Enzalutamide in metastatic castration-resistant prostate cancer, real-world data

Objective: Androgen deprivation therapy (ADT) is used alone or in combination with docetaxel or androgen inhibitors in the initial treatment of metastatic prostate cancer (PC) (mPC). Enzalutamide is an androgen receptor inhibitor that is used orally and plays a role in different steps of the androgen receptor (AR) signal pathway. The aim of this study is to determine the real life data of patients using enzalutamide for metastatic PC. Material and Methods: The 118 patients from a totally 6 centers using enzalutamide treatment were included in this retrospective analysis. Clinical information of patients was recorded from patient files or automation records. Results: Median OS was 71 months, and median PFS was five months (4,1 – 5,9 months). There was no association of Gleason score with OS and PFS (p = 0.5 and p = 0.4, respectively). Although those who were metastatic at the time of diagnosis lived longer than those who developed metastases later, the difference was not statistically significant (p = 0.9). Likewise, there was no relationship between the time of metastasis development and PFS (p = 0.2). There was no difference in OS and PFS between patients with visceral metastasis and those without (p = 0.3, p = 0.5, respectively). Conclusion: Enzalutamide is an effective and safe agent in accordance with the literature in the patient group included in this study, although some patients may have an unresponsiveness to enzalutamide or develop progression under the enzalutamide treatment. More studies are needed to understand which patient group can benefit more from enzalutamide.

Epidermal Growth Factor Receptor as Target for Perioperative Elimination of Circulating Colorectal Cancer Cells

Surgical resection of the tumor is the primary treatment of colorectal cancer patients. However, we previously demonstrated that abdominal surgery promotes the adherence of circulating tumor cells (CTC) in the liver and subsequent liver metastasis development. Importantly, preoperative treatment with specific tumor-targeting monoclonal antibodies (mAb) prevented surgery-induced liver metastasis development in rats. This study investigated whether the epidermal growth factor receptor (EGFR) represents a suitable target for preoperative antibody treatment of colorectal cancer patients undergoing surgery. The majority of patients with resectable colorectal liver metastases were shown to have EGFR + CTCs. Three different anti-EGFR mAbs (cetuximab, zalutumumab, and panitumumab) were equally efficient in the opsonization of tumor cell lines. Additionally, all three mAbs induced antibody-dependent cellular phagocytosis (ADCP) of tumor cells by macrophages at low antibody concentrations in vitro, independent of mutations in EGFR signaling pathways. The plasma of cetuximab-treated patients efficiently opsonized tumor cells ex vivo and induced phagocytosis. Furthermore, neither proliferation nor migration of epithelial cells was affected in vitro, supporting that wound healing will not be hampered by treatment with low anti-EGFR mAb concentrations. These data support the use of a low dose of anti-EGFR mAbs prior to resection of the tumor to eliminate CTCs without interfering with the healing of the anastomosis. Ultimately, this may reduce the risk of metastasis development, consequently improving long-term patient outcome significantly.

The Role of Exosomes in Cancer Progression

Early detection, characterization and monitoring of cancer are possible by using extracellular vesicles (EVs) isolated from non-invasively obtained liquid biopsy samples. They play a role in intercellular communication contributing to cell growth, differentiation and survival, thereby affecting the formation of tumor microenvironments and causing metastases. EVs were discovered more than seventy years ago. They have been tested recently as tools of drug delivery to treat cancer. Here we give a brief review on extracellular vesicles, exosomes, microvesicles and apoptotic bodies. Exosomes play an important role by carrying extracellular nucleic acids (DNA, RNA) in cell-to-cell communication causing tumor and metastasis development. We discuss the role of extracellular vesicles in the pathogenesis of cancer and their practical application in the early diagnosis, follow up, and next-generation treatment of cancer patients.

Serum JAK/STAT profile is related to the IL expression but not with the outcome in pancreatic adenocarcinoma patients

Current genetic characterization of pancreatic ductal adenocarcinoma (PDAC) does not integrate the host reaction to cancer cells and cannot predict the response to chemo- or immunotherapy. The JAK/STAT pathway is an important factor of cytokine-mediated cancer inflammation, but its relationship with pancreatic carcinogenesis and the role of potential biomarkers is not established yet. Our study aimed to assess the significance of serum levels of JAK/STAT3 expression and inflammatory cytokines in PDAC in relation to the clinicopathological features and prognosis. This prospective cohort study included patients with proven adenocarcinoma and a matched group of controls without any malignancies. There were evaluated the serum expression of IL2, 6, 8, 17, JAK2, and STAT3 by ELISA assays in these two groups. The PDAC patients were followed up for 24 months. A Cox regression multivariate analysis model was used to determine factors influencing survival. The study comprised 56 patients with PDAC and 56 controls. The upregulated serum JAK2/STAT3 or cytokines were present in about half of the patients with PDAC, similar to controls. The expression of JAK2 in serum of PDAC patients was significantly associated with the expression of IL2 (p=0.03) and IL6 (p=0.02) but not with survival or metastasis development. Only age and the presence of lymph node metastases were associated with reduced survival in multivariate analyses. The STAT 3/JAK2 expression, although correlated with inflammatory status (IL2, IL6) was not overexpressed in PDAC compared to controls and proved no prognostic value.

Identification and Validation of TYMS as a Potential Biomarker for Risk of Metastasis Development in Hepatocellular Carcinoma

Metastasis is the major cause of hepatocellular carcinoma (HCC) mortality. Unfortunately, there are few reports on effective biomarkers for HCC metastasis. This study aimed to discover potential key genes of HCC, which could provide new insights for HCC metastasis. GEO (Gene Expression Omnibus) microarray and TCGA (The Cancer Genome Atlas) datasets were integrated to screen for candidate genes involved in HCC metastasis. Differentially expressed genes (DEGs) were screened, and then we performed enrichment analysis of Gene Ontology (GO), together with Kyoto Encyclopedia of Genes and Genomes (KEGG). A protein-protein interaction network was then built and analyzed utilizing STRING and Cytoscape, followed by the identification of 10 hub genes by cytoHubba. Four genes were associated with survival, their prognostic value was verified by prognostic signature analysis. Thymidylate synthase (TYMS) gene was identified as significant HCC metastasis-associated genes after mRNA expression validation and IHC analysis. TYMS silencing in HCC cells remarkedly inhibited growth and invasion. Finally, we found TYMS silencing dramatically decrease DNA synthesis and extracellular matrix (ECM) degradation, resulting in the inhibition of HCC metastasis, indicating TYMS had close associations with HCC development. These findings provided new insights into HCC metastasis and identified candidate gene prognosis signatures for HCC metastasis.

Involvement of the TGF-β Signaling Pathway in the Development of YAP-Driven Osteosarcoma Lung Metastasis

BackgroundThe poor survival rate of patients with osteosarcoma (OS), specifically with metastases at diagnosis, undergoes the urgency to develop new therapeutic strategies. Although we recently demonstrated the key role of YAP/TEAD signaling in the growth of OS primary tumor, the molecular mechanisms by which YAP regulates metastases development remain poorly understood.MethodsThe molecular mechanisms by which YAP regulates metastases development were studied using an overexpression of mutated forms of YAP able or not able to interact with TEAD. Molecular signatures were identified using RNA-sequencing analysis and gene set enrichment. Interactions between YAP and Smad3 were studied using proximity ligation assay (PLA), immunoprecipitation, and promoter/specific gene assays. The involvement of the TGF-β pathway in the ability of YAP to stimulate metastatic development in vivo was studied using an inhibitor of the TGF-β cascade in a preclinical model of OS and in vitro on the ability of OS cells to migrate and invade.ResultsOur work shows that a high YAP expression is associated with the presence of lung metastases which predicts a poor prognosis. Molecular analysis indicates that TGF-β signaling is involved in YAP-driven osteosarcoma cell pro-migratory phenotype, epithelial mesenchymal transition, cell migration, and in vivo lung metastasis development. Regardless of its ability to bind to TEAD, YAP interacts with Smad3 and stimulates the transcriptional activity of TGF-β/Smad3, thereby enhancing the ability of TGF-β to stimulate lung metastasis development.ConclusionsWe demonstrated the crucial involvement of the TGF-β/Smad3 signaling pathway in YAP-driven lung metastasis development in OS.

TIMP1 expression underlies sex disparity in liver metastasis and survival in pancreatic cancer

Sex disparity in cancer is so far inadequately considered, and components of its basis are rather unknown. We reveal that male versus female pancreatic cancer (PC) patients and mice show shortened survival, more frequent liver metastasis, and elevated hepatic metastasis-promoting gene expression. Tissue inhibitor of metalloproteinases 1 (TIMP1) was the secreted factor with the strongest male-biased expression in patient-derived pancreatic tumors. Male-specific up-regulation of systemic TIMP1 was demonstrated in PC mouse models and patients. Using TIMP1-competent and TIMP1-deficient PC mouse models, we established a causal role of TIMP1 in determining shortened survival and increased liver metastasis in males. Observing TIMP1 expression as a risk parameter in males led to identification of a subpopulation exhibiting increased TIMP1 levels (T1HI males) in both primary tumors and blood. T1HI males showed increased risk for liver metastasis development not only in PC but also in colorectal cancer and melanoma. This study reveals a lifestyle-independent sex disparity in liver metastasis and may open new avenues toward precision medicine.

Epigenetic reprogramming of DCCs into dormancy suppresses metastasis via restored TGFβ–SMAD4 signaling.

Disseminated cancer cells (DCCs) identified in secondary organs, sometimes before the primary tumor becomes detectable and treated, can remain dormant for years to decades before manifesting. Microenvironmental and epigenetic mechanisms may control the onset and escape from dormancy, and here we reveal how a combination of the DNA methylation inhibitor 5-azacytidine (AZA) and retinoic acid receptor ligands all-trans retinoic acid (atRA), orchestrate a novel program of stable dormancy. Treatment of HNSCC tumor cells with AZA+atRA induced a SMAD2/3/4 dependent regulation of downstream transcriptional program that restored the anti-proliferative function of TGFβ signaling. Significantly, AZA+atRA or AZA+AM80, an RARα specific agonist, strongly suppresses lung metastasis formation. The metastatic suppression occurs via the induction and maintenance of phenotypically homogenous dormant SMAD4+/NR2F1+ non-proliferative DCCs. These findings suggest that strategies that maintain or induce dormancy programs may be a viable alternative strategy to improve patient outcomes by preventing or significantly delaying metastasis development.