Cancer research communications最新文献

Triple-negative breast cancer (TNBC) accounts for 10% to 20% of primary breast cancers and often has early relapses and aggressive progression. An activated tumor immune response can be prognostic in patients with treatment-naïve and chemotherapy-treated TNBC and may be assessed using gene expression data. We derived a stand-alone predictor for a proposed immunomodulatory transcriptional TNBC subtype in a training cohort of 235 patients with primary disease based on random forest modeling of RNA sequencing data. Validation in independent TNBC cohorts totaling more than 1,200 patients demonstrated that the classifier recapitulates the immunomodulatory mRNA subtype classification, is associated with elevated immune expression and diversity of T-cell receptor genes, is associated with response to neoadjuvant chemotherapy, and can separate patients into subgroups with better or worse prognosis after adjuvant chemotherapy. The availability of stand-alone classifiers for mRNA-based prediction may further enhance RNA sequencing's usability in a more routine clinical context and for translational endpoints in clinical trials.

Significance: Tumor immune response has prognostic and treatment predictive value in TNBC and can be estimated by, e.g., mRNA profiling. Translating this association into classifications for single patients requires stand-alone predictors. We have developed one such mRNA classifier that could be applied in future clinical contexts and clinical trials.

Purpose: Metastatic castration-resistant prostate cancer with homologous recombination (HR) deficiency (HRD) is sensitive to PARP inhibitors (PARPi). PI3K inhibitors (PI3Ki) sensitize to PARPi by disrupting HR in preclinical models. This phase Ib/II study investigated copanlisib (Copa; pan-class I PI3Ki) and rucaparib (R).

Patients and methods: Eligible patients had metastatic castration-resistant prostate cancer treated with ≥1 androgen receptor inhibitor and taxanes. Phase I followed a standard 3 + 3 dose-escalation design (rucaparib 400-600 mg orally twice a day; Copa 45-60 mg i.v. on days 1, 8, and 15). Primary goal of phase I was to establish MTD and the recommended phase II dose. The primary endpoint of phase II was PSA50 response rate.

Results: Thirteen patients enrolled had a median age of 64 (55-78) years and PSA was 11.7 ng/mL (0.018-2,101). Seven patients received taxanes, and one patient received PARPi. Eight patients had HRD+ tumors [BRCA2 (four), BRCA1 (one), RAD51C (one), CDK12 (one), and FANCA (one)] and three had PTEN loss. There were two dose-limiting toxicities in dose level 1 (rucaparib 400 mg twice a day; Copa 45 mg on days 1, 8, and 15): grade 3 rash and aspartate aminotransferase/alanine aminotransferase elevation. Treatment-related adverse events ≥ grade 2 included leukopenia (54%), anemia (38%), rash (30%), fatigue (23%), and neutropenia (23%). Six patients were treated at dose level -1 without dose-limiting toxicities, which was established as the recommended phase II dose (rucaparib 400 mg twice a day + Copa 45 mg on day 1/15). Among patients with HRD+, one had confirmed partial response and three had stable disease by RECIST, including one patient treated with prior PARPi, and three patients had PSA50 responses (23%).

Conclusions: Copa/R had an acceptable safety profile with a signal of efficacy supporting future studies of PARPi with PI3Ki.

Significance: Gene alterations in the PI3K and HR pathways are common in prostate cancer. Based on preclinical studies, the inhibition of PI3K disrupts HR, and PARP blockade induces AKT activation, supporting the combination of PI3Ki and PARPi. Herein, we investigated the safety and preliminary efficacy of the PI3Ki copanlisib and the PARPi rucaparib in patients with or without alterations in HR repair pathway genes.

The role of androgen receptor (AR) signaling in modulating antitumor immune responses has received increasing attention in recent years; however, its broader impact across diverse cancer types and between sexes remains largely unexplored. Here, we investigated how AR activity correlates with tumor-infiltrating leukocytes, patient prognosis, and immunotherapy response across cancers and sexes. We inferred AR activity using a network-based approach across bulk RNA-seq (TCGA), single-cell RNA-seq (prostate cancer meta-atlas), and immunotherapy cohorts. Pathway analysis and Cox regression assessed mechanisms and survival. Immune infiltration and signatures were evaluated via TIMER and ssGSEA. Key findings were validated using Digital Spatial Profiling and immunohistochemistry. Our pan-cancer analysis of 33 TCGA cancer types revealed broad variability in AR activity, highest in prostate adenocarcinoma. Genes significantly correlated with AR activity show negative associations and are enriched in immune activation pathways. Notably, AR activity inversely correlated with leukocyte abundance and IFN-γ pathway activity across tumors and sexes-unlike estrogen or progesterone receptors. Longitudinal biopsy analysis in metastatic prostate cancer showed AR inhibition enhanced immune cell and IFN-γ signatures. Single-cell analysis confirmed that tumor-intrinsic AR activity inversely correlates with immune infiltration in prostate cancer. Furthermore, low AR activity is significantly associated with favorable immunotherapy responses in hormone-independent cohorts. Spatial proteomics showed a negative correlation between AR and CD45 protein in sarcoma and ovarian cancers. These findings suggest AR activity as a pan-cancer predictive biomarker of immunotherapy response and support that AR blockade in immunotherapy-refractory tumors represents a promising treatment strategy, regardless of tumor type or patient sex.

Soft tissue sarcomas (STS) are characterized by abundant extracellular matrix (ECM) deposition, yet the functional contribution of specific ECM components remains poorly understood. Here, we identify Periostin (POSTN), a matricellular protein, as a regulator of sarcoma progression and the tumor immune microenvironment. Analysis of human sarcoma datasets revealed that high POSTN expression correlates with poor prognosis and elevated expression of ECM-related and myeloid cell-associated genes. In murine genetic models of sarcoma, tumors expressing high levels of Postn displayed enhanced expression of ECM genes and monocyte-recruiting cytokines. Functional silencing of Postn in vivo reduced tumor growth without altering tumor cell proliferation or intrinsic signaling pathways, suggesting a non-cell-autonomous mechanism. Instead, Postn-deficient tumors showed increased infiltration of CD4⁺ and CD8⁺ T cells and reduced proportions of immunosuppressive myeloid cells, including tumor-associated macrophages (TAMs). Single-cell RNA sequencing revealed that Postn silencing reprograms the myeloid compartment, increasing interferon-responsive and pro-inflammatory subsets. Mechanistically, recombinant POSTN promoted monocyte migration and maturation into macrophages in vitro, supporting its role as a chemoattractant and differentiation cue. Therapeutic neutralization of POSTN partially recapitulated the immunologic remodeling but was insufficient to reduce tumor burden as monotherapy.

Cancer is a leading cause of death in Latin America and the Caribbean (LAC), and up-to-date estimates are essential to guide cancer policy. Using GLOBOCAN 2022 data, we analyzed cancer incidence and mortality across 32 LAC countries, calculated age-standardized rates, and assessed early-onset cancer (diagnosed at ages 15-50). Mortality-to-incidence ratios (MIRs) were used as a proxy for survival, Joinpoint regression estimated annual percent change (APC), and linear regression evaluated correlation between the Human Development Index (HDI) and cancer indicators. In 2022, LAC recorded 1,551,060 new cancer cases (ASIR 186.6 per 100,000) and 749,242 deaths (ASMR 85.2 per 100,000). Prostate and breast cancers were the most common malignancies, while lung and breast cancers caused the highest mortality. Mortality declined for prostate cancer (APC -1.52, 95% CI -1.80 to -1.24) and male lung cancer (-2.50, 95% CI -2.68 to -2.33) but increased for female lung (+1.88, 95% CI 1.71 to 2.05) and colorectal cancer (+2.48, 95% CI 2.30 to 2.67). HDI showed an inverse correlation with MIR (p < 0.001), suggesting improved survival with higher development. Early-onset cancers represented 17% of new cases and 11% of deaths. These findings reveal a growing cancer burden and that persistent disparities in cancer epidemiology persists across LAC, highlighting the urgent need for targeted cancer control strategies and regional cancer control plans.

Neuronal autoantibodies have been identified in immune-mediated encephalitis, and most of which are related to paraneoplastic neurological syndromes (PNS). We detected neuronal autoantibodies in gastric cancer patients without PNS, and illustrated their correlation with clinical prognosis. All serum samples were tested by the mouse brain tissue-based assay (TBA) using immunofluorescence for screening neuronal autoantibodies. Known PNS related neuronal autoantibodies were detected by cell-based assay (CBA). A single-center cohort has been started in Nanfang hospital. T cells status of the tumor microenvironment was assessed. Singel cell sequencing was performed with limited tumor samples. Patients were grouped into TBA positive (n=144) and TBA negative (n=179) groups by the TBA status. Further screening of TBA+ specimens using the CBA method revealed known PNS-related autoantibodies in 13.2% (19/144) of cases. Additionally, TBA positive gastric cancer patients exhibited lower CD8+ T cell infiltration in the tumor tissue. The Survival analysis show that neuronal autoantibodies in patients (TBA positive) were associated with shorter OS (P=0.014). In the multivariate survival analysis, TBA positive was still associated with shortened OS after adjusting the major covariates (HR = 2.28, 95% CI: 1.31-3.97, P = 0.004). Meanwhile, Single-cell sequencing indicates that cell junction assembly and synapse organization may play important roles in biological process. In this cohort study, neuronal autoantibodies were highly prevalent among gastric cancer patients and were associated with shortened OS and features of immunosuppression within the tumor microenvironment, suggesting a candidate for exploring therapeutic relevance, with further mechanistic studies needed to validation.

The incidence of colorectal cancer in young adults (age of diagnosis <50 years) has been rapidly increasing. Although ∼20% of early-onset colorectal cancer (EOCRC) cases are due to germline mutations, the etiology of the majority of EOCRC cases remains poorly understood. Nongenetic factors such as environmental exposure and lifestyle changes are likely to have a direct link to the increased incidence of sporadic EOCRC. We hypothesize that such factors may be observable as alterations in the epigenome, microbiome, and immunome. We characterized the DNA methylation (DNAm) signature and measured DNAm age in EOCRC by using The Cancer Genome Atlas (TCGA). Furthermore, we carefully identified intratumoral microbes from TCGA and the Oncology Research Information Exchange Network datasets and then related the microbes to deconvolved immune cell abundances in EOCRC. We observed that the DNAm age in the EOCRC cohort was 12 years older when compared with the average-onset colorectal cancer (AOCRC) cohort, using three different epigenetic clocks. Differentially methylated sites associated with gene expression include cAMP-responsive element binding protein signaling in neurons, G protein-coupled receptor signaling, phagosome formation, and S100 family signaling. These differences were validated in the gene expression data from TCGA and the Oncology Research Information Exchange Network. When comparing the intratumoral microbes between EOCRC and AOCRC, no consistent differences were observed. Interestingly, the most abundant microbes interacted with the immune systems differently between the EOCRC and AOCRC tumors, characterized by more and larger positive correlations in EOCRC. These data suggest that epigenetic modulation and accelerated aging may play a key role in the development of EOCRC.

Significance: We investigated whether environmentally driven factors contribute to EOCRC. We observed accelerated epigenetic aging in EOCRC and epigenetic changes associated with chronic inflammation. Tumor immune cell abundances correlated more strongly with microbes in EOCRC than in AOCRC. These data suggest a dysregulation of the immune response in EOCRC, driving chronic inflammation and tissue aging.

Endometrioid and mucinous ovarian carcinomas represent nearly a fifth of ovarian cancers, but their molecular characteristics and pathologic origins are poorly understood. To identify the genomic and epigenomic alterations characteristic of these ovarian cancer subtypes and evaluate links to morphologically similar tumors from other sites, we performed a combination of sequence, copy number, mutation signature, and rearrangement analyses from tumor samples and matched normal tissues of 133 patients, as well as methylation analyses of these tumors and tissues of 150 patients from The Cancer Genome Atlas. Genomic analyses included samples from patients with ovarian endometrioid (n = 44), ovarian mucinous (n = 43), uterine endometrioid (n = 15), and gastrointestinal mucinous carcinomas (n = 31), including mucinous carcinomas of the stomach, colon, and pancreas. In addition to identifying genes previously known to be involved in these tumors, we identified alterations in RAD51C, NOTCH4, SMARCA1/4, and JAK1 in ovarian endometrioid, ESR1 in uterine endometrioid, and SMARCA4 in ovarian mucinous carcinomas. Whole-genome sequencing revealed rearrangements involving PTEN, NF1, and NF2 in ovarian endometrioid carcinomas and NF1 and MED1 in ovarian mucinous carcinomas. The number of alterations, affected genes, and genome-wide methylation profiles were not distinguishable between ovarian and uterine endometrioid carcinomas, supporting the hypothesis that these tumors share a tissue of origin. In contrast, mutation and methylation patterns in ovarian mucinous carcinomas were different from gastrointestinal mucinous carcinomas. These analyses provide insights into the genomic landscapes and origins of mucinous and endometrioid ovarian carcinomas, providing new avenues for early clinical intervention and management of patients with these cancers.

Significance: Integrative multi-omic analyses support a common tissue of origin between ovarian endometrioid and uterine endometrioid carcinomas but not between ovarian mucinous and gastric or pancreatic mucinous carcinomas.

We examined the role of SLFN12, a member of the Schlafen (SLFN) family of interferon-regulated genes and proteins in leukemogenesis, and its potential as a therapeutic target in acute myeloid leukemia (AML). We explored the effects of velcrins, a class of small molecules able to modulate SLFN12 biological activity, on AML cells. Velcrin treatment of AML cells stabilized SLFN12 and promoted SLFN12 complex formation with phosphodiesterase 3A or phosphodiesterase 3B. Such effects were associated with growth-inhibitory and proapoptotic responses, as well as potent suppressive effects on leukemic cell growth. In addition, velcrin treatment suppressed clonogenic capacity of primitive leukemic progenitors and significantly extended survival in a mouse AML xenograft model. Taken together, these findings establish an important role of SLFN12 in leukemogenesis and raise the potential for the use of velcrins as a therapeutic strategy for AML.

Significance: Our studies identify SLFN12 as a potential target in AML with important clinical-translational implications.

Purpose: Subasumstat (TAK-981) is a first-in-class inhibitor of SUMOylation that can engage innate and adaptive immune responses in tumors by enhancing type I IFN (IFNI) production. We conducted a phase I/II dose-escalation/-expansion study (NCT03648372) to investigate the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of subasumstat as a single agent in patients with advanced/metastatic solid tumors and relapsed/refractory hematologic malignancies.

Patients and methods: Eligible patients received subasumstat intravenously at escalating doses twice weekly (days 1, 4, 8, and 11) or once weekly (days 1 and 8) in 21-day cycles until disease progression or unacceptable toxicity.

Results: A total of 109 patients were enrolled (solid tumors: n = 100; lymphomas, n = 9). In phase I, four patients reported dose-limiting toxicities of grade 3 alanine transaminase/aspartate transaminase elevation, pneumonitis, stomatitis, and cognitive disorder; 120 mg twice weekly was determined as the MTD. The most common adverse events were fatigue (47%), nausea (41%), diarrhea (36%), and pyrexia (36%). Pharmacodynamic analyses demonstrated target engagement and SUMOylation pathway inhibition, induction of an IFNI-regulated gene signature and cytokine production, and activation of innate and adaptive immune cells. Based on safety, pharmacokinetic, and pharmacodynamic findings, 90 mg twice weekly was proposed as the recommended phase II dosage. Overall, three and 26 patients achieved a partial response and stable disease, respectively.

Conclusions: Subasumstat had a manageable safety profile, with evidence of innate and adaptive immune response engagement in patients with advanced/metastatic solid tumors and relapsed/refractory hematologic malignancies. Further studies are needed to determine the role of subasumstat in cancer treatment.

Significance: Identification of novel and effective therapies for patients who become refractory to standard anticancer treatments remains paramount. In this phase I/II study, subasumstat, a first-in-class SUMOylation inhibitor, had preliminary clinical activity and demonstrated target engagement, upregulation of IFN and plasma cytokines, and activation of innate and adaptive immune cells.