This article provides a comprehensive analysis of the signaling pathways implicated in breast cancer (BC), the most prevalent malignancy among women and a leading cause of cancer-related mortality globally. Special empha...This article provides a comprehensive analysis of the signaling pathways implicated in breast cancer (BC), the most prevalent malignancy among women and a leading cause of cancer-related mortality globally. Special emphasis is placed on the structural dynamics of protein complexes that are integral to the regulation of these signaling cascades. Dysregulation of cellular signaling is a fundamental aspect of BC pathophysiology, with both upstream and downstream signaling cascade activation contributing to cellular process aberrations that not only drive tumor growth, but also contribute to resistance against current treatments. The review explores alterations within these pathways across different BC subtypes and highlights potential therapeutic strategies targeting these pathways. Additionally, the influence of specific mutations on therapeutic decision-making is examined, underscoring their relevance to particular BC subtypes. The article also discusses both approved therapeutic modalities and ongoing clinical trials targeting disrupted signaling pathways. However, further investigation is necessary to fully elucidate the underlying mechanisms and optimize personalized treatment approaches.
The human genome project ushered in a genomic medicine era that was largely unimaginable three decades ago. Discoveries of druggable cancer drivers enabled biomarker-driven gene- and immune-targeted therapy and transform...The human genome project ushered in a genomic medicine era that was largely unimaginable three decades ago. Discoveries of druggable cancer drivers enabled biomarker-driven gene- and immune-targeted therapy and transformed cancer treatment. Minimizing treatment not expected to benefit, and toxicity-including financial and time-are important goals of modern oncology. The Worldwide Innovative Network (WIN) Consortium in Personalized Cancer Medicine founded by Drs. John Mendelsohn and Thomas Tursz provided a vision for innovation, collaboration and global impact in precision oncology. Through pursuit of transcriptomic signatures, artificial intelligence (AI) algorithms, global precision cancer medicine clinical trials and input from an international Molecular Tumor Board (MTB), WIN has led the way in demonstrating patient benefit from precision-therapeutics through N-of-1 molecularly-driven studies. WIN Next-Generation Precision Oncology (WINGPO) trials are being developed in the neoadjuvant, adjuvant or metastatic settings, incorporate real-world data, digital pathology, and advanced algorithms to guide MTB prioritization of therapy combinations for a diverse global population. WIN has pursued combinations that target multiple drivers/hallmarks of cancer in individual patients. WIN continues to be impactful through collaboration with industry, government, sponsors, funders, academic and community centers, patient advocates, and other stakeholders to tackle challenges including drug access, costs, regulatory barriers, and patient support. WIN's collaborative next generation of precision oncology trials will guide treatment selection for patients with advanced cancers through MTB and AI algorithms based on serial liquid and tissue biopsies and exploratory omics including transcriptomics, proteomics, metabolomics and functional precision medicine. Our vision is to accelerate the future of precision oncology care.
Matrix metalloproteinases (MMPs) are crucial in remodeling the extracellular matrix (ECM), modulating key processes involved in cancer progression, such as migration, invasion, angiogenesis, and metastasis. The overexpre...Matrix metalloproteinases (MMPs) are crucial in remodeling the extracellular matrix (ECM), modulating key processes involved in cancer progression, such as migration, invasion, angiogenesis, and metastasis. The overexpression of MMPs, particularly MMP-9, is markedly observed in glioblastoma multiforme (GBM), an aggressive primary brain tumor known for its diffuse and infiltrative nature. Tissue inhibitors of metalloproteinases (TIMPs), endogenous MMP inhibitors, offer significant therapeutic potential due to their wider interaction interfaces relative to small molecule inhibitors. Here, we studied the effect of wild-type human TIMP-1 and TIMP-3 and minimal TIMP variants (mTC1 and mTC3), previously engineered for MMP inhibition, on migration and invasion of GBM cells. Our study focused on minimal TIMP variants, due to their small molecular size and potential in higher cellular uptake and delivery, to assess their potential in cell-based assays. The results demonstrated that the minimal TIMP variants, mTC1, and mTC3, effectively inhibit MMP activity underscoring their potential to limit tumor invasion and progression. Given the lethal nature of GBM and the limited efficacy of current therapies, the application of TIMPs and their engineered minimal variants represents a novel and potentially transformative approach to regulating MMP activity in GBM.
Cancers that retain wild type presumably harbor other clonal alterations that permitted their precursors to bypass p53-mediated growth suppression. Consequently, studies that employ -wild type cancer cells and their iso...Cancers that retain wild type presumably harbor other clonal alterations that permitted their precursors to bypass p53-mediated growth suppression. Consequently, studies that employ -wild type cancer cells and their isogenic derivatives may systematically fail to appreciate the full scope of p53 functionality. Several phenotypes are known to be absent in the widely used isogenic HCT116 colorectal cancer (CRC) model, which originated from a tumor that had retained wild type . In contrast, we show that restoration of p53 in the -mutant CRC cell line DLD-1 impeded cell proliferation, increased levels of senescence and sensitized cells to ionizing radiation (IR). To study p53 in a non-cancer context, we disrupted in hTERT-RPE1 cells. Derived from primary cells that were immortalized , hTERT-RPE1 expressed striking p53-dependent phenotypes and appeared to select for p53 loss during routine culture. hTERT-RPE1 expressed a p53-responsive transcriptome that was highly representative of diverse experimental systems. We discovered several novel downstream p53 targets of potential clinical relevance including , which is involved in the detoxification of aldehydes and the metabolism of reactive oxygen species, and () which encodes a secreted surface protein that is overexpressed in many tumors.
Clinical parameters of leukogram and weight were analyzed in animal models before and after seven days of 5-FU infusions. A comparison of leukograms before and after 5-FU administrations was analyzed. The results showed...Clinical parameters of leukogram and weight were analyzed in animal models before and after seven days of 5-FU infusions. A comparison of leukograms before and after 5-FU administrations was analyzed. The results showed a significant difference ( = 0,004), confirming immunosuppression. There was a decrease in the weight of the animals after 7 days of 5-FU infusions ( = 0.02). After immunosuppression occurred, oral mucositis (OM) ulcerative lesions were observed. Two of the animals were selected to receive PLGA dressings. Then, electrospun PLGA membranes, with or without autologous cells, were applied to the ulcerative lesions, aiming to accelerate the regeneration process. Although this therapeutic innovation for OM lesions was still not tested in the bioengineering area, morphological analysis presented promising results. Lesions covered by cell-free PLGA, exhibited areas of inflammation persistence and angiogenesis. The cell-seeded cell-seeded PLGA membrane exhibited complete reepithelialization after 6 days, with minor inflammatory infiltrate. Interestingly, the present work showed preclinical parameters of cachexia induced by chemotherapy for cancer treatment. Moreover, it showed an innovative approach by applying dressings consisting of electrospun PLGA with the addition of autologous mesenchymal cells for OM ulcerative lesions. This promising innovation will pave the way for future applications in oral mucosa lesions.
BACKGROUND: Anti-epidermal growth factor receptor therapy showed an overall median survival improvement in metastatic colorectal cancer. Maintenance with anti in metastatic colorectal cancer wild type was studied in m...BACKGROUND: Anti-epidermal growth factor receptor therapy showed an overall median survival improvement in metastatic colorectal cancer. Maintenance with anti in metastatic colorectal cancer wild type was studied in many trials with promising results and many of these trials gave combined chemo with the target therapy and this combination had shown benefit in the form of synergistic effect and in delaying the resistance to the anti . METHOD: In our study patients received 6 cycles of 5-FU based chemotherapy with Panitumumab and patients who had partial response, complete response or stationary disease received metronomic Capecitabine with Panitumumab every 2 weeks for one year. The primary end point was progression free survival (PFS) and the secondary end points were safety, toxicity and overall survival (OS). RESULTS: The median PFS for all patients was 18 ± 1.4 months and the median OS was 45 months. Patients with synchronous metastasis and those who received Oxaliplatin based regimen with Panitumumab were found to have longer PFS compared to those with metachronous metastasis or those who received other chemotherapy regimen with accepted toxicity profile to the maintenance therapy. CONCLUSION: Using Panitumumab with metronomic Capecitabine is considered an accepted maintenance regimen in wild type metastatic colorectal cancer regardless of the primary site.
Epigenetic modifications, which reversibly regulate gene expression without altering the DNA sequence, are increasingly described in the literature as essential elements in the processes leading to cancer development. SE...Epigenetic modifications, which reversibly regulate gene expression without altering the DNA sequence, are increasingly described in the literature as essential elements in the processes leading to cancer development. SETDB1 regulates histone 3 (H3) K9 di- and trimethylation, promoting heterochromatin formation, and plays a key role in gene silencing. Epigenetic deregulation of expression appears to be involved in different cancers types, particularly in aggressive, relapsing or treatment-resistant subtypes. Despite advances in research, the full range of mechanisms through which this protein acts remains unclear; however, it is evident that SETDB1 has a pivotal role, particularly in the mesenchymal stem cells differentiation, tumor evasion and treatment resistance. Its role in genetically complex sarcomas, such as osteosarcoma, has not been fully explored, although recent Omics analyses suggest its presence and amplification in osteosarcoma. Given its involvement in osteoblastogenesis and adipogenesis, we discuss the potential of SETDB1 as a key target for new therapeutic strategies in osteosarcoma.
BACKGROUND: The treatment of blood cancers has been revolutionized by hematopoietic stem cell transplantation. Owing to this method, we are able to effectively treat most blood cancers. However, in some cases, one of the...BACKGROUND: The treatment of blood cancers has been revolutionized by hematopoietic stem cell transplantation. Owing to this method, we are able to effectively treat most blood cancers. However, in some cases, one of the greatest problems is the risk of relapse. Most often, relapse of the disease manifests itself as cancer cells with the same characteristics as the primary cancer. Nevertheless, a very small percentage of patients develop other blood cancers from donor cells. Donor cell-derived hematologic neoplasms are extremely rare complications that arise after hematopoietic stem cell transplantation. CASE PRESENTATION: In this study we described a patient who underwent hematopoietic stem cell transplantation due to acute myeloid leukemia and subsequently developed triple-negative myeloproliferative neoplasms with mutations in the , and genes 9 years later. Over the next two years, the disease progressed and MDS/AML developed. Unfortunately, the patient died during induction therapy. CONCLUSIONS: Donor cell-derived hematologic neoplasms are rare but significant complications after HSCT. Early diagnosis and intervention are crucial to improving patient prognosis. Further studies are needed to better understand the pathogenesis of this condition and develop more effective therapeutic strategies.