Among patients with triple-negative breast cancer and high expression of PD-L1, pembrolizumab plus chemotherapy resulted in longer overall survival than chemotherapy alone.
Techniques for analyzing circulating tumor DNA (ctDNA) to detect, characterize and monitor cancer have matured rapidly. An increasing body of clinical evidence is demonstrating the capabilities of ...this technology as a diagnostic test. The full potential of ctDNA liquid biopsy in the diagnosis, characterization and management of solid and hematological malignancies will be uncovered through interventional clinical trials evaluating clinical utility. In this Review, we discuss the current landscape of ctDNA liquid-biopsy applications across the cancer continuum and highlight opportunities for clinical investigation.
Genomic sequencing studies of breast and other cancers have identified patterns of mutations that have been attributed to the endogenous mutator activity of APOBEC3B (A3B), a member of the AID/APOBEC ...family of cytidine deaminases. A3B gene expression is increased in many cancers, but its upstream drivers remain undefined. Furthermore, there exists a common germ-line deletion polymorphism ( A3B ᵈᵉˡ), which has been associated with a paradoxical increase in breast cancer risk. To examine causes and consequences of A3B expression and its constitutive absence in breast cancer, we analyzed two large clinically annotated genomic datasets The Cancer Genome Atlas (TCGA) and the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC). We confirmed that A3B expression is associated with aggressive clinicopathologic characteristics and adverse outcomes and show that A3B expression is highly correlated with proliferative features (mitosis and cell cycle-related gene expression) in breast and 15 of 16 other solid tumor types. However, breast cancers arising in homozygous A3B ᵈᵉˡ individuals with A3B absent did not differ in these features, indicating that A3B expression is a reflection rather than a direct cause of increased proliferation. Using gene set enrichment analysis (GSEA), we detected a pattern of immune activation in A3B ᵈᵉˡ breast cancers, which seems to be related to hypermutation arising in A3B ᵈᵉˡ carriers. Together, these results provide an explanation for A3B overexpression and its prognostic effect, giving context to additional study of this mutator as a cancer biomarker or putative drug target. In addition, although immune features of A3B ᵈᵉˡ require additional study, these findings nominate the A3B ᵈᵉˡ polymorphism as a potential predictor for cancer immunotherapy.
Significance Somatic mutagenesis is fundamental to the development and evolution of cancers. APOBEC3B (A3B) is a cellular deaminase, which is overexpressed in cancers and believed to be an important cause of cancer-associated mutations. The factors responsible for A3B up-regulation are unknown. Interestingly, a germ-line deletion polymorphism exists, such that a significant proportion of the global population does not express A3B protein. Using large human cancer datasets, we show that A3B expression is strongly associated with cellular proliferation. Furthermore, we identify a pattern of immune activation related to hypermutation in tumors arising in A3B deletion carriers suggesting that these patients could respond differently to immune-directed therapies. These results provide important context for the ongoing study of A3B as a therapeutic target or biomarker.
PLK4 was identified as a promising therapeutic target through a systematic approach that combined RNAi screening with gene expression analysis in human breast cancers and cell lines. A drug discovery ...program culminated in CFI-400945, a potent and selective PLK4 inhibitor. Cancer cells treated with CFI-400945 exhibit effects consistent with PLK4 kinase inhibition, including dysregulated centriole duplication, mitotic defects, and cell death. Oral administration of CFI-400945 to mice bearing human cancer xenografts results in the significant inhibition of tumor growth at doses that are well tolerated. Increased antitumor activity in vivo was observed in PTEN-deficient compared to PTEN wild-type cancer xenografts. Our findings provide a rationale for the clinical evaluation of CFI-400945 in patients with solid tumors, in particular those deficient in PTEN.
•CFI-400945 is a PLK4 small molecule inhibitor with significant anticancer activity•CFI-400945 causes dysregulated centriole duplication, mitotic errors, and cell death•CFI-400945 may represent a therapeutic option for a range of solid tumors
Mason et al. show that PLK4 is a potential therapeutic target in human cancers. Mason et al. further identify a PLK4 inhibitor, CFI-400945, and demonstrate its potential as a clinically useful cancer therapeutic.
Controversy over the role of antioxidants in cancer has persisted for decades. Here, we demonstrate that synthesis of the antioxidant glutathione (GSH), driven by GCLM, is required for cancer ...initiation. Genetic loss of Gclm prevents a tumor’s ability to drive malignant transformation. Intriguingly, these findings can be replicated using an inhibitor of GSH synthesis, but only if delivered prior to cancer onset, suggesting that at later stages of tumor progression GSH becomes dispensable potentially due to compensation from alternative antioxidant pathways. Remarkably, combined inhibition of GSH and thioredoxin antioxidant pathways leads to a synergistic cancer cell death in vitro and in vivo, demonstrating the importance of these two antioxidants to tumor progression and as potential targets for therapeutic intervention.
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•The GSH antioxidant pathway is required for cancer initiation•After cancer initiation, GSH is dispensable due to alternative antioxidant pathways•The TXN antioxidant pathway is upregulated in tumors•Inhibition of both GSH and TXN pathways causes synergistic cancer cell death
Harris et al. show that the antioxidant glutathione (GSH) is required for cancer initiation but not for established tumors partly due to upregulation of the thioredoxin (TXN) antioxidant pathway in the latter. Consequently, blocking both GSH and TXN pathways synergistically inhibits tumor growth.
Estrogen receptor (ER+) breast cancer is the most frequently diagnosed breast cancer subtype. Currently, adjuvant treatment for early stage disease consists of endocrine therapy, with or without ...chemotherapy and bone-targeted therapy, delivered in a risk-adapted manner. Despite this multimodal approach, a significant proportion of high risk patients will develop incurable distant recurrences. There is an ongoing need to develop new treatment strategies that address the biologic causes of treatment failure and to identify the individual patients who can benefit from such interventions. Here we review the clinical investigation of targeted and novel therapies, including inhibitors of the PI3K-AKT-mTOR pathway, oral selective estrogen receptor degraders (SERDs), and PARP-inhibitors for the treatment of early ER+ breast cancer. Furthermore, we highlight opportunities in biomarker development to help guide the delivery of escalated adjuvant strategies.
Patient-derived tumor organoids (PDOs) are a highly promising preclinical model that recapitulates the histology, gene expression, and drug response of the donor patient tumor. Currently, PDO culture ...relies on basement-membrane extract (BME), which suffers from batch-to-batch variability, the presence of xenogeneic compounds and residual growth factors, and poor control of mechanical properties. Additionally, for the development of new organoid lines from patient-derived xenografts, contamination of murine host cells poses a problem. We propose a nanofibrillar hydrogel (EKGel) for the initiation and growth of breast cancer PDOs. PDOs grown in EKGel have histopathologic features, gene expression, and drug response that are similar to those of their parental tumors and PDOs in BME. In addition, EKGel offers reduced batch-to-batch variability, a range of mechanical properties, and suppressed contamination from murine cells. These results show that EKGel is an improved alternative to BME matrices for the initiation, growth, and maintenance of breast cancer PDOs.
Identifying robust biomarkers of drug response constitutes a key challenge in precision medicine. Patient-derived tumor xenografts (PDX) have emerged as reliable preclinical models that more ...accurately recapitulate tumor response to chemo- and targeted therapies. However, the lack of computational tools makes it difficult to analyze high-throughput molecular and pharmacologic profiles of PDX. We have developed Xenograft Visualization & Analysis (Xeva), an open-source software package for
pharmacogenomic datasets that allows for quantification of variability in gene expression and pathway activity across PDX passages. We found that only a few genes and pathways exhibited passage-specific alterations and were therefore not suitable for biomarker discovery. Using the largest PDX pharmacogenomic dataset to date, we identified 87 pathways that are significantly associated with response to 51 drugs (FDR < 0.05). We found novel biomarkers based on gene expressions, copy number aberrations, and mutations predictive of drug response (concordance index > 0.60; FDR < 0.05). Our study demonstrates that Xeva provides a flexible platform for integrative analysis of preclinical
pharmacogenomics data to identify biomarkers predictive of drug response, representing a major step forward in precision oncology. SIGNIFICANCE: A computational platform for PDX data analysis reveals consistent gene and pathway activity across passages and confirms drug response prediction biomarkers in PDX.
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Molecularly targeted treatments and immunotherapy are cornerstones in oncology, with demonstrated efficacy across different tumor types. Nevertheless, the overwhelming majority metastatic disease is ...incurable due to the onset of drug resistance. Preclinical models including genetically engineered mouse models, patient-derived xenografts and two- and three-dimensional cell cultures have emerged as a useful resource to study mechanisms of cancer progression and predict efficacy of anticancer drugs. However, variables including tumor heterogeneity and the complexities of the microenvironment can impair the faithfulness of these platforms. Here, we will discuss advantages and limitations of these preclinical models, their applicability for drug testing and in co-clinical trials and potential strategies to increase their reliability in predicting responsiveness to anticancer medications.
Triple negative breast cancer (TNBC) has poor prognosis when compared to other breast cancer subtypes. Despite pre-clinical data supporting an immune targeted approach for TNBCs, immunotherapy has ...failed to demonstrate the impressive responses seen in other solid tumor malignancies. Additional strategies to modify the tumor immune microenvironment and potentiate response to immunotherapy are needed. In this review, we summarise phase III data supporting the use of immunotherapy for TNBC. We discuss the role of IL-1β in tumorigenesis and summarize pre-clinical data supporting IL-1β inhibition as a potential therapeutic strategy in TNBC. Finally, we present current trials evaluating IL-1β in breast cancer and other solid tumor malignancies and discuss future studies that may provide a strong scientific rationale for the combination of IL-1β and immunotherapy in the neoadjuvant and metastatic setting for people with TNBC.
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