Translational Strategies to Target Metastatic Bone Disease

Metastatic bone disease is a common and devastating complication to cancer, confounding treatments and recovery efforts and presenting a significant barrier to de-escalating the adverse outcomes associated with disease progression. Despite significant advances in the field, bone metastases remain presently incurable and contribute heavily to cancer-associated morbidity and mortality. Mechanisms associated with metastatic bone disease perpetuation and paralleled disruption of bone remodeling are highlighted to convey how they provide the foundation for therapeutic targets to stem disease escalation. The focus of this review aims to describe the preclinical modeling and diagnostic evaluation of metastatic bone disease as well as discuss the range of therapeutic modalities used clinically and how they may impact skeletal tissue

Translational Strategies to Target Metastatic Bone Disease

Metastatic bone disease is a common and devastating complication to cancer, confounding treatments and recovery efforts and presenting a significant barrier to de-escalating the adverse outcomes associated with disease progression. Despite significant advances in the field, bone metastases remain presently incurable and contribute heavily to cancer-associated morbidity and mortality. Mechanisms associated with metastatic bone disease perpetuation and paralleled disruption of bone remodeling are highlighted to convey how they provide the foundation for therapeutic targets to stem disease escalation. The focus of this review aims to describe the preclinical modeling and diagnostic evaluation of metastatic bone disease as well as discuss the range of therapeutic modalities used clinically and how they may impact skeletal tissue

The Role of TGF-β in Bone Metastases

Complications associated with advanced cancer are a major clinical challenge and, if associated with bone metastases, worsen the prognosis and compromise the survival of the patients. Breast and prostate cancer cells exhibit a high propensity to metastasize to bone. The bone microenvironment is unique, providing fertile soil for cancer cell propagation, while mineralized bone matrices store potent growth factors and cytokines. Biologically active transforming growth factor β (TGF-β), one of the most abundant growth factors, is released following tumor-induced osteoclastic bone resorption. TGF-β promotes tumor cell secretion of factors that accelerate bone loss and fuel tumor cells to colonize. Thus, TGF-β is critical for driving the feed-forward vicious cycle of tumor growth in bone. Further, TGF-β promotes epithelial-mesenchymal transition (EMT), increasing cell invasiveness, angiogenesis, and metastatic progression. Emerging evidence shows TGF-β suppresses immune responses, enabling opportunistic cancer cells to escape immune checkpoints and promote bone metastases. Blocking TGF-β signaling pathways could disrupt the vicious cycle, revert EMT, and enhance immune response. However, TGF-β’s dual role as both tumor suppressor and enhancer presents a significant challenge in developing therapeutics that target TGF-β signaling. This review presents TGF-β’s role in cancer progression and bone metastases, while highlighting current perspectives on the therapeutic potential of targeting TGF-β pathways

The Potential of Wnt Signaling Pathway in Cancer: A Focus on Breast Cancer

Cancer development and progression as well as tumor recurrence are largely due to the presence of cancer stem cells (CSCs) that are maintained through various pathways. Wnt/β-catenin signaling is the fundamental pathway, which when deregulated leads to tumor development by sustaining CSC population. Along with the upregulation of its various components, Wnt pathway is highly active in cancer cells resulting in increased expression of the target genes. In breast cancer condition, convincing results are available wherein the Wnt pathway activation in breast cancer cells increases the cell motility while its blockade suppresses their aggressive behavior in vitro. Further, numerous reports on breast cancer patients have documented the importance of activation of Wnt pathway and its components to an extent that the regulation can be exploited therapeutically with promising results. In addition, recent research has laid emphasis on the significance of Wnt pathway in the triple-negative breast cancer, a molecular subtype of breast cancer, which lacks targeted therapy till date. Hence, understanding of Wnt signaling and its targeting to treat such patients can be an assuring approach

Clinical utility of interleukin-18 in breast cancer patients: A pilot study

Aim: The aim of this study is to analyze the protein expression of interleukin 18 (IL-18) in patients with untreated breast cancer and further to evaluate its clinical efficacy in predicting treatment outcome. Methods: In the present study, a total of 50 untreated patients with invasive ductal carcinoma of breast were included in the study. Expression of IL-18 was studied by immunohistochemistry method. Statistical analysis was carried out using Statistical Package for Social Sciences statistical software and P ≤ 0.05 was considered statistically significant. Results: Seventy-two percent of the breast cancer patients showed the presence of cytoplasmic and/or nuclear IL-18 immunoreactivity. IL-18 expression was significantly and positively correlated with the stromal response (χ2 = 3.97, r = 0.282, P = 0.044). Further, the IL-18 immunoreactivity was significantly higher in patients with HER2 amplification as compared to luminal B (χ2 = 2.82, r = −0.523, P = 0.047) breast cancer patients. Moreover, a trend of increased IL-18 expression was observed in estrogen/progesterone receptor (ER/PR) negative patients as compared to ER/PR positive patients (χ2 = 3.41, r = −0.282, P = 0.066). Conclusion: IL-18 could be used as a potential predictive marker and guide clinicians for recommendations to newer treatment. It might serve as a potential therapeutic target to establish novel treatment approaches along with the current treatment protocol used

Predictive models of choroidal neovascularization and geographic atrophy incidence applied to clinical trial design.

PURPOSE: To develop comprehensive predictive models for choroidal neovascularization (CNV) and geographic atrophy (GA) incidence within 3 years that can be applied realistically to clinical practice. DESIGN: Retrospective evaluation of data from a longitudinal study to develop and validate predictive models of CNV and GA. METHODS: The predictive performance of clinical, environmental, demographic, and genetic risk factors was explored in regression models, using data from both eyes of 2011 subjects from the Age-Related Eye Disease Study (AREDS). The performance of predictive models was compared using 10-fold cross-validated receiver operating characteristic curves in the training data, followed by comparisons in an independent validation dataset (1410 AREDS subjects). Bayesian trial simulations were used to compare the usefulness of predictive models to screen patients for inclusion in prevention clinical trials. RESULTS: Logistic regression models that included clinical, demographic, and environmental factors had better predictive performance for 3-year CNV and GA incidence (area under the receiver operating characteristic curve of 0.87 and 0.89, respectively), compared with simple clinical criteria (AREDS simplified severity scale). Although genetic markers were associated significantly with 3-year CNV (CFH: Y402H; ARMS2: A69S) and GA incidence (CFH: Y402H), the inclusion of genetic factors in the models provided only marginal improvements in predictive performance. CONCLUSIONS: The logistic regression models combine good predictive performance with greater flexibility to optimize clinical trial design compared with simple clinical models (AREDS simplified severity scale). The benefit of including genetic factors to screen patients for recruitment to CNV prevention studies is marginal and is dependent on individual clinical trial economics