Prolonged Survival Research Articles

Prognostic and onco-immunological value of immune-related eRNAs-driven genes in lung adenocarcinoma

BackgroundWe aimed to comprehensively analyze the clinical value of immune-related eRNAs-driven genes in lung adenocarcinoma (LUAD) and find the potential biomarkers for prognosis and therapeutic response to improve the survival of this malignant disease.Materials and methodsPearson’s correlation analysis was performed to identify the immune-related eRNAs-driven genes. Cox regression and least absolute shrinkage and selection operator (LASSO) analyses were used to construct this prognostic risk signature. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were used to investigate the underlying molecular mechanism. The single sample gene set enrichment analysis (ssGSEA) algorithm was conducted to evaluate the immune status based on the signature. The quantitative real-time PCR (qRT-PCR) analysis was performed to evaluate the expression value of the signature genes between LUAD tissues and adjacent lung tissues.ResultsFive immune-related eRNAs-driven genes (SHC1, GDF10, CCL14, FYN, and NOD1) were identified to construct a prognostic risk signature with favorable predictive capacity. The patients with high-risk scores based on the signature were significantly associated with the malignant clinical features compared with those with low-risk scores. Kaplan–Meier analysis demonstrated that the sample in the low-risk group had a prolonged survival compared with those in the high-risk group. This risk signature was validated to have a promising predictive capacity and reliability in diverse clinical situations and independent cohorts. The functional enrichment analysis demonstrated that humoral immune response and intestinal immune network for IgA production pathway might be the underlying molecular mechanism related to the signature. The proportion of the vast majority of immune infiltrating cells in the high-risk group was significantly lower than that in the low-risk group, and the immunotherapy response rate in the low-risk group was significantly higher than that in the high-risk group. Moreover, BI-2536, sepantronium bromide, and ULK1 were the potential drugs for the treatment of patients with higher risk scores. Finally, the experiment in vivo and database analysis indicated that CCL14, FYN, NOD1, and GDF10 are the potential LUAD suppressor and SHC1 is a potential treatment target for LUAD.ConclusionAbove all, we constructed a prognostic risk signature with favorable predictive capacity in LUAD, which was significantly associated with malignant features, immunosuppressive tumor microenvironment, and immunotherapy response and may provide clinical benefit in clinical decisions.

Transitioning to a Personalized Approach in Molecularly Subtyped Small-Cell Lung Cancer (SCLC).

Lung cancer has become a major public health concern, standing as the leading cause of cancer-related deaths worldwide. Among its subtypes, small-cell lung cancer (SCLC) is characterized by aggressive and rapid growth, poor differentiation, and neuroendocrine features. Typically, SCLC is diagnosed at an advanced stage (extensive disease, ED-SCLC), with distant metastases, and is strongly associated with tobacco smoking and has a poor prognosis. Recent clinical trials, such as CASPIAN and IMpower133, have demonstrated promising outcomes with the incorporation of immune checkpoint inhibitors in first-line chemotherapy, leading to prolonged progression-free survival and overall survival in patients with ED-SCLC compared to standard chemotherapy. Other studies have emphasized the potential for future development of molecularly targeted therapies in SCLC patients, including inhibitors of IGF-1R, DLL3, BCL-2, MYC, or PARP. The molecular subdivision of SCLC based on transcriptomic and immunohistochemical analyses represents a significant advancement in both diagnostic and clinical approaches in SCLC patients. Specific molecular pathways are activated within distinct transcriptome subtypes of SCLC, offering the potential for personalized treatment strategies, such as targeted therapies and immunotherapies. Such tailored approaches hold promise for significantly improving outcomes in SCLC patients.

A novel approach toward the multigram synthesis of a novel Bcl2-specific inhibitor, and evaluation of its biological activity

The antiapoptotic protein BCL2 is overexpressed in several cancers. It contributes to prolonged cell survival and chemoresistance, making it an excellent target for targeted cancer therapy. Over the years, several BCL2 inhibitors have been investigated extensively for their anticancer potential; however, most of them were abolished before clinical use due to their pan activity. There is only one FDA-approved BCL2-specific inhibitor, Venetoclax, currently used in clinics. Previously, we reported the characterization and development of a novel BCL2 inhibitor, Disarib, which is selective against BCL2 and predominantly binds to the BH1 domain of BCL2. Importantly, the efficacy of Disarib was equally good or better than Venetoclax in various in vitro and in vivo assays. In the present study, we report the development of a scalable and practical method for the large-scale synthesis of Disarib to support the ongoing pre-clinical studies. The parameters of each step were optimized through prior knowledge, helping in improving the yield and purity to 98.8 %. Further, we compared the efficiency of a large-scale synthesized Disarib in a GLP-certified laboratory with that of an in-house synthesized Disarib. The results showed that the biological activity, including Disarib-induced cytotoxicity and cell cycle progression, were comparable. Besides, the tumor regression efficacy and pharmacokinetics analysis of Disarib have shown comparable results when Disarib synthesized in both routes were tested. Thus, a robust and scalable synthetic pathway of Disarib has developed to address small-scale synthesis's limitations in supporting their expanded applications and use.

Association between quality of life and mortality risk in patients with breast cancer: a systematic review and meta-analysis.

Patients with breast cancer present with various problems that have an adverse effect on the quality of life (QOL). However, the association between the QOL and mortality among patients with breast cancer remains controversial. Therefore, this systematic review and meta-analysis aimed to determine whether QOL impacts prognosis in patients with breast cancer. The databases of CINAHL, Scopus, and PubMed databases were searched to retrieve observational studies that assessed the QOL and mortality risk in patients with breast cancer published before December 2022. Among the 119,061 articles retrieved, six observational studies were included in the meta-analysis. Physical QOL (hazard ratio [HR]: 1.04, 95% confidence interval [CI]: 1.01-1.07, p = 0.003), emotional QOL (HR: 1.01, 95% CI: 1.00-1.03, p = 0.05), and role QOL (HR: 1.01, 95% CI: 1.00-1.01, p = 0.007) showed significant associations with mortality risk. In contrast, global QOL, cognitive QOL, and social QOL showed no associations with mortality risk. Subgroup analysis performed according to treatment time points revealed that the post-treatment physical QOL was associated with mortality risk. Physical QOL, emotional QOL, and role QOL are associated with mortality risk in patients with breast cancer. Furthermore, post-treatment physical QOL showed a more significant association with prolonged survival than pre-treatment physical QOL.

Immunoinformatics Design and In Vivo Immunogenicity Evaluation of a Conserved CTL Multi-Epitope Vaccine Targeting HPV16 E5, E6, and E7 Proteins.

Human papillomavirus type 16 (HPV16) infection is responsible for more than 50% of global cervical cancer cases. The development of a vaccine based on cytotoxic T-lymphocyte (CTL) epitopes is a promising strategy for eliminating pre-existing HPV infections and treating patients with cervical cancer. In this study, an immunoinformatics approach was used to predict HLA-I-restricted CTL epitopes in HPV16 E5, E6, and E7 proteins, and a set of conserved CTL epitopes co-restricted by human/murine MHCs was screened and characterized, with the set containing three E5, four E6, and four E7 epitopes. Subsequently, the immunogenicity of the epitope combination was assessed in mice, and the anti-tumor effects of the multi-epitope peptide vaccine E5E6E7pep11 and the recombinant protein vaccine CTB-Epi11E567 were evaluated in the TC-1 mouse tumor model. The results demonstrated that mixed epitope peptides could induce antigen-specific IFN-γ secretion in mice. Prophylactic immunization with E5E6E7pep11 and CTB-Epi11E567 was found to provide 100% protection against tumor growth in mice. Moreover, both types of the multi-epitope vaccine significantly inhibited tumor growth and prolonged mouse survival. In conclusion, in this study, a multi-epitope vaccine targeting HPV16 E5, E6, and E7 proteins was successfully designed and evaluated, demonstrating potential immunogenicity and anti-tumor effects and providing a promising strategy for immunotherapy against HPV-associated tumors.

IFI35 regulates non-canonical NF-κB signaling to maintain glioblastoma stem cells and recruit tumor-associated macrophages.

Glioblastoma (GBM) is the most aggressive malignant primary brain tumor characterized by a highly heterogeneous and immunosuppressive tumor microenvironment (TME). The symbiotic interactions between glioblastoma stem cells (GSCs) and tumor-associated macrophages (TAM) in the TME are critical for tumor progression. Here, we identified that IFI35, a transcriptional regulatory factor, plays both cell-intrinsic and cell-extrinsic roles in maintaining GSCs and the immunosuppressive TME. IFI35 induced non-canonical NF-kB signaling through proteasomal processing of p105 to the DNA-binding transcription factor p50, which heterodimerizes with RELB (RELB/p50), and activated cell chemotaxis in a cell-autonomous manner. Further, IFI35 induced recruitment and maintenance of M2-like TAMs in TME in a paracrine manner. Targeting IFI35 effectively suppressed in vivo tumor growth and prolonged survival of orthotopic xenograft-bearing mice. Collectively, these findings reveal the tumor-promoting functions of IFI35 and suggest that targeting IFI35 or its downstream effectors may provide effective approaches to improve GBM treatment.

Ibrutinib disrupts blood-tumor barrier integrity and prolongs survival in rodent glioma model

In malignant glioma, cytotoxic drugs are often inhibited from accessing the tumor site due to the blood-tumor barrier (BTB). Ibrutinib, FDA-approved lymphoma agent, inhibits Bruton tyrosine kinase (BTK) and has previously been shown to independently impair aortic endothelial adhesion and increase rodent glioma model survival in combination with cytotoxic therapy. Yet additional research is required to understand ibrutinib’s effect on BTB function. In this study, we detail baseline BTK expression in glioma cells and its surrounding vasculature, then measure endothelial junctional expression/function changes with varied ibrutinib doses in vitro. Rat glioma cells and rodent glioma models were treated with ibrutinib alone (1–10 µM and 25 mg/kg) and in combination with doxil (10–100 µM and 3 mg/kg) to assess additive effects on viability, drug concentrations, tumor volume, endothelial junctional expression and survival. We found that ibrutinib, in a dose-dependent manner, decreased brain endothelial cell–cell adhesion over 24 h, without affecting endothelial cell viability (p < 0.005). Expression of tight junction gene and protein expression was decreased maximally 4 h after administration, along with inhibition of efflux transporter, ABCB1, activity. We demonstrated an additive effect of ibrutinib with doxil on rat glioma cells, as seen by a significant reduction in cell viability (p < 0.001) and increased CNS doxil concentration in the brain (56 ng/mL doxil alone vs. 74.6 ng/mL combination, p < 0.05). Finally, Ibrutinib, combined with doxil, prolonged median survival in rodent glioma models (27 vs. 16 days, p < 0.0001) with brain imaging showing a − 53% versus − 75% volume change with doxil alone versus combination therapy (p < 0.05). These findings indicate ibrutinib’s ability to increase brain endothelial permeability via junctional disruption and efflux inhibition, to increase BTB drug entry and prolong rodent glioma model survival. Our results motivate the need to identify other BTB modifiers, all with the intent of improving survival and reducing systemic toxicities.

Efficacy and safety of neoadjuvant immunotherapy plus chemotherapy followed by adjuvant immunotherapy in resectable non-small cell lung cancer: a meta-analysis of phase 3 clinical trials.

At present, several important trials have been published show that perioperative immunotherapy combined with chemotherapy can improve the prognosis of patients with resectable non-small cell lung cancer, which further optimizes treatment options. Therefore, we conducted a systematic review and meta-analysis to evaluate the efficacy and safety of perioperative immunotherapy combined with chemotherapy in resectable non-small cell lung cancer. The following databases were searched for relevant studies: PubMed, EMBASE, Cochrane library (updated 12 October 2023). All randomized trials comparing perioperative immunotherapy combined with chemotherapy versus chemotherapy alone in resectable non-small cell lung cancer were eligible for inclusion. Data were analyzed using Review Manager 5.4.1 (Cochrane collaboration software). Primary outcomes and measures included overall survival (OS), event-free survival (EFS), pathological complete response (pCR), major pathological response (MPR), R0 resection rate, rate of underwent surgery and adverse events (AEs). A total of 2912 patients (1453 receiving perioperative immunotherapy plus chemotherapy and 1459 receiving chemotherapy alone) were included in this systematic review and meta-analysis. The result showed that compared with chemotherapy alone, combined therapy significantly improved OS (HR = 0.68;95% CI: 0.56-0.83), EFS (HR = 0.58;95% CI: 0.51-0.65), pCR (OR = 7.53;95% CI: 4.63-12.26), MPR (OR = 5.03;95% CI: 3.40-7.44), R0 resection (OR = 1.58;95% CI: 1.152.18) and rate of underwent surgery (OR = 1.25;95% CI: 1.04-1.49). However, combination therapy was associated with higher risk of severe adverse event (OR = 1.46;95% CI: 1.19-1.78; P=0.0002), grade 3 and higher treatment-related adverse event (TRAE) (OR = 1.25;95% CI: 1.06-1.49; P=0.010), TRAE that led to interruption (OR = 1.90;95% CI: 1.34-2.68; P=0.0003) and immune-related adverse event (OR = 2.78;95% CI: 2.18-3.55; P<0.00001). Significant benefits were observed across most subgroups of EFS and pCR. However, no statistical differences were observed for EFS of never smoked (HR= 0.73;95% CI: 0.51-1.05) and EGFR-mutation positive (HR = 0.35;95% CI: 0.04-3.03). This systematic review and meta-analysis found superior efficacy associated with perioperative immunotherapy plus chemotherapy compared with chemotherapy alone in both tumor regression and prolonged survival in resectable NSCLC, but increased the risk of TRAE, so monitoring for adverse events is warranted. https://www.crd.york.ac.uk/prospero, identifier (CRD42023476786).

Prognostic value of serum tartrate‑resistant acid phosphatase‑5b for bone metastasis in patients with resectable breast cancer.

Bone metastasis significantly affects the quality of life of patients with metastatic breast cancer, and can shorten overall survival. Identifying patients with early-stage breast cancer at high risk for bone metastasis and preventing bone metastasis may lead to a better quality of life and prolonged survival. The present study investigated whether serum tartrate-resistant acid phosphatase-5b (TRACP-5b), a bone turnover marker, can be a prognostic factor for bone metastasis. Female patients who underwent resectable breast surgery between May 2002 and August 2006 were consecutively investigated. A total of 304 patients with a median follow-up of 3,722 days were retrospectively analyzed. TRACP-5b levels in sera prepared from patients' blood drawn preoperatively without any presurgical treatments were measured using an enzyme-linked immunosorbent assay. The cutoff of TRACP-5b levels, in order to separate patients into high and low TRACP-5b groups, was set at median (347 mU/dl). The associations of clinicopathological factors, including TRACP-5b, with bone metastasis-free interval (BMFI), which was defined as the duration between surgery and the diagnosis of bone metastasis at any time point, were examined. Multivariate analysis of various clinicopathological features revealed that lymph node metastasis and histological grade were independent factors associated with BMFI (P=0.017 and 0.030, respectively). In patients with node-positive breast cancer (n=114), a high TRACP-5b level and a high grade were significantly and independently associated with worse BMFI (log-rank P=0.041 and 0.011, respectively). In conclusion, these findings indicated that TRACP-5b may predict bone metastasis in patients with node-positive breast cancer.

Abstract CT074: ELECTRA: An open-label, multicenter, phase 1b/2 study of elacestrant in combination with abemaciclib in patients with brain metastasis from estrogen receptor-positive (ER+), HER2-negative (HER2-) breast cancer (BC)

Abstract Background: Endocrine therapy (ET) + cyclin dependent kinase 4/6 inhibitor (CDK4/6i) is the mainstay for the management of ER+/HER2- mBC as 1st-line therapy. However, tumors eventually develop resistance to ET, leading to disease progression. In the EMERALD phase 3 trial, single-agent elacestrant was associated with significantly prolonged progression-free survival (PFS) and a manageable safety profile vs standard of care (SOC) ET, leading to the first oral SERD approval. Patients receiving elacestrant experienced a median PFS (mPFS) of 3.8 months vs 1.9 months with SOC (Bidard, 2022). Patients who received ≥12 months of prior CDK4/6i experienced a mPFS of 8.6 months with elacestrant vs 1.9 months with SOC (SABCS, 2022). Currently, there are no approved systemic treatments for patients with ER+/HER2- BC who have brain metastasis. The rationale for the ELECTRA study is to combine elacestrant with abemaciclib in patients with brain metastasis, given both compounds have demonstrated the ability to cross the blood-brain barrier (Conlan, 2020; Tolaney, 2020). Methods: ELECTRA (NCT05386108) is an open-label phase 1b/2, multicenter study evaluating elacestrant in combination with abemaciclib. Eligibility includes patients with ER+/HER2- locally advanced or metastatic BC and measurable brain metastasis. For phase 1b, the presence of brain metastasis is not required for eligibility. For phase 2, patients must have ≥ 1 active and measurable brain metastasis per RECIST v1.1. Patients must have received prior therapy in the metastatic setting, including ≥ 1 endocrine therapy, ≤ 2 chemotherapy regimens, and 0-2 prior CDK4/6i (excluding abemaciclib). The phase 1b primary objective is to determine the recommended phase 2 dose (RP2D); secondary objectives include safety, pharmacokinetics (PK), overall response rate (ORR), duration of response (DoR), clinical benefit rate (CBR), PFS, and overall survival (OS). The phase 2 primary objective is ORR per RECIST v1.1; secondary objectives include intracranial response rate, DoR, CBR, PFS, OS, PK, and quality of life. The phase 1b portion of the trial is actively ongoing to determine the RP2D with study sites open worldwide. Citation Format: Erika Hamilton, Sung-Bae Kim, Nancy U. Lin, Ahmad Awada, Eva Ciruelos Gil, Alessandro Di Sanzo, Bartomeu Piza Vallespir, Kathy Puyana Theall, Nuhad Ibrahim. ELECTRA: An open-label, multicenter, phase 1b/2 study of elacestrant in combination with abemaciclib in patients with brain metastasis from estrogen receptor-positive (ER+), HER2-negative (HER2-) breast cancer (BC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT074.

Abstract LB048: Unleashing the power of p53 mRNA therapeutics to suppress proliferation of p53 mutant tumors

Abstract The p53 protein, recognized as the guardian of the genome, plays a pivotal role in suppressing tumor formation. The TP53 gene, which encodes the p53 protein, is commonly subject to mutations and deletions in many cancer types resulting in loss of tumor suppressor activity. A significant proportion of patients diagnosed with lung, pancreatic, ovarian, and head and neck cancers exhibit the expression of mutant p53 in their tumors, correlating with unfavorable prognosis and survival outcomes.This study endeavors to assess the efficacy of therapeutic tumor suppressive mRNA which induces expression of wild-type p53 protein across diverse cancer types. Optimization of the 5’ and 3’ untranslated regions (UTRs) and the 5’ cap has been undertaken to enhance the efficient expression of p53 mRNA. The growth inhibitory potential of p53 mRNA therapy has been evaluated across p53 mutant cancer cell lines representing various cancer origins, along with normal or p53 wild-type cancer cell lines. We have substantiated that the p53 mRNA therapeutics can selectively inhibit the proliferation of p53 mutant cancer cells. Furthermore, we have confirmed that p53 mRNA treatment upregulated modulator of apoptosis (PUMA) and B-cell translocation gene 2 (BTG2) and cell cycle arrest via p21 upregulation. In vivo efficacy assessments of the lipid nanoparticle (LNP)-encapsulated p53 mRNA have been conducted in lung, pancreatic, and ovarian cancer xenograft models. Both regional intratumoral (i.t) and systemic intravenous (i.v) administrations of the p53 mRNA therapeutics have shown substantial suppression of tumor growth, leading to prolonged mouse survival. These results underscore the potential of the p53 mRNA therapeutics as a promising avenue for targeted cancer treatment, offering insights into the selective inhibition of p53 mutant cancer cells. Citation Format: Yong Ho Heo, Seung-Hyun Shin, Youngjin Han, Chang Gyu Lim, Innah Kim, Ji Hee Lee, Gunwoo Lee, Seongju Jeong, Yunjae Kim, Jooyun Byun, Daejin Kim, In Young Choi. Unleashing the power of p53 mRNA therapeutics to suppress proliferation of p53 mutant tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB048.

Efficacy and safety of lenalidomide in the treatment of B-cell non-Hodgkin lymphoma

BackgroundThe combination of rituximab and chemotherapy is a first-line treatment for patients with B-cell non-Hodgkin lymphoma. Lenalidomide is an immunomodulatory drug that has shown promising properties and activity in a variety of hematological malignancies. This study evaluated the efficacy and safety of lenalidomide-based regimens in the treatment of B-cell non-Hodgkin lymphoma.MethodsThe PubMed, Science Direct, ClinicalTrials.gov, and Web of Science databases were searched for relevant studies published up to May 2022. Studies with patients diagnosed with non-Hodgkin B-cell lymphoma, who were randomly assigned to a lenalidomide treatment group or a non-lenalidomide control group were considered for inclusion in this review and meta-analysis. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) of the time-to-event outcomes and risk ratios (RRs) with 95% CIs of dichotomous data were estimated.ResultsA total of 3593 patients from 10 studies were evaluated. The results of the pooled analysis indicated that the lenalidomide-based regimen was associated with prolonged overall survival (HR, 0.85; 95% CI 0.74–0.97; P = 0.02) and progression-free survival (HR, 0.70; 95% CI 0.57–0.88; P = 0.002). Significant differences were found in the overall response rate (RR, 1.18; 95% CI 1.04–1.33; P = 0.01) and complete response rate (RR, 1.18; 95% CI 1.00–1.39; P = 0.05) between the treatment and control groups.ConclusionsLenalidomide appears to be a promising therapeutic agent that offers the possibility of a novel combination of chemotherapy free regimen for patients with B-cell non-Hodgkin lymphoma.

Abstract LB117: Virus-inspired Particles (ViPs) harnessing cytomegalovirus immune memory for local and systemic cancer immunotherapy

Abstract VerImmune is pioneering a First-in-Class treatment known as “Anti-tumor Immune Redirection” (AIR). This approach repurposes a patient’s pre-existing anti-viral or childhood vaccine immunity towards tumor cells for targeted destruction. VerImmune’s lead product, VERI-101, leverages pre-existing CD8+ T-cell immune memory acquired from past human cytomegalovirus (HCMV) infections. VERI-101 consists of VerImmune’s proprietary platform technology known as ViPs (Virus-inspired Particles) that are conjugated on their surface with a CD8+ T cell viral peptide antigen. ViPs are based on a modified mouse papillomavirus capsid protein of which 60 copies self-assemble into a 20-30nm T=1 icosahedral structure. In the case of VERI-101, the ViP is conjugated with an HLA-A*0201 restricted peptide epitope (NLVPMVATV, [NLV]), derived from the CMV pp65 antigen with an upstream furin protease cleavage site. The mechanism of action of AIR-ViPs including VERI-101 has been previously presented and involves three steps. Briefly, (1) VERI-101 targets the surface of the tumor cells and (2) enables the presentation of the CMV viral epitopes on their surface MHC, together (3) stimulating a recall of the pre-existing CMV memory response to attack the cancer cells (Dorrier et al., 2023 AACR). Here, we sought to study the in vivo anti-tumor efficacy of AIR-ViPs via both intra-tumoral and systemic treatment routes in two murine tumor models with pre-existing murine CMV (MCMV) immunity: (1) MC38 subcutaneous tumors for local and (2) B16.F10 lung metastasis for systemic treatments. As human CMV is species-specific, instead of VERI-101, a surrogate product, VERI-003 which redirects MCMV immunity, was tested as a single agent or in combination with anti-PD-1 in these tumor models. Our intra-tumoral studies with VERI-003 alone showed a dose-dependent anti-tumor effect (from 5 to 100ug) compared to no treatment controls. Surprisingly, no dose dependence was observed across the same three dose levels when combined with anti-PD-1, although significantly better anti-tumor effects occurred leading to complete tumor clearances in 50% of mice. Statistically significant prolonged survival was observed in most treated groups compared to controls. Our systemic studies with VERI-003 were consistent with our intratumoral studies in showing statistically significant single agent anti-tumor efficacy against B16.F10 lung metastases compared to no treatment. Anti-tumor effects of anti-PD-1 and combination were also observed. Additional studies are on-going to assess dose dependence and analysis of PK/PD effects. Taken together, our initial in vivo results demonstrate the tumor antigen-agnostic therapeutic potential of AIR and our AIR-ViP technology as a novel class of immuno-therapeutic drugs that could be used either as a monotherapy or in combination with checkpoint inhibitors. Citation Format: Cayce Dorrier, Felagot Abebe, Olivia Pak, Emily De-Bodene, Joshua Wang. Virus-inspired Particles (ViPs) harnessing cytomegalovirus immune memory for local and systemic cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB117.

Clinical features and molecular landscape of cuproptosis signature‐related molecular subtype in gastric cancer

AbstractRecent studies have highlighted the biological significance of cuproptosis in disease occurrence and development. However, it remains unclear whether cuproptosis signaling also has potential impacts on tumor initiation and prognosis of gastric cancer (GC). In this study, 16 cuproptosis‐related genes (CRGs) transcriptional profiles were harnessed to perform the regularized latent variable model‐based clustering in GC. A cuproptosis signature risk scoring (CSRS) scheme, based on a weighted sum of principle components of the CRGs, was used to evaluate the prognosis and risk of individual tumors of GC. Four distinct cuproptosis signature‐based clusters, characterized by differential expression patterns of CRGs, were identified among 1136 GC samples across three independent databases. The four clusters were also associated with different clinical outcomes and tumor immune contexture. Based on the CSRS, GC patients can be divided into CSRS‐High and CSRS‐Low subtypes. We found that DBT, MTF1, and ATP7A were significantly elevated in the CSRS‐High subtype, while SLC31A1, GCSH, LIAS, DLAT, FDX1, DLD, and PDHA1 were increased in the CSRS‐Low subtype. Patients with CSRS‐Low score were characterized by prolonged survival time. Further analysis indicated that CSRS‐Low score also correlated with greater tumor mutation burden (TMB) and higher mutation rates of significantly mutated genes (SMG) in GC. In addition, the CSRS‐High subtype harbored more significantly amplified focal regions related to tumorigenesis (3q27.1, 12p12.1, 11q13.3, etc.) than the CSRS‐Low tumors. Drug sensitivity analyses revealed the potential compounds for the treatment of gastric cancer with CSRS‐High score, which were experimentally validated using GC cells. This study highlights that cuproptosis signature‐based subtyping is significantly associated with different clinical features and molecular landscape of GC. Quantitative evaluation of the CSRS of individual tumors will strengthen our understanding of the occurrence and development of cuproptosis and the treatment progress of GC.

MTOR Inhibition Prolongs Survival and Has Beneficial Effects on Heart Function After Onset of Lamin A/C Gene Mutation Cardiomyopathy in Mice.

Mutations in LMNA encoding nuclear envelope proteins lamin A/C cause dilated cardiomyopathy. Activation of the AKT/mTOR (RAC-α serine/threonine-protein kinase/mammalian target of rapamycin) pathway is implicated as a potential pathophysiologic mechanism. The aim of this study was to assess whether pharmacological inhibition of mTOR signaling has beneficial effects on heart function and prolongs survival in a mouse model of the disease, after onset of heart failure. We treated male LmnaH222P/H222P mice, after the onset of heart failure, with placebo or either of 2 orally bioavailable mTOR inhibitors: everolimus or NV-20494, a rapamycin analog highly selective against mTORC1. We examined left ventricular remodeling, and the cell biological, biochemical, and histopathologic features of cardiomyopathy, potential drug toxicity, and survival. Everolimus treatment (n=17) significantly reduced left ventricular dilatation and increased contractility on echocardiography, with a 7% (P=0.018) reduction in left ventricular end-diastolic diameter and a 39% (P=0.0159) increase fractional shortening compared with placebo (n=17) after 6 weeks of treatment. NV-20494 treatment (n=15) yielded similar but more modest and nonsignificant changes. Neither drug prevented the development of cardiac fibrosis. Drug treatment reactivated suppressed autophagy and inhibited mTORC1 signaling in the heart, although everolimus was more potent. With regards to drug toxicity, everolimus alone led to a modest degree of glucose intolerance during glucose challenge. Everolimus (n=20) and NV-20494 (n=20) significantly prolonged median survival in LmnaH222P/H222P mice, by 9% (P=0.0348) and 11% (P=0.0206), respectively, compared with placebo (n=20). These results suggest that mTOR inhibitors may be beneficial in patients with cardiomyopathy caused by LMNA mutations and that further study is warranted.

Mesenchymal glioma stem cells trigger vasectasia—distinct neovascularization process stimulated by extracellular vesicles carrying EGFR

Targeting neovascularization in glioblastoma (GBM) is hampered by poor understanding of the underlying mechanisms and unclear linkages to tumour molecular landscapes. Here we report that different molecular subtypes of human glioma stem cells (GSC) trigger distinct endothelial responses involving either angiogenic or circumferential vascular growth (vasectasia). The latter process is selectively triggered by mesenchymal (but not proneural) GSCs and is mediated by a subset of extracellular vesicles (EVs) able to transfer EGFR/EGFRvIII transcript to endothelial cells. Inhibition of the expression and phosphorylation of EGFR in endothelial cells, either pharmacologically (Dacomitinib) or genetically (gene editing), abolishes their EV responses in vitro and disrupts vasectasia in vivo. Therapeutic inhibition of EGFR markedly extends anticancer effects of VEGF blockade in mice, coupled with abrogation of vasectasia and prolonged survival. Thus, vasectasia driven by intercellular transfer of oncogenic EGFR may represent a new therapeutic target in a subset of GBMs.

Progress in Biological Research and Treatment of Pseudomyxoma Peritonei.

Pseudomyxoma peritonei (PMP) is a rare disease characterized by extensive peritoneal implantation and mass secretion of mucus after primary mucinous tumors of the appendix or other organ ruptures. Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) is currently the preferred treatment, with excellent efficacy and safety, and is associated with breakthrough progress in long-term disease control and prolonged survival. However, the high recurrence rate of PMP is the key challenge in its treatment, which limits the clinical application of multiple rounds of CRS-HIPEC and does not benefit from conventional systemic chemotherapy. Therefore, the development of alternative therapies for patients with refractory or relapsing PMP is critical. The literature related to PMP research progress and treatment was searched in the Web of Science, PubMed, and Google Scholar databases, and a literature review was conducted. The overview of the biological research, treatment status, potential therapeutic strategies, current research limitations, and future directions associated with PMP are presented, focuses on CRS-HIPEC therapy and alternative or combination therapy strategies, and emphasizes the clinical transformation prospects of potential therapeutic strategies such as mucolytic agents and targeted therapy. It provides a theoretical reference for the treatment of PMP and the main directions for future research.

Lactobacillus rhamnosus HN001 facilitates the efficacy of dual PI3K/mTOR inhibition prolonging cardiac transplant survival and enhancing antitumor effect.

We observed that the combination of phosphoinositide 3-kinase/mammalian target of rapamycin (PI3K/mTOR) dual inhibitor BEZ235 and Lactobacillus rhamnosus HN001 notably prolonged cardiac transplant survival while also inhibiting the progression of primary liver cancer. The combination therapy was efficacious in treating antitumor immunity and allograft rejection, as demonstrated by the efficacy results. We also found that this phenomenon was accompanied by the regulation of inflammatory IL-6 expression. Our study presents a novel and effective therapeutic approach to address antitumor immunity and prevent allograft rejection.

Hypobaric hypoxia exposure regulates tissue distribution of nanomedicine for enhanced cancer therapy

BackgroundEffective drug delivery of nanomedicines to targeted sites remains challenging. Given that hypobaric hypoxia and hyperbaric oxygen exposure can significantly change pharmacokinetics of drugs, it is interesting to determine whether they can regulate tissue distribution of nanomedicine, especially in tumor, for enhanced cancer therapy.ResultsHypobaric hypoxia exposure improved the pharmacokinetics of paclitaxel-loaded liposomes and facilitated their distribution in the heart and liver, whereas hyperbaric oxygen exposure did not benefit and even impaired the pharmacokinetics and distribution. Particularly, both hypobaric hypoxia and hyperbaric oxygen exposure could not improve the distribution in subcutaneous tumor. Thus, we constructed orthotopic liver tumor model and discussed whether high distribution of the liposomal nanomedicine in the liver, facilitated by hypobaric hypoxia exposure, could ensure their effective accumulation in liver tumor for enhanced cancer therapy.ConclusionsThe liposomal nanomedicine with adjuvant hypobaric hypoxia exposure significantly inhibited the growth of orthotopic liver tumor for prolonged survival time, achieved by hypobaric hypoxia-promoted accumulation at tumor sites of the liver. It might be the first example of the application of adjuvant intermittent hypobaric hypoxia exposure in treating liver cancer.

Prolonged survival and novel prognostic factors in women with pleural mesothelioma treated with extended pleurectomy decortication.

Pleural mesothelioma (PM) is an uncommon and extremely aggressive malignancy associated with past exposure to asbestos. The low representation of women among PM patients is likely due to differences in occupational asbestos exposure. Due to the controversial role of female sex as a prognostic factor in PM, the study aims to evaluate the survival of females treated with lung-sparing surgery. We present a cohort of 114 consecutive female patients with PM who underwent intended extended pleurectomy decortication (ePD) over 11 years in a high-volume single institution. All women from 2007-2017 who underwent intended ePD were enrolled in the study. Data on clinical, operative, and outcome were collected. Kaplan-Meier estimators and log-rank tests were employed to assess the overall survival, and Cox regression models were utilized to analyze prognostic factors. During the study period, 454 patients underwent thoracotomy with intended ePD in a single institution. There were 114 females (25%), and macroscopic complete resection (MCR) was achieved in 97 (85.1%). The median age was 65 years, histology was epithelioid in 81 (71.0%), biphasic in 31 (27.2%), and sarcomatoid in 2 (1.8%). The 30- and 90-day mortality were 3.5% and 6.1%, respectively. Median survival in females was 38 months, and 5-year survival was 28.2%. The median survival and 5-year survival rate for patients with epithelioid histology and MCR were 44.4 months and 36.4%, respectively. In a univariate analysis, several factors were found to be associated with patient overall survival including MCR [hazard ratio (HR): 0.3, P<0.001], early T status (HR: 1.6, P=0.03), adjuvant therapy (HR: 0.5, P=0.006), intraoperative heated chemotherapy (IOHC) (HR: 0.8, P=0.03), age (HR: 1.02, P=0.03) and epithelioid histology (HR: 0.5, P=0.009). For women with epithelioid PM undergoing intended ePD within a multimodal setting, prolonged survival is anticipated.