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The use of nanoparticles for breast cancer targeting and treatment has become a reality. They are safe and possess interesting peculiarities such as the unspecific accumulation into the tumor site and the possibility to activate controlled drug release as compared to free drugs. However, there are still many areas of improvement which can certainly be addressed with the use of peptide-based elements.The article reviews different preclinical strategies employing peptides and proteins in combination with nanoparticles for breast cancer targeting and treatment as well as peptide and protein-targeted encapsulated drugs, and it lists the current clinical status of therapies using peptides and proteins for breast cancer.The conjugation of protein and peptides can improve tumor homing of nanoparticles, increase cellular penetration and attack specific drivers and vulnerabilities of the breast cancer cell to promote tumor cytotoxicity while reducing secondary effects in healthy tissues. Examples are the use of antibodies, arginylglycylaspartic acid (RGD) peptides, membrane disruptive peptides, interference peptides, and peptide vaccines. Although their implementation in the clinic has been relatively slow up to now, we anticipate great progress in the field which will translate into more efficacious and selective nanotherapies for breast cancer.

Simple Summary Colorectal cancer is a disease associated with a high mortality rate. During the tumorigenic process, several factors and signaling molecules produced by tumor cells and the cells that surround them (forming the tumor microenvironment) regulate and modify cancer proliferation and metastasis. These regulatory agents include reactive oxygen species (ROS), which are involved in different metabolic networks and in the maintenance of cell homeostasis. Their excess, however, can cause oxidative stress and be detrimental to the cell. In fact, oxidative stress has been linked to several processes related to colorectal cancer initiation and progression. The different activities where ROS are involved suggest that ROS level modulators could be used to benefit cancer patients. Abstract Colorectal cancer (CRC) is the fourth most common cause of cancer deaths worldwide. Although screening programs have reduced mortality rates, there is a need for research focused on finding the main factors that lead primary CRC to progress and metastasize. During tumor progression, malignant cells modify their habitat, corrupting or transforming cells of different origins and creating the tumor microenvironment (TME). Cells forming the TME like macrophages, neutrophils, and fibroblasts generate reactive oxygen species (ROS) that modify the cancer niche. The effects of ROS in cancer are very diverse: they promote cellular proliferation, epithelial-to-mesenchymal transition (EMT), evasion of cell death programs, migration, and angiogenesis. Due to the multifaceted role of ROS in cancer cell survival and function, ROS-modulating agents such as antioxidants or pro-oxidants could have therapeutic potential in cancer prevention and/or as a complement to systemic treatments. In this review, we will examine the main ROS producer cells and their effects on cancer progression and metastasis. Furthermore, we will enumerate the latest clinical trials where pro-oxidants and antioxidants have therapeutic uses in CRC.

Aberrant gene expression is a hallmark of cancer. Although transcription is traditionally considered ‘undruggable’, the development of CRISPR-associated protein 9 (Cas9) systems offers enormous potential to rectify cancer-associated transcriptional abnormalities in malignant cells. However delivery of this technology presents a critical challenge to overcome in order to realize clinical translation for cancer therapy. In this article we demonstrate for the first time, a fully synthetic strategy to enable CRISPR-mediated activation (CRISPRa) of tumour suppressor genes in vivo using a targeted intravenous approach. We show this via highly efficient transcriptional activation of two model tumour suppressor genes, Mammary Serine Protease Inhibitor (MASPIN, SERPINB5) and cysteine-rich 61/connective tissue growth factor/nephroblastoma-overexpressed 6 (CCN6, WISP3), in a mouse model of breast cancer. In particular, we demonstrate that targeted intravenous delivery of can be achieved using a novel nanoscale dendritic macromolecular delivery agent, with negligible toxicity and long lasting therapeutic effects, outlining a targeted effective formulation with potential to treat aggressive malignancies.

Simple Summary Malignant pleural effusion is a common complication arising as the natural progression of many tumors, such as lung cancer. When this occurs, the common protocol consists of analyzing the pleural fluid for the presence of malignant cells. However, on many occasions no malignant cells are found despite a clear suspicion of cancer. Thus, the current diagnostic methodology is imperfect and more precise methods for the identification of malignancy are needed. Nonetheless, these methods are often invasive, which may be counterproductive, especially for patients with poor health condition. These concerns have made clinicians consider alternative non-invasive strategies to diagnose cancer using the generally abundant pleural fluid (e.g., liquid biopsy). Thus, a liquid sample can be analyzed for the presence of cancer footprints, such as circulating malignant cells and tumor nucleic acids. Herein, we review the literature for studies considering pleural fluid as a successful source of liquid biopsy. Abstract Liquid biopsy is emerging as a promising non-invasive diagnostic tool for malignant pleural effusions (MPE) due to the low sensitivity of conventional pleural fluid (PF) cytological examination and the difficulty to obtain tissue biopsies, which are invasive and require procedural skills. Currently, liquid biopsy is increasingly being used for the detection of driver mutations in circulating tumor DNA (ctDNA) from plasma specimens to guide therapeutic interventions. Notably, malignant PF are richer than plasma in tumor-derived products with potential clinical usefulness, such as ctDNA, micro RNAs (miRNAs) and long non-coding RNAs (lncRNAs), and circulating tumor cells (CTC). Tumor-educated cell types, such as platelets and macrophages, have also been added to this diagnostic armamentarium. Herein, we will present an overview of the role of the preceding biomarkers, collectively known as liquid biopsy, in PF samples, as well as the main technical approaches used for their detection and quantitation, including a proper sample processing. Technical limitations of current platforms and future perspectives in the field will also be addressed. Using PF as liquid biopsy shows promise for use in current practice to facilitate the diagnosis and management of metastatic MPE.

Simple Summary Metastasis is responsible for most of the deaths related to cancer patients. One of the hypotheses that explains the initiation of metastasis is a process called epithelial-to-mesenchymal transition (EMT), in which tumor cells change shape and acquire more aggressive properties that allows them to escape from the tumor and invade other organs. This also occurs in colorectal cancer (CRC), one of the most diagnosed types of cancer worldwide. During the past years, many scientists have discovered that certain molecules or biomarkers participating in this EMT process are able to predict the severity of the cancer and this is helping clinicians to manage treatments. Nevertheless, we think that all this information needs a detailed revision because a lot of biomarkers have been described but have not been analyzed whether they interact with each other in the same mechanism or not. Herein, we performed a bibliographic revision on this topic and identified a great number of biomarkers participating in oxidative stress, a cellular phenomenon that could have a role on the patient’s prognosis because its presence or absence on the patient’s tumor or blood had an influence on survival. Our findings suggest that oxidative stress deserves further study to understand metastasis better and to predict prognosis in a more efficient way. Abstract Epithelial-to-mesenchymal transition (EMT) is one of the most accepted mechanisms leading to metastasis, which is responsible for most of the cancer-related deaths. In order to identify EMT-related biomarkers able to predict clinical outcomes in colorectal cancer (CRC), a systematic review and meta-analysis of prognostic factors associated to overall survival (OS) and progression free survival (PFS) was conducted. The systematic literature search included studies from June 2014 to June 2019 available at PubMed and Scopus databases. Meta-analysis was performed for those markers appearing in minimum three works with a total number of 8656 participants. The rest were enlisted and subjected to functional enrichment. We identified nine clinical biomarkers and 73 EMT-related molecular biomarkers associated to OS and/or PFS in CRC. The significant enrichment of biomarkers found involved in cellular oxidoreductase activity suggests that ROS generation plays an active role in the EMT process. Clinical practice needs new biomarkers with a reliable prognostic value able to predict clinical outcomes in CRC. Our integrative work supports the role of oxidative stress in tumorigenesis and EMT progress highlighting the importance of deciphering this specific mechanism to get a better understanding of metastasis.

Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting …

Triple-negative breast cancers (TNBC) are highly aggressive malignancies comprising ~15-20 % of all breast cancers. TNBCs quickly acquire drug resistance mechanisms and are inherently resistant to radiotherapy, which significantly limits therapeutic options. Thus, there is a need to develop more selective and efficient therapeutic approaches to target this cancer subtype. In this study we investigate the applicability of MMW radiation as co-factor for prolonged sensitisation of TRPV1 receptor to promote the maximal channel activation with minimal tachyphylaxis to increase cancer cell death in TNBC.

OBJECTIVE Endometrial carcinoma is the most frequent gynecological cancer. About 15% of these cancers are of high risk and radiotherapy still remains the most suitable treatment. In this context, agents able to promote radiosensitization are of great interest. Here, we describe for the first time the radiosensitization ability of sunitinib in endometrial carcinoma. METHODS Four endometrial carcinoma cell lines were used for the study. The activation of apoptosis signalling pathways and tyrosine kinase receptors were analysed by Western blot, luciferase assays and Immunoprecipitation. Radiosensitization effects were assessed using clonogenic assays. p65 and phosphatase and tensin homolog (PTEN) were upregulated by lentiviral transduction. RESULTS We discovered that ionizing radiation activates the pro-oncogenic proteins and signalling pathways KIT, protein kinase B (AKT), and nuclear factor kappa B (NF-κB) and these activations were abrogated by sunitinib, resulting in a radiosensitization effect. We found out that AKT pathway is greatly involved in this process as PTEN restoration in the PTEN-deficient cell line RL95-2 is sufficient to inhibit AKT, rendering these cells more susceptible to ionizing radiation and sunitinib-induced radiosensitization. In Ishikawa 3-H-12 cells, radiosensitization effects and inhibition of AKT were achieved by PTEN restoration plus treatment with the phosphoinositide-3-kinase inhibitor LY294002. This suggests that endometrial tumors could have different sensitivity degree to radiotherapy and susceptibility to sunitinib-induced radiosensitization depending on their AKT activation levels. CONCLUSIONS Our results provide the rationale of using sunitinib as neoadjuvant treatment prior radiotherapy which could be a starting point for the implementation of sunitinib and radiotherapy in the clinic for the treatment of recalcitrant endometrial cancers.

Research into molecular targets for drug development in melanoma is starting to bear fruit. Of the drugs tested to date in patients with metastatic melanoma, those that have yielded the best results are V600E BRAF inhibitors in melanomas carrying the V600E mutation; c- kit tyrosine kinase activity inhibitors in melanomas carrying c-kit mutations; and anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) antibodies, which block the mechanisms involved in immune tolerance. Many problems have yet to be resolved in these areas, however, such as the rapid development of resistance to BRAF and c-kit inhibitors and the lack of biomarkers to predict treatment response in the case of CTLA-4 blockers. We review the results of targeted therapy with these and other drugs in metastatic melanoma and discuss what the future holds for this field.

Sorafenib induces apoptosis and enhances Tumour Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL)-induced cell killing of tumoural cells. We have investigated the effects of the multikinase inhibitor Sorafenib alone or in combination with TRAIL and agonistic Fas antibodies on endometrial carcinoma cells. We have also focused on the search of the differential molecular mechanisms by which Sorafenib induces cell death and the ones involved in sensitisation to TRAIL. In the present study, we show that Sorafenib induces apoptosis of both endometrial cancer cell lines and human primary cultures and sensitises these cells to TRAIL and agonistic Fas antibodies (aFas)-induced apoptosis. However, Raf/MEK/ERK inhibition by Sorafenib was not responsible for Sorafenib cell death or TRAIL sensitisation of endometrial cancer cells. Sorafenib treatment correlated with a downregulation of both FLICE-Inhibitory Protein (FLIP) and myeloid cell leukaemia-1 (Mcl-1), caused by a proteasomal degradation of both proteins. We evaluated the contribution of FLIP and Mcl-1 downregulation in apoptosis triggered by Sorafenib alone or Sorafenib plus TRAIL. Interestingly, cell death caused by Sorafenib was mediated by downregulation of Mcl-1, but not by FLIP. In contrast, we found that Sorafenib sensitisation of endometrial carcinoma cells to TRAIL- and Fas-induced apoptosis was dependent on FLIP but not on Mcl-1 downregulation. Altogether, we discern the dual mechanisms by which Sorafenib causes cell death from those involved in death receptor sensitisation.

Endometrial carcinoma is one of the most common malignancies in the female genital tract, usually treated by surgery and radiotherapy. Chemotherapy is used when endometrial carcinoma is associated with widespread metastasis or when the tumor recurs after radiation therapy. In the present study, we demonstrate that the tyrosine kinase receptor inhibitor Sunitinib reduces cell viability, proliferation, clonogenicity and induces apoptotic cell death in endometrial carcinoma cell lines, which is not due to its action through the most known targets like VEGFR, nor through EGFR as demonstrated in this work. Interestingly, Sunitinib reduces NFκB transcriptional activity either at basal level or activation by EGF or TNF-α. We observed that Sunitinib was able to inhibit the Bortezomib-induced NFκB transcriptional activity which correlates with a decrease of the phosphorylated levels of IKKα and β, p65 and IκBα. We evaluated the nature of the interaction between Sunitinib and Bortezomib by the dose effect method and identified a synergistic effect (combination index

Malignant melanoma, once disseminated, is a malignant neoplasm extremely resistant to conventional anticancer treatment, such as chemo or radiation therapies. Therefore, new therapeutic strategies are under investigation as, for instance, immunotherapy, gene therapy or so called targeted therapy. Proteasome appears as one of these new possible targets. The ubiquitin proteasome pathway is a complex multicatalytic system specialized in the degradation of proteins of intracellular origin, unlike lysosomes that are specialized in the degradation of proteins of extracellular origin. Many of the proteins degraded by the proteasome are molecules involved in cell proliferation and apoptosis, such as cyclins and cyclin dependent kinases, the proapoptotic protein p53 or the nuclear transcription factor NFkappaB. It has been demonstrated that inhibition of proteasome induces cell death, more strongly in neoplastic cells than in normal cells, and, even more, that proteasome inhibition sensitizes neoplastic cells to other proapoptotic stimulus such as chemo o radiation therapy, probably by the NFkappaB pathway. Therefore, the proteasome could be a good target for cells so resistant to apoptosis as melanoma cells are. We and others have demonstrated that melanoma cells are sensitive in vitro to Bortezomib and other proteasome inhibitors, that are able to decrease melanoma cell viability, to induce a reduction in cell proliferation rate and a cell cycle arrest and to trigger apoptotic cell death through both caspase dependent and independent pathways. Bortezomib is a commercially available proteasome inhibitor, mainly used for the treatment of multiple myeloma and other malignant hematological disorders. Although the only published phase II clinical trial using single agent Bortezomib in patients with advanced melanoma yielded disappointing results, the potential use of proteasome inhibitors for the treatment of metastatic melanoma patients is still under assessment. Based on the knowledge of the physiological role of the proteasome system and on preclinical studies, employment of proteasome inhibitors in combined therapies seems the best way to afford the use of these compounds for advanced melanoma treatment.

The article reviews the main molecular pathology alterations of endometrial and ovarian carcinomas and melanoma. Several promising drugs targeting the genes most frequently altered in these tumors are under consideration. The most promising signaling pathways to be targeted for therapies in these tumors are the tyrosine kinase receptor (EGFR, HER2, c-KIT), the RAS/B-RAF/MAPK, the PI3K–mTOR, and apoptosis signaling pathways.

e16555 Background: Endometrial carcinoma (EC) frequently shows deregulation of the extrinsic apoptotic pathway. One of the critical regulators of apoptosis resistance in EC is FLIP, under the control of NFkB and a cellular complex composed of CK2, KSR1, and BRAF. Methods: Four different EC cell lines, which are known to exhibit resistance to TRAIL/FAS-induced apoptosis (Ishikawa, KLE, HEC1A, and RL-95) were exposed to various pharmacologic substances that target proteins involved in the regulation of the extrinsic apoptotic pathway and receptor tyrosine kinases including bortezomib, sorafenib, sunitinib, DRB, apigenin, MG-132, epoxomicin, and ALLN. Moreover, EC cell lines were subjected to down-regulation of several of these genes (FLIP, CK2, KSR1, and BRAF) by shRNA. Cell viability and apoptotic morphology was determined. Results were validated in tumor cell explants. Results: Bortezomib induced cell death on EC cells and primary explants to a 70% extent. However, 100% of treated explants and cell lines activated NF-kB instead of blocking its transcriptional potential. Combination of sunitinib plus bortezomib induced 75% fold reduction in NFkB activity and induced a 5% of synergistic increse of apoptotic cell death in Ishikawa cells. Treatment of the four cell lines with TRAIL failed to induce cell death. However, FLIP knock-down sensitized the cells to TRAIL-induced apoptosis (80%). Moreover, down-regulation of CK2, KSR1, and BRAF by pharmacological inhibition, or shRNA, reduced FLIP cellular levels, and induced TRAIL-dependent apoptosis in 70%-100% of EC cell lines tested. Sorafenib induced a dose-dependent cell death in all four cell lines, to a 70%-100% extent at 48 hours. Conclusions: In vitro pharmacologic targeting of the apoptotic pathway effectively induces cell death in EC cell lines. These findings justify clinical trials with these agents in EC. [Table: see text]

Radiotherapy is one of the cornerstone treatments for endometrial cancer and has successfully diminished the risk of local recurrences after surgery. However, a considerable percentage of patients suffers tumor relapse due to radioresistance mechanisms. Knowledge about the molecular determinants that confer radioresistance or radiosensitivity in endometrial cancer is still partial, as opposed to other cancers. In this review, we have highlighted different central cellular signaling pathways and processes that are known to modulate response to radiotherapy in endometrial cancer such as PI3K/AKT, MAPK and NF-κB pathways, growth factor receptor signaling, DNA damage repair mechanisms and the immune system. Moreover, we have listed different clinical trials employing targeted therapies against some of the aforementioned signaling pathways and members with radiotherapy. Finally, we have identified the latest advances in radiotherapy that have started being utilized in endometrial cancer, which include modern radiotherapy and radiogenomics. New molecular and genetic studies in association with the analysis of radiation responses in endometrial cancer will assist clinicians in taking suitable decisions for each individual patient and pave the path for personalized radiotherapy.