planned for enrollment at 8 sites. The primary objectives are to evaluate safety and tolerability (Phase I) and determine intracranial disease control at 6 months (Phase II). Secondary objectives include assessing intracranial and global progression-free survival, overall survival, and intracranial and extracranial response rate. Exploratory objectives will assess potential biomarkers of treatment response, including changes in circulating tumor cells and DNA in blood and cerebrospinal fluid, germline and tumor mutations in DNA repair pathway genes, and PD-L1 expression, as well as quality of life and patient-reported outcomes. As of May 2024, phase I has been completed without dose-limiting toxicity, and phase II is currently enrolling. Funding/drug provision from AstraZeneca.

BIOM-36. DETECTION OF CIRCULATING TUMOR DNA (CTDNA) IN CEREBROSPINAL FLUID (CSF) IN PATIENTS WITH GLIOBLASTOMA TREATED IN PHASE I CLINICAL TRIAL

Abstract BACKGROUND As circulating tumor DNA (ctDNA) has been shown to be a source of tumor-specific biomarkers, liquid biopsy has emerged as a novel noninvasive tool in diagnosis, disease monitoring and treatment selection in several solid tumors. However, its use in brain tumors remains challenging because ctDNA is commonly not detected in blood. Thus, CSF (cerebrospinal fluid) has emerged as a potential source of ctDNA in the context of brain tumors. PATIENTS AND METHODS We prospectively evaluated the detection of ctDNA in CSF (CSF-ctDNA) +/- blood of patients with pre-treated MTAP-deleted glioblastoma, currently treated in a phase I clinical trial evaluating PRMT5 inhibitors. We did CSF samples at C2D15 and at progression, after patient’s oral and written consent. CSF was collected by lumbar puncture and analyzed with a panel of 35 genes including IDH1-2, TERT promoter and EGFR. Blood was collected, synchronously with CSF, by peripheral veinous punction and analyzed with the Foundation One Liquid CDx panel. RESULTS Between January and April 2024, five patients were included. All of them undergone initial surgical resection and received at least one previous systemic treatment associated with radiotherapy. At least one somatic mutation was identified in each patient, including EGFR amplification in 2/5 patients (40%). CSF was not available at baseline. One patient provided CSF only at progression. Four patients provided CSF at C2D15 on treatment, and among them, one patient was also collected at progression. At data cut-off, one patient was still on treatment. We identified a detectable level of CSF-ctDNA in only one patient with occipital tumor localization, with detection of EGFR amplification known at diagnosis. Synchronous blood analysis showed only clonal hematopoiesis variants. CONCLUSION We showed in this small cohort of patients that detection of CSF-ctDNA is technically feasible. The type of panel used might be optimized for this population especially to monitor patients as a potential surrogate biomarker for treatment response.

MicroRNAs as potential biomarkers of response to modified Atkins diet in treatment of adults with drug-resistant epilepsy: A proof-of-concept study

BackgroundAccurate predictors of response to modified Atkins diet (MAD) are needed. MicroRNAs are potential biomarkers in epilepsy. This study aimed to explore the value of circulating miR-146a, miR-155, miR-22, miR-21 and miR-134 levels in predicting response to MAD. MethodsPatients who completed 3 months of MAD were selected from a prospective cohort of adults with DRE followed in a specialized MAD outpatient clinic. Patients were classified as responders if any reduction in seizure frequency at follow-up, calculated through seizure-calendars). The >50 % seizure reduction cut-off was also explored. Qualitative benefits in seizures and cognition were analysed. Blood samples were collected prior to initiate MAD and microRNAs were quantified by qRT-PCR. ResultsThirty-nine patients were included (56 %males, mean age=33.1±8.5yo, 62 %focal epilepsies, 59 %structural aetiology): 20(51 %) were responders [mean reduction in seizure frequency=54 %(17–100 %); 10 had ≥50 % reduction]; 25(64 %) reported qualitative benefit in seizures and 21(54 %) reported cognitive benefits. At pre-treatment baseline, a panel combining serum levels of all studied microRNAs predicted seizure reduction (AUC=0.839, p<0.0001), qualitative benefit in seizures (AUC=0.683, p=0.048) and in cognition (AUC=0.751, p<0.01) at 3months. miR-146a was the only significant microRNA when evaluated in isolation. There was no statistical correlation in the biomarkers when a ≥50 % seizure reduction was compared to <50 %. ConclusionsA panel combining pre-treatment serum levels of miR-146a, miR-155, miR-134, miR-21 and miR-22 predicted any reduction in seizures with MAD in adults with DRE at 3months. This panel may be a promising biomarker and a useful tool in the selection of patients.

Repair-assisted damage detection as a potential predictive biomarker for immunotherapy response in ovarian cancer

Repair-assisted damage detection as a potential predictive biomarker for immunotherapy response in ovarian cancer

The intra-tumoral microbiome as a potential biomarker of response to external beam radiation therapy in cervical cancer

BackgroundWe aimed to determine the potential predictive value of the intra-tumoral microbiome as a marker of the response to external beam radiation therapy (EBRT) in cervical cancer (CC).MethodsA prospective longitudinal trial of 36 CC patients receiving pelvic radiotherapy was designed to investigate microbial characteristic signatures and diversity (alpha and beta) of multiple sites (tumor, vaginal, gut, urethral, and oral) in the superior response (SR) and inferior response (IR) groups of CC patients by 16S rRNA sequencing. Utilized the least absolute shrinkage and selection operator (LASSO) logistic regression method to analyze clinicopathological factors that potentially influenced the efficacy of EBRT. LEfSe analysis highlighted the microbiome features that best distinguished the categorized patient samples. Selected parameters were validated with Spearman correlation analysis, receiver operating characteristic (ROC) area under the curve (AUC) analysis and Kaplan-Meier survival analysis.ResultsFirstly, in our cohort, LASSO logistic regression analysis revealed no association between clinicopathological factors and EBRT efficacy. Subsequently, we employed 16S rRNA sequencing to compare microbiome differences across multiple sites and their correlations with major clinicopathological factors. We discovered that the intra-tumoral microbiome was independent of clinicopathologic features and represented the most direct and reliable reflection of the microbial differences between the SR and IR groups. We found lower alpha diversity in the tumor microbiome of SR group and identified the most relevant microbiome taxa (Bifidobacteriaceae, Beijerinckiaceae, and Orbaceae) associated with the efficacy of the response to EBRT in CC patients. We then conducted ROC analysis, finding that specific microbial taxa had an AUC of 0.831 (95% CI, 0.667–0.995), indicating the potential of these taxa as biomarkers for predicting EBRT efficacy. Kaplan-Meier survival analysis showed a better prognosis for patients with lower alpha diversity and higher relative abundance of Bifidobacteriaceae.ConclusionsOur data suggested that intra-tumoral specific microbiome taxa and lower alpha diversity may play an important role in the CC patient sensitivity to EBRT and offer novel potential biomarkers for predicting the response to EBRT efficacy.

Altered Expression of Neuroplasticity-Related Genes in Alcohol Addiction and Treatment.

Alcohol use disorder's complexity arises from genetic and environmental factors, with alcohol metabolism genes and neurotransmitter pathways being critical. This study aims to analyze synaptic plasticity gene expression changes in individuals with AUD in order to study their contribution to AUD development and to identify potential biomarkers of treatment response. RNA was extracted from whole peripheral blood (20 patients, 10 healthy controls), before and after treatment (Qiagen AllPrep RNA/DNA Mini Kit), and the gene expression of 84 genes related to neuroplasticity was studied using the RT2 Profiler for Human Synaptic Plasticity RT-PCR Array (PAHS-126ZA, Qiagen), comparing AUD patients to control and responders to non-responders. The potential prognostic/predictive biomarkers were searched using machine learning models. A total of 35 dysregulated genes were found in AUD patients. EPHB2, EGR, and AKT1 were increased, while TIMP1, NCAM1, and GRM2 were decreased. Responders showed distinct gene expression profiles at baseline. After treatment, the expression of 57 genes was normalized, while NCAM1, GRM2, and BDNF showed the most significant recovery. EGR4, INHBA, and NCAM1 emerged as potential biomarkers to predict treatment success. These results indicate that gene profiles in peripheral blood can serve as prognostic markers for the prognosis and treatment of AUD, although further validation is required.

Secreted Apoe rewires melanoma cell state vulnerability to ferroptosis.

A major therapeutic barrier in melanoma is the coexistence of diverse cellular states marked by distinct metabolic traits. Transitioning from a proliferative to an invasive melanoma phenotype is coupled with increased ferroptosis vulnerability. However, the regulatory circuits controlling ferroptosis susceptibility across melanoma cell states are unknown. In this work, we identified Apolipoprotein E (APOE) as the top lipid-metabolism gene segregating the melanoma MITFhigh/AXLlow proliferative/ferroptosis-resistant from MITFlow/AXLhigh invasive/ferroptosis-sensitive state. Mechanistically, ApoE secreted by the MITFhigh/AXLlow cells protects the invasive phenotype from ferroptosis-inducing agents by reducing the content of peroxidation-prone polyunsaturated fatty acids and boosting GPX4 levels both in vitro and in vivo. Whole-exome sequencing indicates that APOEhigh expression in patients with melanoma is associated with resistance to ferroptosis, regardless of APOE germline status. In aggregate, we found a ferroptosis-resistance mechanism between melanoma cell states relying on secreted ApoE and APOEhigh expression as a potential biomarker for poor ferroptosis response in melanoma.

CD74 is a potential biomarker predicting the response to immune checkpoint blockade

BackgroundImmune checkpoint blockade (ICB) has been improving the patient outcome in multiple cancer types. However, not all patients respond to ICB. Biomarkers are needed for selecting appropriate patients to receive ICB. CD74 is an important chaperone that regulates antigen presentation for immune response. However, the relationship between CD74 expression and ICB response remains elusive.MethodsThe unified normalized pan-cancer dataset was downloaded from the UCSC database. Wilcoxon Rank Sum Rank Tests were used to analyze the expression differences between normal and tumor samples in each tumor type. Then, the prognostic value of CD74 was determined using univariable Cox proportional hazards regression analysis. The STRING database was utilized to construct the protein-protein interaction (PPI) network of CD74 and the signal pathways were analyzed as well. The correlation of CD74 expression with immune cells and immune regulating genes was investigated in the TIMER database. The TIDE framework was utilized to evaluate the relationship between CD74 expression and the response to immunotherapy. Moreover, the localization of CD74 in the tumor immune microenvironment was verified using multiplex immunohistochemistry. Clinically annotated samples from 38 patients with esophageal cancer treated with neoadjuvant chemotherapy combined with ICB were analyzed for CD74 expression using immunohistochemistry.ResultsIn this study, we investigated the prognostic and predictive value of CD74 in different types of cancer. Compared with normal tissue, the expression of CD74 was higher in tumor tissue in various cancers. High expression of CD74 was associated with improved patient prognosis in the majority of cancers. CD74 and its interacting proteins were mainly enriched in the immune-related pathways. The expression of CD74 was significantly positively correlated with B cells, CD4 T-cells, CD8 T-cells, neutrophils, macrophages and dendritic cells. TIDE analysis showed that tumors with high CD74 expression may have better responses to immunotherapy and improved patient survival. In patients with esophageal cancer who had received ICB, higher intratumoral CD74 expression was associated with improved response to ICB.ConclusionsThe findings of this study suggest that the high expression of CD74 may be a potential predictive biomarker of response to ICB.

Phase II Trial of Gemcitabine and Nab-Paclitaxel for Recurrent Osteosarcoma with Serial Monitoring Using Liquid Biopsy: A Report from the National Pediatric Cancer Foundation.

The combination of gemcitabine and docetaxel is often used to treat patients with recurrent osteosarcoma. Nab-paclitaxel has preclinical activity against osteosarcoma and is potentially less myelosuppressive than docetaxel. We conducted a prospective multi-institutional phase II trial combining gemcitabine and nab-paclitaxel for patients aged 12 to 30 years with recurrent osteosarcoma and measurable disease. A Simon's two-stage design was used to test a 4-month progression-free survival (PFS-4) of 10% vs. 35%. Patients received nab-paclitaxel 125 mg/m2 and gemcitabine 1,000 mg/m2 weekly × 3 in 4-week cycles. Immunohistochemical analysis of archival tissue and serial assessment of circulating tumor cells (CTC) and circulating tumor DNA (ctDNA) using ultralow passage whole-genome sequencing were performed to identify potential biomarkers of response. Eighteen patients received 56 total cycles (median 2, range 1-12). Two patients (11%) experienced confirmed partial response and six (33%) received >2 cycles. The PFS-4 was 28% (95% confidence interval, 13%-59%). Six patients required dose reductions and three patients were removed due to toxicities. All 18 patients had detectable CTCs and 10 had ctDNA identified. All eight patients with MYC amplification at study entry experienced disease progression. Gemcitabine and nab-paclitaxel demonstrated similar clinical activity and toxicity compared to previous retrospective reports utilizing gemcitabine and docetaxel in patients with recurrent osteosarcoma. Serial analysis of CTC and ctDNA was feasible in this prospective multi-institution study and provides preliminary data on the use of these assays in patients with relapsed disease.

Neurofilament heavy chain and chitinase 3-like 1 as markers for monitoring therapeutic response in multiple sclerosis

AimsThe aim of this study was to evaluate the association of serum neurofilament heavy chain (sNfH) and chitinase 3-like 1 (sCHI3L1) with treatment response and disease activity in multiple sclerosis (MS). MethodsThis single-center, prospective, observational cohort study was conducted at the MS Centre, University Hospital Ostrava, Czech Republic, from May 2020 to August 2023. sNfH and sCHI3L1 were determined using ELISA. A mixed-effects linear model with a log-transformed outcome variable was applied. ResultsWe analyzed 459 samples from 57 people with MS. Patients were sampled an average of 8.05 times during 21.9 months of follow-up. Those experiencing a relapse at sampling had a sNfH concentration 50 % higher than those in remission (exp(β) 1.5, 95 % CI 1.15–1.96). A longer duration of treatment was associated with lower sNfH (exp(β) 0.95, 95 % CI 0.94–0.96). Patients switched from low- to high-efficacy disease-modifying therapies (DMTs) had higher sNfH than patients treated with low-efficacy DMTs only (exp(β) 1.95, 95 % CI 1.35–2.81). Higher sCHI3L1 was associated with older age (exp(β) 1.01, 95 % CI 1.00–1.02) and longer DMT use (exp(β) 1.01, 95 % CI 1.00–1.02). sCHI3L1 values were not associated with relapse at the time of sampling, renal function, sex, or type of DMT. ConclusionIn contrast to sCHI3L1, sNfH may be a potential biomarker for monitoring treatment response and confirming clinical relapse in MS. Further research is needed to determine the long-term dynamics of sNfH and develop related treatment strategies.

Changing of gamma-H2AX in peripheral blood mononuclear cells during concurrent chemoradiation in locally advanced rectal cancer patients: a potential response predictor.

The most detrimental effect of DNA damage from radiation is DNA double-strand breaks, making it critical to identify reliable biomarkers for treatment response in cancer therapy. Gamma-H2AX (γ-H2AX), a marker of DNA double-strand breaks, was evaluated in this study as a potential biomarker for treatment response in locally advanced rectal cancer patients undergoing preoperative concurrent chemoradiation (CCRT). Thirty patients with locally advanced rectal cancer received preoperative CCRT. Peripheral blood mononuclear cells (PBMCs) were collected at five time points: baseline, 24 hours after the first radiation fraction, mid-treatment, end of treatment, and six weeks post-CCRT. γ-H2AX levels were measured in these samples. MRI was used to assess treatment response based on magnetic resonance tumor regression grade (mrTRG). Patients were classified as responders or non-responders based on mrTRG. T-test and repeated measures analysis of variance (ANOVA) evaluated dynamic changes in γ-H2AX levels, and a multilevel linear regression model analyzed the relationship between γ-H2AX levels and treatment response. Nineteen out of thirty patients (63.33%) were classified as responders. Significant dynamic changes in γ-H2AX levels were observed between non-responders and responders (P=0.01). The multilevel linear regression model showed a trend towards increased γ-H2AX levels in responders [1.17, 95% confidence interval (CI): -0.02 to 2.34, P=0.053]. Significant differences in γ-H2AX levels were observed from baseline to mid-treatment, end of treatment, and six weeks post-CCRT. Pathologic complete response (pCR) after CCRT was associated with significantly higher γ-H2AX ratios compared to those without pCR (P=0.04). However, no significant difference was identified in the multilevel linear regression model. γ-H2AX may have potential as a biomarker for treatment response in locally advanced rectal cancer patients undergoing preoperative CCRT, although further validation is required.

175P Thrombospondin-4 as potential cerebrospinal fluid biomarker for therapy response in pediatric 5q-associated spinal muscular atrophy patients

175P Thrombospondin-4 as potential cerebrospinal fluid biomarker for therapy response in pediatric 5q-associated spinal muscular atrophy patients

DDB2 expression lights the way for precision radiotherapy response in PDAC cells, with or without olaparib

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers. Therapeutic options for PDAC are primarily restricted to surgery in the early stages of the disease or chemotherapy in advanced disease. Only a subset of patients with germline defects in BRCA1/2 genes can potentially benefit from personalized therapy, with the PARP inhibitor olaparib serving as a maintenance treatment for metastatic disease. Although the role of radiotherapy in PDAC remains controversial, the use of radiosensitizers offers hope for improving cancer management. Previously, we have shown that damage-specific DNA binding protein 2 (DDB2) is a potential prognostic and predictive biomarker for chemotherapy response in PDAC. In this study, we investigated the function of DDB2 in radiotherapy response, with and without radiosensitization by olaparib in PDAC cells. Our findings demonstrated DDB2 resistance to radiation effects, thereby improving cell survival and enhancing the repair of ionizing radiation-induced DNA double-strand breaks. We observed that DDB2 expression enhances the cell cycle arrest in the G2 phase by phosphorylating Chk1 and Chk2 cell cycle checkpoints. Additionally, we identified a novel link between DDB2 and PARP1 in the context of radiotherapy, which enhances the expression and activity of PARP1. Our findings highlight the potential of low-DDB2 expression to potentiate the radiosensitization effect of olaparib in PDAC cells. Collectively, this study provides novel insights into the impacts of DDB2 in the radiotherapy response in PDAC, enabling its employment as a potential biomarker to predict resistance to radiation. Furthermore, DDB2 represents a significant step forward in precision radiotherapy by widening the scope of patients who can be benefiting from olaparib as a radiosensitizer. Hence, this research has the potential to enrich the limited use of radiotherapy in the care of patients with PDAC.

Neoadjuvant immunotherapy for dMMR and pMMR colorectal cancers: therapeutic strategies and putative biomarkers of response.

Approximately 15% of locally advanced colorectal cancers (CRC) have DNA mismatch repair deficiency (dMMR), resulting in high microsatellite instability and a high tumour mutational burden. These cancers are frequently sensitive to therapy with immune-checkpoint inhibitors (ICIs) in the metastatic setting. This sensitivity seems to be even more pronounced in locally advanced disease, and organ preservation has become a realistic aim in ongoing clinical trials involving patients with dMMR rectal cancer. By contrast, metastatic CRCs with proficient DNA mismatch repair (pMMR) are generally resistant to ICIs, although a proportion of locally advanced pMMR tumours seem to have a high degree of sensitivity to ICIs. In this Review, we describe the current and emerging clinical evidence supporting the use of neoadjuvant ICIs in patients with dMMR and pMMR CRC, and the potential advantages (based on a biological rationale) of such an approach. We discuss how neoadjuvant 'window-of-opportunity' trials are being leveraged to progress biomarker discovery and we provide an overview of potential predictive biomarkers of response to ICIs, exploring the challenges faced when evaluating such biomarkers in biopsy-derived samples. Lastly, we describe how these discoveries might be used to drive a rational approach to trialling novel immunotherapeutic strategies in patients with pMMR CRC, with the ultimate aim of disease eradication and the generation of long-term immunosurveillance.

New advances in the treatment of intermediate and advanced hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer, affecting millions of people worldwide. Due to the complexity and variability of the disease, there are major challenges in the treatment of HCC in its intermediate and advanced stages; despite advances in various treatment modalities, there are still gaps in our understanding of effective therapeutic strategies. Key findings from several studies have shown that the combination of immunotherapy and targeted therapy has a synergistic anti-tumor effect, which can significantly enhance efficacy with a favorable safety profile. In addition, other studies have identified potential biomarkers of therapeutic response, such as tumor protein 53 (TP53) and CTNNB1 (encoding β-conjugated proteins), thus providing personalized treatment options for patients with intermediate and advanced hepatocellular carcinoma. The aim of this article is to review the recent advances in the treatment of intermediate and advanced HCC, especially targeted immune-combination therapy, chimeric antigen receptor T cell therapy (CAR-T cell therapy), and gene therapy for these therapeutic options that fill in the gaps in our knowledge of effective treatment strategies, providing important insights for further research and clinical practice.

An in vitro assessment of ionizing radiation impact on the efficacy of radiotherapy for breast cancer

Abstract Objectives Ionizing radiation is still one of the most effective treatment options for various cancers. It is possible to reduce the side effects of this effective treatment method and increase the chance of success by elucidating the responses it creates at the molecular level in the cell. This study aims to investigate of the molecular effects of therapeutic ionizing radiation on breast cancer, which is the most prevalent cancer type. Methods MDA-MB-231 and MCF7 cell lines were irradiated with 4 and 8 Gy ionizing radiation and monitored for up to 7 days. RNA was collected at 48 and 96 h, when cellular molecular mechanisms became most evident, and quantitative expression levels of microRNAs (miR-208a, miR-124, miR-145), for which cancer-radiation associations have been determined from existing literature and databases, were evaluated. Results Exposure to ionizing radiation resulted in a dose-dependent reduction in cell viability in both MCF7 and MDA-MB-231 breast cancer cell lines. Furthermore, microRNA expression analysis revealed notable changes at all levels. The research demonstrates that miR-208a, miR-145, and miR-124 are crucial in the biological response to ionizing radiation. Conclusions Therapeutic ionizing radiation profoundly affects cell viability and microRNA expression in breast cancer cell lines, showing dose and time-dependent effects. The observed microRNA expression patterns suggest potential biomarkers for radiation response and therapeutic targets to improve radiotherapy efficacy. Further in vivo validation and exploration of these microRNAs’ roles in modulating cellular response to ionizing radiation are needed.

High ratio of resident to exhausted CD4 + T cells predicts favorable prognosis and potentially better immunotherapeutic efficacy in hepatocellular carcinoma

BackgroundTumor-infiltrating lymphocytes (TILs) are significantly implicated in regulating the tumor immune microenvironment (TIME) and immunotherapeutic response. However, little is known about the impact of the resident and exhausted status of TILs in hepatocellular carcinoma (HCC).MethodsSingle-cell RNA sequencing data was applied to discover resident and exhausted signatures of TILs. Survival outcomes, biological function, immune infiltration, genomic variation, immunotherapeutic efficacy, and sorafenib response were further explored the clinical significance and molecular association of TILs in HCC. Moreover, a candidate gene with predictive capability for the dismal subtype was identified through univariate Cox regression analysis, survival analysis, and the BEST website.ResultsSingle-cell analysis revealed that CD8 + T, CD4 + T, and NK cells were strongly associated with resident and exhausted patterns. Specific resident and exhausted signatures for each subpopulation were extracted in HCC. Further multivariate Cox analysis revealed that the ratio of resident to exhausted CD4 + T cells in TIME was an independent prognostic factor. After incorporating tumor purity with the ratio of resident to exhausted CD4 + T cells, we stratified HCC patients into three subtypes and found that (i) CD4 residencyhighexhaustionlow subtype was endowed with favorable prognosis, immune activation, and sensitivity to immunotherapy; (ii) CD4 exhaustionhighresidencylow subtype was characterized by genome instability and sensitivity to sorafenib; (iii) Immune-desert subtype was associated with malignant-related pathways and poor prognosis. Furthermore, spindle assembly abnormal protein 6 homolog (SASS6) was identified as a key gene, which accurately predicted the immune-desert subtype. Prognostic analysis as well as in vitro and in vivo experiments further demonstrated that SASS6 was closely associated with tumor prognosis, proliferation, and migration.ConclusionsThe ratio of resident to exhausted CD4 + T cells shows promise as a potential biomarker for HCC prognosis and immunotherapy response and SASS6 may serve as a biomarker and therapeutic target for prognostic assessment of HCC.

Sintilimab combined with anlotinib and chemotherapy as second-line or later therapy in extensive-stage small cell lung cancer: a phase II clinical trial

Treatment options for patients with relapsed extensive-stage small cell lung cancer (ES-SCLC) remain scarce. This study aims to evaluate the efficacy and safety of combining anlotinib and sintilimab plus chemotherapy as a second line or later therapy for ES-SCLC patients. This is a phase II clinical trial (ChiCTR2100049390) conducting at Shandong Cancer Hospital. Patients with ES-SCLC and received at least one prior systemic treatment were enrolled. The trial design involved a combination therapy (sintilimab, anlotinib, and nab-paclitaxel) administered over six 21-day cycles, followed by maintenance sintilimab therapy. The primary endpoint was objective response rate (ORR). Circulating tumor DNA sequencing was employed for exploratory analysis. From July 2021 to April 2023, 25 eligible patients were enrolled. The confirmed ORR was 60% (95% CI: 38.7–78.9%) and the DCR was 76% (95% CI: 54.9–90.6%). The mPFS was 6.0 months (95% CI: 5.4–9.7), and the 6-month PFS rate was 49.2%. The mOS was 13.4 months (95% CI: 11.8-NR), with a 12-month survival rate of 62.2%. Treatment-related adverse events (TRAEs) of any grade occurred in 80% of patients, with the most common being fatigue (40%) and nausea (32%). TRAEs of Grade 3 or higher were reported in 12% of patients. ctDNA analysis indicated that low on-treatment blood tumor mutation burden was associated with longer PFS and OS and a potential role of KMT2D mutation in treatment resistance. This combination therapy shows promising efficacy and a manageable safety profile as a second-line or later treatment for ES-SCLC, with genomic insights providing potential biomarkers for treatment response.