Clinical Trials For Cancer Therapy Research Articles

Enhanced pyrazolopyrimidinones cytotoxicity against glioblastoma cells activated by ROS-Generating cold atmospheric plasma.

Pyrazolopyrimidinones are fused nitrogen-containing heterocyclic systems, which act as a core scaffold in many pharmaceutically relevant compounds. Pyrazolopyrimidinones have been demonstrated to be efficient in treating several diseases, including cystic fibrosis, obesity, viral infection and cancer. In this study using glioblastoma U-251MG cell line, we tested the cytotoxic effects of 15 pyrazolopyrimidinones, synthesised via a two-step process, in combination with cold atmospheric plasma (CAP). CAP is an adjustable source of reactive oxygen and nitrogen species as well as other unique chemical and physical effects which has been successfully tested as an innovative cancer therapy in clinical trials. Significantly variable cytotoxicity was observed with IC50 values ranging from around 11μM to negligible toxicity among tested compounds. Interestingly, two pyrazolopyrimidinones were identified that act in a prodrug fashion and display around 5-15 times enhanced reactive-species dependent cytotoxicity when combined with cold atmospheric plasma. Activation was evident for direct CAP treatment on U-251MG cells loaded with the pyrazolopyrimidinone and indirect CAP treatment of the pyrazolopyrimidinone in media before adding to cells. Our results demonstrated the potential of CAP combined with pyrazolopyrimidinones as a programmable cytotoxic therapy and provide screened scaffolds that can be used for further development of pyrazolopyrimidinone prodrug derivatives.

Enhanced cancer immunotherapy by microneedle patch-assisted delivery of HBc VLPs based cancer vaccine

Tumor vaccines have made a significant breakthrough in clinical trials of cancer therapy, but have shown limited efficacy. Herein, we develop a novel tumor vaccine delivery strategy through a biodegradable microneedle patch (MN), which allows sustained release of tumor antigen and induces long term anti-tumor response. A tumor antigen peptide (OVA257–264: SIINFEKL) was fused with hepatitis B core (HBc) protein virus like particles (OVA-HBc VLPs) to increase the immunogenicity of tumor antigen. Mesoporous silica nanoparticles (MSN) were adopted as a vaccine adjuvant for enhancing the function of dendritic cells (DCs). OVA-HBc VLPs and MSN were capsulated into microneedles together [MSN/OVA-HBc@MN]. MSN/OVA-HBc@MN could significantly stimulate DC maturation and increase the presentation of OVA on DCs in vitro. MSN/OVA-HBc@MN can effectively stimulate antigen specific anti-tumor immune response and be used as prophylactic vaccines to effectively inhibit tumor formation. Moreover, the addition of CpG-DNA can enhance the therapeutic effect of MSN/OVA-HBc@MN in distant tumors and long term immune memory effect. Our results thus demonstrate that MSN-CpG/OVA-HBc@MN could be as a potential tumor-specific vaccination platform for tumor therapy.

Defects in Macrophage Reprogramming in Cancer Therapy: The Negative Impact of PD-L1/PD-1.

Classically activated M1 macrophages and alternatively activated M2 macrophages are two polarized subsets of macrophages at the extreme ends of a constructed continuum. In the field of cancer research, M2 macrophage reprogramming is defined as the repolarization of pro-tumoral M2 to anti-tumoral M1 macrophages. It is known that colony-stimulating factor 1 (CSF1)/CSF1 receptor (CSF1R) and CSF2/CSF2R signaling play important roles in macrophage polarization. Targeting CSF1/CSF1R for M2 macrophage reprogramming has been widely performed in clinical trials for cancer therapy. Other targets for M2 macrophage reprogramming include Toll-like receptor 7 (TLR7), TLR8, TLR9, CD40, histone deacetylase (HDAC), and PI3Kγ. Although macrophages are involved in innate and adaptive immune responses, M1 macrophages are less effective at phagocytosis and antigen presenting, which are required properties for the activation of T cells and eradication of cancer cells. Similar to T and dendritic cells, the “functionally exhausted” status might be attributed to the high expression of programmed death-ligand 1 (PD-L1) or programmed cell death protein 1 (PD-1). PD-L1 is expressed on both M1 and M2 macrophages. Macrophage reprogramming from M2 to M1 might increase the expression of PD-L1, which can be transcriptionally activated by STAT3. Macrophage reprogramming or PD-L1/PD-1 blockade alone is less effective in the treatment of most cancers. Since PD-L1/PD-1 blockade could make up for the defect in macrophage reprogramming, the combination of macrophage reprogramming and PD-L1/PD-1 blockade might be a novel treatment strategy for cancer therapy.

Recent Advances in Plasma-Based Cancer Treatments: Approaching Clinical Translation through an Intracellular View

Plasma medicine is a multidisciplinary field of research which is combining plasma physics and chemistry with biology and clinical medicine to launch a new cancer treatment modality. It mainly relies on utilizing low temperature plasmas in atmospheric pressure to generate and instill a cocktail of reactive species to selectively target malignant cells for inhibition the cell proliferation and tumor progression. Following a summarized review of primary in vitro and in vivo studies on the antitumor effects of low temperature plasmas, this article briefly outlines the plasma sources which have been developed for cancer therapeutic purposes. Intracellular mechanisms of action and significant pathways behind the anticancer effects of plasma and selectivity toward cancer cells are comprehensively discussed. A thorough understanding of involved mechanisms helps investigators to explicate many disputes including optimal plasma parameters to control the reactive species combination and concentration, transferring plasma to the tumors located in deep, and determining the optimal dose of plasma for specific outcomes in clinical translation. As a novel strategy for cancer therapy in clinical trials, designing low temperature plasma sources which meet the technical requirements of medical devices still needs to improve in efficacy and safety.

Reversible Lysine Specific Demethylase 1 (LSD1) Inhibitors: A Promising Wrench to Impair LSD1.

As a flavin adenine dinucleotide (FAD)-dependent monoamine oxidase, lysine specific demethylase 1 (LSD1/KDM1A) functions as a transcription coactivator or corepressor to regulate the methylation of histone 3 lysine 4 and 9 (H3K4/9), and it has emerged as a promising epigenetic target for anticancer treatment. To date, numerous inhibitors targeting LSD1 have been developed, some of which are undergoing clinical trials for cancer therapy. Although only two reversible LSD1 inhibitors CC-90011 and SP-2577 are in the clinical stage, the past decade has seen remarkable advances in the development of reversible LSD1 inhibitors. Herein, we provide a comprehensive review about structures, biological evaluation, and structure-activity relationship (SAR) of reversible LSD1 inhibitors.

Protein arginine methyltransferase 5: a potential cancer therapeutic target.

PRMT5 is a type II protein arginine methyltransferase that methylates histone or non-histone proteins. Arginine methylation by PRMT5 has been implicated in gene transcription, ribosome biogenesis, RNA transport, pre-mRNA splicing and signal transduction. High expression of PRMT5 has been observed in various cancers and PRMT5 overexpression has been reported to improve cancer cell survival, proliferation, migration and metabolism and to inhibit cancer cell apoptosis. In addition, PRMT5 has been found to be required for cancer stem cell survival, self-renewal and differentiation. Several microRNAs have been shown to regulate PRMT5 expression. As PRMT5 has oncogene-like properties, several PRMT5 inhibitors have been used to explore their efficacy as potential drugs for different types of cancer, and three of them are now being tested in clinical trials. In this review, we summarize current knowledge on the role of PRMT5 in cancer development and progression, including its functions andunderlying mechanisms. In addition, we highlight the rapid development of PRMT5 inhibitors and summarize ongoing clinical trials for cancer therapy. By affecting both tumor cells and the tumor microenvironment, PRMT5 inhibitors mayserve as effectiveanti-cancer agents, especially when combined with immune therapies.

Neospora caninum: a new class of biopharmaceuticals in the therapeutic arsenal against cancer

BackgroundMicroorganisms that can be used for their lytic activity against tumor cells as well as inducing or reactivating antitumor immune responses are a relevant part of the available immunotherapy strategies....

Magnetotactic bacteria for cancer therapy

Magnetotactic bacteria (MTB) are aquatic microorganisms that are able to biomineralize membrane-enclosed magnetic nanoparticles called magnetosomes. Inside the MTB, magnetosomes are arranged in a chain that allows MTB to align and navigate along the Earth's magnetic field. When isolated from the MTB, magnetosomes display a number of potential applications for targeted cancer therapies, such as magnetic hyperthermia, localized drug delivery, or tumor monitoring. The characteristics and properties of magnetosomes for these applications exceed in several aspects those of synthetic magnetic nanoparticles. Likewise, the whole MTB can also be considered as promising agents for cancer treatment, taking advantage of their self-propulsion capability provided by their flagella and the guidance capabilities ensured by their magnetosome chain. Indeed, MTB are envisaged as nanobiots that can be guided and manipulated by external magnetic fields and are naturally attracted toward hypoxic areas, such as the tumor regions, while retaining the therapeutic and imaging capacities of the isolated magnetosomes. Moreover, unlike most of the bacteria currently tested in clinical trials for cancer therapy, MTB are not pathogenic but could be engineered to deliver and/or express specific cytotoxic molecules. In this article, we will review the progress and perspectives of this emerging research field and will discuss the main challenges to overcome before the use of MTB can be successfully applied in the clinic.

Abstract 2402: Apoptosis induced by non-thermal atmospheric pressure bio-compatible soft jet plasma on brain tumor through p38/MAPK signaling pathways

Abstract Brain tumor is one of the most lethal forms of cancer to human beings, among which Glioblastoma astrocytoma is the most familiar and quickly progressing type of astrocytic brain tumor in adults with poor prognosis are still a therapeutic challenge. Current therapy options at diagnosis are multimodal and include surgical resection, radiation, and chemotherapy but difficulty to failure of drug delivery through the blood-brain barrier, tumor response to chemotherapy and intrinsic resistance of tumor cells. Therefore new therapy is needed that can afford selective targeting of proliferating cells to promote current therapies. Non-thermal plasma can be considered as a potential cancer therapy for the alteration of biological and clinical applications by generating reactive oxygen species (ROS) and reactive nitrogen species (RNS). In our study, we designate the effects of a NBP-J device to U87MG cell line. Previous research work established that jet plasma could induce apoptosis of various cancer cells, in particular indicative the selective cytotoxicity of cancer cells over normal cells. In this study, we assessed the effects of NBP-J on the U87MG brain cancer cell line including different effects and the physicochemical and biological correlation between the RONS cascade and p38/MAPK signaling pathway on the dose (time) dependent manner. The results of this study shows that the soft jet plasma significantly inhibits cell proliferation, inhibit survival pathway and induce apoptosis by p38/MAPK pathway in U87MG cells. The current results reveal that soft jet plasma has a powerful cytotoxic effect against brain cancer cells. Taken together, our results showed that NBP-J can become potential applications for effective and safe clinical trials for cancer therapy. Keywords: Non-thermal atmospheric-pressure plasma, soft jet plasma, Human glioblastoma, Cancer therapy. Acknowledgement This work was supported by the Leading Foreign Research Institute Recruitment Program through the National Research Foundation of Korea (NRF- 2016K1A4A3914113) funded by the Ministry of Science, ICT, and Future Planning (MSIP) of the Korean Government for EH. Choi, I. Han. Also this work was supported by the Basic Science Research Program through the Ministry of Science ICT of Korea (2019R1H1A2101686) for I. Han. Citation Format: Ihn Han. Apoptosis induced by non-thermal atmospheric pressure bio-compatible soft jet plasma on brain tumor through p38/MAPK signaling pathways [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2402.

Bacteria-derived minicells for cancer therapy.

Bacteria are always a considerable tool for the cancer therapy. The bacteria-derived minicells are re-emerged as a promising drug delivery system for cancer therapy. The minicells are nano-sized, anucleated, non-dividing, and metabolically active cells produced by abnormal bacterial cell division that are able to transcribe and translate the gene of interest. Minicells encapsulate a wide range of chemotherapeutic and molecular drugs, si/shRNA, antigens and therapeutic toxins to precisely deliver them to the cancer cells through the easy modification of minicell surface with bi-specific antibodies against receptor-targeted cancer cells. Minicell-mediated chemotherapy may inhibit the growth of drug-resistant tumors and exhibits the potential to successfully deliver the chemotherapeutics into hypoxic and necrotic region in solid tumors. This novel approach significantly overcomes drug leakage and severe toxicity by enhancing targeting specificity and therapeutic index of drugs in cancer therapy. Many antibody-conjugated drug-loaded minicells are being investigated in clinical trials for cancer therapy. This review summarizes the advantages of bacteria-derived minicells as delivery systems for anti-cancer drugs or agents and the recent advances and emerging future in cancer therapy.

Combination treatment of Src inhibitor Saracatinib with GMI, a Ganoderma microsporum immunomodulatory protein, induce synthetic lethality via autophagy and apoptosis in lung cancer cells.

Saracatinib is an oral Src-kinase inhibitor and has been studied in preclinical models and clinical trials of cancer therapy. GMI, a fungal immunomodulatory protein from Ganoderma microsporum, possesses antitumor capacity. The aim of this study is to evaluate the cytotoxic effect of combination treatment with saracatinib and GMI on parental and pemetrexed-resistant lung cancer cells. Cotreatment with saracatinib and GMI induced synergistic and additive cytotoxic effect in A549 and A400 cells by annexin V/propidium iodide assay and combination index. Using western blot assay, saracatinib, and GMI combined treatment synergistically induced caspase-7 activation in A549 cells. Different from A549 cells, saracatinib and GMI cotreatment markedly increased LC3B-II in A400 cells. ATG5 silencing abolished the caspase-7 activation and reduced cell death in A549 cells after cotreatment. This is the first study to provide a novel strategy of treating lung cancer with or without drug resistance via combination treatment with GMI and saracatinib.

Exploring Promises of siRNA in Cancer Therapeutics

Since the discovery of the RNA interference (RNAi) in 2006, several attempts have been made to use it for designing and developing drug treatments for a variety of diseases, including cancer. In this mini-review, we focus on the potential of small interfering RNAs (siRNA) in anticancer treatment. We first describe the significant barriers that exist on the path to clinical application of siRNA drugs. Then the current delivery approaches of siRNAs using lipids, polymers, and, in particular, polymeric carriers that overcome the aforementioned obstacles have been reviewed. Also, few siRNA mediated drugs currently in clinical trials for cancer therapy, and a collated list of siRNA databases having a qualitative and/ or quantitative summary of the data in each database have been briefly mentioned. This mini review aims to facilitate our understanding about the siRNA, their delivery systems and the possible barriers in their in vivo usage for biomedical applications.

Single Amino Acid Differences between Closely Related Reovirus T3D Lab Strains Alter Oncolytic Potency In Vitro and In Vivo.

Little is known about how genetic variations in viruses affect their success as therapeutic agents. The type 3 Dearing strain of Mammalian orthoreovirus (T3D) is undergoing clinical trials as an oncolytic virotherapy. Worldwide, studies on reovirus oncolysis use T3D stocks propagated in different laboratories. Here, we report that genetic diversification among T3D stocks from various sources extensively impacts oncolytic activity. The T3D strain from the Patrick Lee laboratory strain (TD3PL) showed significantly stronger oncolytic activities in a murine model of melanoma than the strain from the Terence Dermody laboratory (T3DTD). Overall in vitro replication and cytolytic properties of T3D laboratory strains were assessed by measuring virus plaque size on a panel of human and mouse tumor cells, and results were found to correlate with in vivo oncolytic potency in a melanoma model. T3DPL produced larger plaques than T3DTD and than the T3D strain from the ATCC (T3DATCC) and from the Kevin Coombs laboratory (T3DKC). Reassortant and reverse genetics analyses were used to decipher key genes and polymorphisms that govern enhanced plaque size of T3DPL Five single amino acid changes in the S4, M1, and L3 genome segments of reovirus were each partially correlated with plaque size and when combined were able to fully account for differences between T3DPL and T3DTD Moreover, polymorphisms were discovered in T3DTD that promoted virus replication and spread in tumors, and a new T3DPL/T3DTD hybrid was generated with enhanced plaque size compared to that of T3DPL Altogether, single amino acid changes acquired during laboratory virus propagation can have a large impact on reovirus therapeutic potency and warrant consideration as possible confounding variables between studies.IMPORTANCE The reovirus serotype 3 Dearing (T3D) strain is in clinical trials for cancer therapy. We find that closely related laboratory strains of T3D exhibit large differences in their abilities to replicate in cancer cells in vitro, which correlates with oncolytic activity in a in a murine model of melanoma. The study reveals that five single amino acid changes among three reovirus genes strongly impact reovirus therapeutic potency. In general, the findings suggest that attention should be given to genomic divergence of virus strains during research and optimization for cancer therapy.

Polymorphisms in the Most Oncolytic Reovirus Strain Confer Enhanced Cell Attachment, Transcription, and Single-Step Replication Kinetics.

Reovirus serotype 3 Dearing (T3D) replicates preferentially in transformed cells and is in clinical trials as a cancer therapy. Laboratory strains of T3D, however, exhibit differences in plaque size on cancer cells and differences in oncolytic activity in vivo This study aimed to determine why the most oncolytic T3D reovirus lab strain, the Patrick Lee laboratory strain (T3DPL), replicates more efficiently in cancer cells than other commonly used laboratory strains, the Kevin Coombs laboratory strain (T3DKC) and Terence Dermody laboratory (T3DTD) strain. In single-step growth curves, T3DPL titers increased at higher rates and produced ∼9-fold higher burst size. Furthermore, the number of reovirus antigen-positive cells increased more rapidly for T3DPL than for T3DTD In conclusion, the most oncolytic T3DPL possesses replication advantages in a single round of infection. Two specific mechanisms for enhanced infection by T3DPL were identified. First, T3DPL exhibited higher cell attachment, which was attributed to a higher proportion of virus particles with insufficient (≤3) σ1 cell attachment proteins. Second, T3DPL transcribed RNA at rates superior to those of the less oncolytic T3D strains, which is attributed to polymorphisms in M1-encoding μ2 protein, as confirmed in an in vitro transcription assay, and which thus demonstrates that T3DPL has an inherent transcription advantage that is cell type independent. Accordingly, T3DPL established rapid onset of viral RNA and protein synthesis, leading to more rapid kinetics of progeny virus production, larger virus burst size, and higher levels of cell death. Together, these results emphasize the importance of paying close attention to genomic divergence between virus laboratory strains and, mechanistically, reveal the importance of the rapid onset of infection for reovirus oncolysis.IMPORTANCE Reovirus serotype 3 Dearing (T3D) is in clinical trials for cancer therapy. Recently, it was discovered that highly related laboratory strains of T3D exhibit large differences in their abilities to replicate in cancer cells in vitro, which correlates with oncolytic activity in a murine model of melanoma. The current study reveals two mechanisms for the enhanced efficiency of T3DPL in cancer cells. Due to polymorphisms in two viral genes, within the first round of reovirus infection, T3DPL binds to cells more efficiency and more rapidly produces viral RNAs; this increased rate of infection relative to that of the less oncolytic strains gives T3DPL a strong inherent advantage that culminates in higher virus production, more cell death, and higher virus spread.

From cachexia to obesity: the role of host metabolism in cancer immunotherapy.

Currently, several clinical trials in cancer therapy have demonstrated the success of immunomodulatory therapies. However, only a variable fraction of patients actually benefit from these treatments. The understanding of key mechanisms behind this response heterogeneity is one of the major unmet need and intense research field in immuno-oncology. This review will discuss the host metabolic dysfunctions derived from cachexia or obesity that can affect the response to cancer immunotherapy. Preclinical studies demonstrated that chronic inflammation, nutritional intake impairment and endocrine dysfunction may affect anticancer innate and adaptive immunity, both in cachexia and obesity. New emerging clinical findings have highlighted the impact of metabolic biomarkers in predicting response to immune checkpoint inhibitors in cancer patients. Patient's weight and inflammatory status could be relevant in the clinical decision-making process before starting cancer immunotherapy and for an effective patient selection and stratification in future clinical trials employing this class of anticancer agents.

EGFR signaling confers resistance to BET inhibition in hepatocellular carcinoma through stabilizing oncogenic MYC

BackgroundThe bromodomain and extra-terminal domain (BET) inhibitor is a type of anti-tumor agent, currently being evaluated in phase I and II clinical trials for cancer therapy. It can decrease MYC expression levels and cause effective anti-tumor effects in diverse human cancers. However, its cytotoxic effect and related mechanisms of drug resistance are poorly understood in hepatocellular carcinomas (HCC). Here, we investigated the anti-tumor effects of BET inhibitor on HCC and the molecular mechanisms involved in its associated drug resistance.MethodsWe assessed the cytotoxicity of BET inhibitor on HCC cells compared with sorafenib by cell viability assay, metastasis assay and reproduced the anti-tumor effect in xenograft mouse model. In addition, the molecular mechanisms involved in drug resistance on JQ1-resistant HCC cells were revealed by western blotting, qRT-PCR, whole exome-sequencing and gene-editing technology. Finally, with specific inhibition of EGFR or ERK activity by interference RNAs or inhibitors, the efficacy of the synergistic treatment was investigated using cell viability assay, colony formation, apoptosis and xenograft mouse model.ResultsWe found that JQ1, a commonly used BET bromo-domain inhibitor, offered a better anti-tumor response than sorafenib in MYC-positive HCC cells by inducing apoptosis in vitro and in vivo. Unlike sorafenib, JQ1 treatment significantly impaired mitochondrial respiration and glycolysis in HCC cells. Importantly, we revealed that MAPK activation by a previously undescribed activating mutation of EGFR-I645L, was critical for JQ1 sensitivity through stabilizing oncogenic MYC protein in JQ1-resistant HCC cells. Inhibition of either EGFR or ERK activity overcame the JQ1 resistance and significantly decreased MYC protein level in vitro and in vivo.ConclusionSince MYC amplification is frequently identified in HCC, co-occurring with EGFR amplification, our findings suggest that targeting EGFR signaling might be essential for JQ1 therapy in advanced HCC.

Epigenetic Targets and their Inhibitors in Cancer Therapy.

Epigenetics is defined as the stable and heritable alternations in gene expression without changing the DNA nucleotide sequence. The initiation and progression of cancer result from not only genetic mutation, but also aberrant epigenetic regulation, such as DNA methylation and histones acetylation. Although Genetic alternations cannot be reversed, epigenetic modification is a dynamic and reversible process. Over the past few decades, much progress has been made in the research of epigenetic medications and a variety of drugs have been developed targeting at epigenetic regulatory proteins, which are capable of restoring malignant cancer cells to the normal state. The epigenetic drugs currently approved for cancer treatment mainly target at DNA methylation and histones acetylation. In addition, there are a great many epigenetic drugs in clinical trials for cancer therapy, such as inhibitors of DNA methyltransferases, histone deacetylases, histone methyltransferases, lysine specific demethylases, and BET (bromodomain and extra-terminal domain) family proteins. We will discuss the latest developments of these inhibitors and their applications in cancer therapy.

A novel anti-DR5 antibody-drug conjugate possesses a high-potential therapeutic efficacy for leukemia and solid tumors.

It is well known that tumor necrosis factor-related apoptosis inducing ligand receptor 1 or 2 (DR4/DR5) is specifically expressed in various tumor cells, but less or no expression in most normal cells. Many first generations of TRAIL agonists including recombinant preparations of TRAIL, agonistic antibodies against DR4/DR5 have been developed in phase I/II clinical trials for cancer therapy. However, the outcomes of clinical trials by using DR4/DR5 agonist mono-therapy were disappointed even though the safety profile was well tolerance. In the present study, we report an anti-DR5 antibody-drug conjugate (ADC, named as Zapadcine-1) possesses a higher potential for the therapy of lymphocyte leukemia and solid cancers.Methods: Zapadcine-1 was made by a fully humanized DR5-specific monoclonal antibody (Zaptuzumab) coupled via a cleavable linker to a highly toxic inhibitor of tubulin, monomethyl auristatin D (MMAD), by using ThioBridge technology. Cytotoxicity of the ADC in various tumor cells was identified by luminescent cell viability assay and the efficacy in vivo was determined in cells derived xenografts (CDX) of Jurkat E6-1, BALL-1, Reh, and patient derived xenografts (PDX) of human acute leukemia. Preliminary safety evaluation was carried out in rat and monkey. Results: Zapadcine-1 possesses a similar binding ability to the death receptor DR5 as the naked monoclonal antibody Zaptuzumab, and can be rapidly endocytosed into the lysosome of cancer cells. Zapadcine-1 specifically kills human lymphocyte leukemia cells and solid tumor cells, but not normal cells tested. More importantly, Zapadcine-1 drastically eliminates the xenografts in both CDX and PDX models of human acute leukemia. The excellent and comparable therapeutic efficacy is also observed in lung cancer NCI-H1975 CDX mouse model. The maximum-tolerated dose (MTD) of single injected Zapadcine-1 in rat and cynomolgus monkey shows an acceptable safety profile.Conclusion: These data demonstrate a promising anti-cancer activity, meriting further exploration of its potential as a novel cancer therapeutic agent, especially for the acute lymphocyte leukemia.

Repurposing suramin for the treatment of breast cancer lung metastasis with glycol chitosan-based nanoparticles

Suramin (SM), a drug for African sleeping sickness and river blindness therapy, has been investigated in various clinical trials for cancer therapy. However, SM was eventually withdrawn from the market because of its narrow therapeutic window and the side effects associated with multiple targets. In this work, we developed a simple but effective system based on a nontoxic dose of SM combined with a chemotherapeutic agent for the treatment of metastatic triple-negative breast cancer (TNBC). SM and glycol chitosan (GCS) formed nanogels because of the electrostatic effect, whereas doxorubicin (DOX) was incorporated into the system through the hydrophilic and hydrophobic interactions between DOX and GCS as well as the ionic interactions between DOX and SM to yield GCS-SM/DOX nanoparticles (NPs). GCS-SM/DOX NPs have a size of approximately 186 nm and a spherical morphology. In vitro experiments showed that GCS-SM NPs could effectively inhibit cancer cell migration and invasion, as well as angiogenesis. Furthermore, in a TNBC lung metastasis animal model, GCS-SM/DOX NPs significantly reduced tumor burden and extended the lifespan of animals, while not inducing cardio and renal toxicities associated with the DOX and SM, respectively. As all the components used in this system are biocompatible and easy for large-scale fabrication, the GCS-SM/DOX system is highly translatable for the metastatic breast cancer treatment. Statement of SignificanceThe doxorubicin-loaded glycol chitosan-suramin nanoparticle (GCS-SM/DOX) is novel in the following aspects: SM acts as not only a gelator for the first time in the preparation of the nanoparticle but also an active pharmaceutical agent in the dosage form. GCS-SM/DOX NP significantly reduced tumor burden and extended the lifespan of animals with triple-negative breast cancer lung metastasis. GCS-SM/DOX NPs attenuate cardio and renal toxicities associated with the DOX and SM. The GCS-SM/DOX system is highly translatable because of its simple, one-pot, and easy-to-scale-up preparation protocol.

The Role of Interleukin-1 in the Pathogenesis of Cancer and its Potential as a Therapeutic Target in Clinical Practice.

Interleukin-1 (IL-1) has long been known to be a key mediator of immunity and inflammation. Its dysregulation has been implicated in recent years in tumorigenesis and tumor progression, and its upregulation is thought to be associated with many tumors. Overexpression of the IL-1 agonists IL-1α and IL-1β has been shown to promote tumor invasiveness and metastasis by inducing the expression of angiogenic genes and growth factors. IL-1 blockers such as anakinra and canakinumab are already approved and widely used for the treatment of some autoimmune and autoinflammatory diseases and are currently being tested in preclinical and human clinical trials for cancer therapy. In this paper we review the most recent discoveries regarding the association between IL-1 dysregulation and cancer and present the novel IL-1 blockers currently being tested in cancer therapy and their corresponding clinical trials.