Strategy For Solid Tumors Research Articles

Epigenetically modified AP-2α by DNA methyltransferase facilitates glioma immune evasion by upregulating PD-L1 expression

Programmed death-ligand 1 (PD-L1) ensures that tumor cells escape T-cell-mediated tumor immune surveillance. However, gliomas are characteristic of the low immune response and high-resistance therapy, it is necessary to understand molecular regulatory mechanisms in glioblastoma, especially the limited regulation of PD-L1 expression. Herein, we show that low expression of AP-2α is correlated with high expression of PD-L1 in high-grade glioma tissues. AP-2α binds directly to the promoter of the CD274 gene, not only inhibits the transcriptional activity of PD-L1 but enhances endocytosis and degradation of PD-L1 proteins. Overexpression of AP-2α in gliomas enhances CD8+ T cell-mediated proliferation, effector cytokine secretion, and cytotoxicity in vitro. Tfap2a could increase the cytotoxic effect of Cd8+ T cells in CT26, B16F10, and GL261 tumor-immune models, improve anti-tumor immunity, and promote the efficacy of anti-PD-1 therapy. Finally, the EZH2/H3K27Me3/DNMT1 complex mediates the methylation modification of AP-2α gene and maintains low expression of AP-2α in gliomas. 5-Aza-dC (Decitabine) treatment combines with anti-PD-1 immunotherapy to efficiently suppress the progression of GL261 gliomas. Overall, these data support a mechanism of epigenetic modification of AP-2α that contributes to tumor immune evasion, and reactivation of AP-2α synergizes with anti-PD-1 antibodies to increase antitumor efficacy, which may be a broadly applicable strategy in solid tumors.

The New Frontier of Immunotherapy: Chimeric Antigen Receptor T (CAR-T) Cell and Macrophage (CAR-M) Therapy against Breast Cancer.

Breast cancer represents one of the most common tumor histologies. To date, based on the specific histotype, different therapeutic strategies, including immunotherapies, capable of prolonging survival are used. More recently, the astonishing results that were obtained from CAR-T cell therapy in haematological neoplasms led to the application of this new therapeutic strategy in solid tumors as well. Our article will deal with chimeric antigen receptor-based immunotherapy (CAR-T cell and CAR-M therapy) in breast cancer.

Inflammation-Regulated Nanodrug Sensitizes Hepatocellular Carcinoma to Checkpoint Blockade Therapy by Reprogramming the Tumor Microenvironment.

Immune checkpoint blockade (ICB) utilizing programmed death ligand-1 (PD-L1) antibody is a promising treatment strategy in solid tumors. However, in fact, more than half of hepatocellular carcinoma (HCC) patients are unresponsive to PD-L1-based ICB treatment due to multiple immune evasion mechanisms such as the hyperactivation of inflammation pathway, excessive tumor-associated macrophages (TAMs) infiltration, and insufficient infiltration of T cells. Herein, an inflammation-regulated nanodrug was designed to codeliver NF-κB inhibitor curcumin and PD-L1 antibody to reprogram the tumor microenvironment (TME) and activate antitumor immunity. The nanodrug accumulated in TME by an enhanced permeability and retention effect, where it left antibody to block PD-L1 on the membrane of tumor cells and TAMs due to pH-responsiveness. Simultaneously, a new curcumin-encapsulated nanodrug was generated, which was easily absorbed by either tumor cells or TAMs to inhibit the nuclear factor kappa-B (NF-κB) signal and related immunosuppressive genes. The inflammation-regulated nanodrug possessed good biocompatibility. Simultaneously, it reprogrammed TME effectively and exhibited an effective anticancer effect in immunocompetent mice. Overall, this study provided a potent strategy to improve the efficiency of ICB-based treatment for HCC.

Targeting LIPA independent of its lipase activity is a therapeutic strategy in solid tumors via induction of endoplasmic reticulum stress

Triple-negative breast cancer (TNBC) has a poor clinical outcome, due to a lack of actionable therapeutic targets. Herein we define lysosomal acid lipase A (LIPA) as a viable molecular target in TNBC and identify a stereospecific small molecule (ERX-41) that binds LIPA. ERX-41 induces endoplasmic reticulum (ER) stress resulting in cell death, and this effect is on target as evidenced by specific LIPA mutations providing resistance. Importantly, we demonstrate that ERX-41 activity is independent of LIPA lipase function but dependent on its ER localization. Mechanistically, ERX-41 binding of LIPA decreases expression of multiple ER-resident proteins involved in protein folding. This targeted vulnerability has a large therapeutic window, with no adverse effects either on normal mammary epithelial cells or in mice. Our study implicates a targeted strategy for solid tumors, including breast, brain, pancreatic and ovarian, whereby small, orally bioavailable molecules targeting LIPA block protein folding, induce ER stress and result in tumor cell death.

Non-invasive monitoring of the kinetic infiltration and therapeutic efficacy of nanoparticle-labeled chimeric antigen receptor T cells in glioblastoma via 7.0-Tesla magnetic resonance imaging

Background aimsChimeric antigen receptor (CAR) T-cell therapy is a promising treatment strategy in solid tumors. In vivo cell tracking techniques can help us better understand the infiltration, persistence and therapeutic efficacy of CAR T cells. In this field, magnetic resonance imaging (MRI) can achieve high-resolution images of cells by using cellular imaging probes. MRI can also provide various biological information on solid tumors. MethodsThe authors adopted the amino alcohol derivatives of glucose-coated nanoparticles, ultra-small superparamagnetic particles of iron oxide (USPIOs), to label CAR T cells for non-invasive monitoring of kinetic infiltration and persistence in glioblastoma (GBM). The specific targeting CARs included anti-human epidermal growth factor receptor variant III and IL13 receptor subunit alpha 2 CARs. ResultsWhen using an appropriate concentration, USPIO labeling exerted no negative effects on the biological characteristics and killing efficiency of CAR T cells. Increasing hypointensity signals could be detected in GBM models by susceptibility-weighted imaging MRI ranging from 3 days to 14 days following the injection of USPIO-labeled CAR T cells. In addition, nanoparticles and CAR T cells were found on consecutive histopathological sections. Moreover, diffusion and perfusion MRI revealed significantly increased water diffusion and decreased vascular permeability on day 3 after treatment, which was simultaneously accompanied by a significant decrease in tumor cell proliferation and increase in intercellular tight junction on immunostaining sections. ConclusionThese results establish an effective imaging technique that can track CAR T cells in GBM models and validate their early therapeutic effects, which may guide the evaluation of CAR T-cell therapies in solid tumors.

Targeting tumor-associated macrophages: A potential treatment for solid tumors.

Tumor-associated macrophages (TAMs) in solid tumors exert protumor activities by releasing cytokines or growth factors into the tumor microenvironment. Increasing studies have also shown that TAMs play a key role in tumor progression, such as tumor angiogenesis, immunosuppression, cell proliferation, migration, invasion, and metastasis. A large body of evidence shows that the abundance of TAMs in solid tumors is correlated with poor disease prognosis and resistance to therapies. Therefore, targeting TAMs in solid tumors is considered to be a promising immunotherapeutic strategy. At present, the therapeutic strategies of targeting macrophages mainly include limiting monocyte recruitment, depletion strategies, promoting macrophage phagocytic activity, and induction of macrophage reprogramming. Additionally, targeting TAMs in combination with conventional therapies has been demonstrated to be a promising therapeutic strategy in solid tumors. In the present review, we summarized various TAMs-targeting therapeutic strategies for treating solid tumors. This review also discusses the challenges for targeting TAMs as tumor treatments, the obstacles in clinical trials, and the perspective for the future development of TAMs-targeting therapies for various cancers.

ATF3 Coordinates Antitumor Synergy between Epigenetic Drugs and Protein Disulfide Isomerase Inhibitors.

Histone deacetylase inhibitors (HDACi) are largely ineffective in the treatment of solid tumors. In this study, we describe a new class of protein disulfide isomerase (PDI) inhibitors that significantly and synergistically enhance the antitumor activity of HDACi in glioblastoma and pancreatic cancer preclinical models. RNA-sequencing screening coupled with gene silencing studies identified ATF3 as the driver of this antitumor synergy. ATF3 was highly induced by combined PDI and HDACi treatment as a result of increased acetylation of key histone lysine residues (acetylated histone 3 lysine 27 and histone 3 lysine 18) flanking the ATF3 promoter region. These chromatin marks were associated with increased RNA polymerase II recruitment to the ATF3 promoter, a synergistic upregulation of ATF3, and a subsequent apoptotic response in cancer cells. The HSP40/HSP70 family genes DNAJB1 and HSPA6 were found to be critical ATF3-dependent genes that elicited the antitumor response after PDI and HDAC inhibition. In summary, this study presents a synergistic antitumor combination of PDI and HDAC inhibitors and demonstrates a mechanistic and tumor suppressive role of ATF3. Combined treatment with PDI and HDACi offers a dual therapeutic strategy in solid tumors and the opportunity to achieve previously unrealized activity of HDACi in oncology. SIGNIFICANCE: This study uses a first-in-class PDI inhibitor entering clinical development to enhance the effects of epigenetic drugs in some of the deadliest forms of cancer.

Abstract CT148: Clinical results of the multiparameter phase 1 trial EVESOR meant to optimize the doses and dosing schedules of the combination EVErolimus and SORafenib in solid tumors

Abstract Objectives: Defining the optimal doses & dosing schedules of combined targeted drugs is a challenge. Blocking both the PI3K-AKT-mTor and RAS-RAF-ERK pathways is a rationale therapeutic strategy in solid tumors. However, the phase 1 trials of everolimus (EVE) and sorafenib (SOR) failed to define the recommended phase II trial doses (RP2D) of both drugs, due to the toxicity when given continuously; and the combination was abandoned. The academic multi-parameter EVESOR trial (NCT01932177) was designed to assess alternative doses & dosing schedules of EVE & SOR, and to provide data that would be used to define the optimal doses & dosing schedules of both drugs associated with the best efficacy/toxicity ratio by modeling/simulation. Methods: EVESOR is an open dose-escalation phase 1 trial assessing the combination of EVE and SOR in patients with multi-treated advanced solid tumors. Enrolled patients were allocated to 1 of the 4 arms: A) EVE 5 mg QD for 2 weeks followed by continuous EVE + SOR 200 mg BID; B) SOR 200 mg BID for 2 weeks followed by continuous EVE 5 mg QD + SOR; C) alternating EVE 5-10 mg QD with SOR 200-400 mg BID every week; D) continuous EVE 5-10 mg QD + SOR 200-400 mg BID for 3 days on-4 days off. Multiple tumor & blood pharmacokinetic (PK) and pharmacodynamic (PD) parameters were sampled at baseline and during treatment (Nanostring panels). The 1st endpoint was the RP2D of both drugs in each arm A+B; C; and D. Results: 43 patients were included from 2013 to 2019: arm A n= 7; arm B n= 7; arm C n= 16; arm D n = 13. Most of them had gynecological (25.6%), cholangiocarcinomas (23.2%), colorectal (14%), and breast cancers (11.6%). Dose escalations to EVE 10 mg QD and SOR 400 mg BID were possible in both arms C and D. Five dose-limiting toxicities (DLTs) were observed (1; 3; and 1 in arms B, C and D respectively). Dose reductions were needed in 40% patients, stabilizing at EVE 5 mg and SOR 200 mg BID for the majority of them (58%). The overall response rate was 7%, and the disease control rate (DCR) was 73%. No relationships between dose levels and efficacy were found. However, the intermittent dosing schedules (arms C and D) were associated with better DCR. The median progression-free survival (PFS) was 3.6 months (2.7; 6.3; 2.7; and 3.6 months in arms A, B, C and D). Longer PFS were observed with cholangiocarcinomas (9.8 months) and gynecological cancers (3.7 months). Baseline activation of RAS-RAF-ERK was associated with higher non-progression rates at 4 months (50% vs 10%, P=0.12) and longer PFS (4.2 vs 2.1 months, P = 0.016). Decreases in S6K and AKT phosphorylations were observed in 89% and 70% of patients, respectively, with no significant impact on efficacy. Conclusions: EVE 5 mg QD and SOR 200 mg BID combination is the RP2D in solid tumor patients, in both intermittent arms C & D. Intermittent dosing was associated with higher efficacy. Long responses were found in cholangiocarcinomas. Adequately designed multi-schedules phase 1 trials can help for drug development, and avoid abandon of effective targeted drug combinations. Modeling/simulation will be used to optimize dose & dosing schedules of EVE and SOR based on collected data, and then tested. Citation Format: Benoit You, Michel Tod, Lea Payen, Jonathan Lopez, Jerome Guitton, Pascal Rousset, Juliette Fontaine, Julien Peron, Denis Maillet, Sophie Tartas, Nathalie Bonnin, Veronique Trillet-Lenoir, Olivier Colomban, Diane Augu-Denechere, Gilles Freyer, Alicja Puszkiel. Clinical results of the multiparameter phase 1 trial EVESOR meant to optimize the doses and dosing schedules of the combination EVErolimus and SORafenib in solid tumors [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 CT148.

Abstract 4042: Potent synergistic tumor cell suppression from combination of ONC201 and epigenetic modulators EZH2 or HDAC inhibitors provides a novel treatment strategy for solid tumors

Abstract ONC201 is a promising anti-cancer agent that upregulates cytotoxic TRAIL pathway signaling in cancer cells. It has broad spectrum anti-tumor activity and achieved tumor regression and prolonged disease stabilization in clinical trials, especially in patients with H3K27M mutant gliomas. Based on the fact that the H3K27M mutation reduces the level of H3K27 dimethylation (H3K27me2) and trimethylation (H3K27me3), we hypothesized that cancer cells could be sensitized to ONC201 by epigenetic modulators that impact on histone methylation or acetylation. We tested the synergy between epigenetic modulators and ONC201 in tumor cell lines. We treated cancer cells from different tissue origins including breast cancer, pancreatic cancer, colorectal cancer, GBM, and DIPG with single agent ONC201, EZH2 inhibitor EPZ-6438 or the combination of ONC201 plus EPZ-6438. We also treated cancer cell lines originating from colorectal cancer, breast cancer, gastric cancer, prostate cancer, GBM and DIPG with combination of histone deacetylase inhibitor (HADCi), vorinostat, and ONC201. Cell viability was determined with the Cell Titer-Glo assay. Apoptosis was evaluated through flow cytometry analysis of cell distribution. Integrated stress response (ISR) activity widely observed in ONC201-treated tumor cells was evaluated using Western blot analysis of ATF4 and apoptosis by analysis of PARP cleavage. Cytotoxic TRAIL pathway signaling was evaluated using Western blot analysis of DR5. Our results demonstrate that ONC201 synergistically reduced cell viability, induced integrated stress response, cytotoxic TRAIL pathway signaling and apoptosis in combination with epigenetic modulators. There was greater induction of ATF4 and DR5 in combination therapy-treated tumor cells versus monotherapy. Immunoblotting analysis showed that combination of ONC201 and EZH2 inhibitor EPZ-6438 reduced H3K27me3 and EZH2. ONC201 is an antagonist of dopamine receptor D2 (DRD2). Dopamine receptor D5 (DRD5) is a dopamine receptor family member that opposes DRD2 signaling. The DRD2+DRD5- biomarker signature is associated with enhanced ONC201 tumor cell sensitivity. In order to investigate the role of dopamine receptors in anti-tumor effect of ONC201, we also tested the mRNA level of dopamine receptors by RT-PCR and observed that both vorinostat and EPZ-6438 upregulated DRD5 more than DRD2. Thus, we suspect other target genes may be involved in sensitization to ONC201 due to epigenetic modulation. We are currently investigating the interplay between H3K27 methylation versus acetylation in ONC201 sensitivity with or without additional therapeutic modulation by epigenetic drugs. Our results unravel potent synergy between ONC201 and EZH2 inhibitors or HDAC inhibitors and provide further insights into the role of H3K27me3 in ONC201 drug sensitivity. Citation Format: Yiqun Zhang, Lanlan Zhou, Michael Glantz, Howard Safran, Attila Seyhan, Wafik S. El-Deiry. Potent synergistic tumor cell suppression from combination of ONC201 and epigenetic modulators EZH2 or HDAC inhibitors provides a novel treatment strategy for solid tumors [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 4042.

Prognosis of PD-L1 in human breast cancer: protocol for a systematic review and meta-analysis

BackgroundBreast cancer is one of the most common malignancies in women worldwide, and one of the leading causes of cancer-related death. Programmed cell death 1 (PD-1) and its ligand (PD-L1) are key physiologic suppressors of the cytotoxic immune reaction. Some authors advocate that PD-L1 expression may help in breast cancer prognosis.MethodsWe will conduct a systematic review of observational or interventional studies evaluating the prognostic ability of PD-L1 expression levels in predicting positive clinical outcomes in Human Breast Cancer. A sensitive search strategy will be employed in MEDLINE, EMBASE, LILACS, The Grey Literature Report, OpenGrey, OAIster, and Cochrane CENTRAL. Two reviewers will independently screen all identified references for eligibility and extract data. The outcomes evaluated will be Overall Survival, Breast Cancer-specific Survival, Disease-free Survival, Recurrence-free Survival, Positive Lymph Node, and Distant Metastasis. The outcomes will be extracted directly from the studies, if available. Methodological quality and bias of included studies will be assessed using a standardized checklist and overall quality of evidence will be assessed through the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. If meta-analysis is possible, the measures of association will be calculated using bivariate random-effects models. Statistical heterogeneity will be evaluated with I2 statistics and explored through sensitivity analysis.DiscussionImmunomodulation seems to be a promising strategy in solid tumors. Breast cancer is the most common malignancies in women worldwide, and one of the leading causes of cancer death. PD-1 and PD-L1 are key physiologic suppressors of the cytotoxic immune reaction.Trial registrationSystematic review registration: CRD42019121118 (PROSPERO)

Immunothérapie des glioblastomes

Targeting the immune system as a therapeutic strategy in solid tumors has shown great efficacy in various tumor types. However the role and success of this approach in glioblastomas remain to be determined. Recent studies demonstrated that central nervous system is no longer considered as an immunoprivileged sanctuary with impressive immune response without blood brain barrier's disruption. Improving our understanding of immune privilege in the central nervous system could lead to better treatment strategies in gliobastomas. This review focuses on describing the immune system in the central nervous system and immuno-therapeutic strategies under development in glioblastomas.

Carbohydrate Targets for CAR T Cells in Solid Childhood Cancers.

Application of the CAR targeting strategy in solid tumors is challenged by the need for adequate target antigens. As a consequence of their tissue origin, embryonal cancers can aberrantly express membrane-anchored gangliosides. These are carbohydrate molecules consisting of a glycosphingolipid linked to sialic acids residues. The best-known example is the abundant expression of ganglioside GD2 on the cell surface of neuroblastomas which derive from GD2-positive neuroectoderm. Gangliosides are involved in various cellular functions, including signal transduction, cell proliferation, differentiation, adhesion and cell death. In addition, transformation of human cells to cancer cells can be associated with distinct glycosylation profiles which provide advantages for tumor growth and dissemination and can serve as immune targets. Both gangliosides and aberrant glycosylation of proteins escape the direct molecular and proteomic screening strategies currently applied to identify further immune targets in cancers. Due to their highly restricted expression and their functional roles in the malignant behavior, they are attractive targets for immune engineering strategies. GD2-redirected CAR T cells have shown activity in clinical phase I/II trials in neuroblastoma and next-generation studies are ongoing. Further carbohydrate targets for CAR T cells in preclinical development are O-acetyl-GD2, NeuGc-GM3 (N-glycolyl GM3), GD3, SSEA-4, and oncofetal glycosylation variants. This review summarizes knowledge on the role and function of some membrane-expressed non-protein antigens, including gangliosides and abnormal protein glycosylation patterns, and discusses their potential to serve as a CAR targets in pediatric solid cancers.

Mechanism and Its Countermeasure of Hypomethylating Agent Resistance in Patients with Myelodysplastic Syndrome--Review

Hypomethylating agents(HMA) currently are widely used in the treatment of myelodysplastic syndromes (MDS), provide a significant improvement in the treatment of MDS. However, resistance to HMA is an almost universal phenomenon. This review was focused on immune effects related to DNA methylation, and to explore the mechanism underlying HMA resistance involved in immune checkpoint pathways. However, the optimal role of checkpoint blockade therapy (CBT) and immune checkpoint pathways remain in HMA failure questionable. The better understanding of immune checkpoint pathways in resistance of HMA offers a compelling rationale to introduce CBT in patients as a novel treatment option. CBT is an established strategy in solid tumors with potential as an adjunctive therapy in hematologic malignancies, therefore, may alter the treatment landscape in MDS. The suitability and effectiveness of combining HMA with CBT need to be confirmed by the results of ongoing clinical trials, so as to find novel strategies to improve outcome after failure of HMA.

Protective effect of Gelofusine against cRGD-siRNA-induced nephrotoxicity in mice

Based on successful targeting to the αvβ3 integrin of cyclic arginine–glycine–aspartic acid (cRGD), cRGD-conjugated small interfering RNA (siRNA) exhibits tumor targeting and has become a new treatment strategy for solid tumors. However, the nephrotoxicity caused by its renal retention limits its clinical application. Here, we evaluated the protective effect of Gelofusine against cRGD-conjugated siRNA-induced nephrotoxicity in mice. Male Kunming mice (six per group) were either co-injected with Gelofusine and cRGD-siRNA or injected with cRGD-siRNA alone. After administration of these treatments five times, creatinine and blood urea nitrogen (BUN) levels were determined. Hematoxylin–eosin staining (HE staining) and transferase dUTP nick end labeling (TUNEL) analysis were used to compare the difference in renal damage between the groups. Additionally, fluorescence imaging was used to observe the distribution of cRGD-siRNA in vivo. The group co-injected with Gelofusine and cRGD-siRNA displayed lower creatinine and BUN levels than the cRGD-siRNA-alone group and showed less renal damage upon HE staining and TUNEL analysis. Gelofusine decreased the retention time and accelerated the elimination of cRGD-siRNA from the organs, as observed in the fluorescence images. These data indicate that Gelofusine significantly increased the excretion of cRGD-conjugated siRNA and reduced the associated renal damage.

Non-Invasive Radiofrequency Field Treatment of 4T1 Breast Tumors Induces T-cell Dependent Inflammatory Response

Previous work using non-invasive radiofrequency field treatment (RFT) in cancer has demonstrated its therapeutic potential as it can increase intratumoral blood perfusion, localization of intravenously delivered drugs, and promote a hyperthermic intratumoral state. Despite the well-known immunologic benefits that febrile hyperthermia can induce, an investigation of how RFT could modulate the intra-tumoral immune microenvironment had not been studied. Thus, using an established 4T1 breast cancer model in immune competent mice, we demonstrate that RFT induces a transient, localized, and T-cell dependent intratumoral inflammatory response. More specifically we show that multi- and singlet-dose RFT promote an increase in tumor volume in immune competent Balb/c mice, which does not occur in athymic nude models. Further leukocyte subset analysis at 24, 48, and 120 hours after a single RFT show a rapid increase in tumoral trafficking of CD4+ and CD8+ T-cells 24 hours post-treatment. Additional serum cytokine analysis reveals an increase in numerous pro-inflammatory cytokines and chemokines associated with enhanced T-cell trafficking. Overall, these data demonstrate that non-invasive RFT could be an effective immunomodulatory strategy in solid tumors, especially for enhancing the tumoral trafficking of lymphocytes, which is currently a major hindrance of numerous cancer immunotherapeutic strategies.

Differentiation-inducing therapeutic effect of Notch inhibition in reversing malignant transformation of liver normal stem cells via MET

BackgroundLiver cancer stem cells (LCSCs) are the key factors for cancer metastasis, recurrent, and drug resistance. LCSCs are originated from either hepatocytes dedifferentiation or differentiation arresting of liver normal stem cells (LNSCs). Differentiation-inducing therapy is a novel strategy in solid tumors. Furthermore, Notch signaling pathway has been proved to play important role in the process of hepatocytes differentiation. In previous study, a malignant transformation cellular model of LNSCs has been built up, and in this study we are trying to illustrate whether inhibition of Notch can reverse this malignant tendency and drive these malignant cells back to differentiate into mature hepatocytes.ResultsInhibition of Notch signaling pathway can down-regulate the stemness-related cancer markers, lower the proliferative status, alleviate the invasive characteristic, or attenuate the metastasis tendency. What is more, it can help the malignantly transformed cells to regain the mature hepatic function of glucagon synthesis, urea metabolism, albumin production, and indocyanine-green (ICG) clearance.Materials and MethodsHOX transcript antisense RNA (HOTAIR) expression was enhanced in LNSCs via lentivirus transduction to set up the malignant transformation cellular model. Then, a Notch inhibitor was applied to induce malignantly transformed cells differentiate into mature hepatocytes, and malignant abilities of proliferation, invasiveness, tumorigenesis as well as mature hepatocyte function were observed and compared.ConclusionsThe data demonstrate that the anti-tumor effects of Notch inhibition may lie not only on killing the cancer cells or LCSCs directly, it can also induce the LCSCs differentiation into mature hepatocytes via mesenchymal-epithelial transition (MET) progress or downgrade the malignancy.

Incorporating DNA Methyltransferase Inhibitors (DNMTis) in the Treatment of Genitourinary Malignancies: A Systematic Review.

Inhibition of DNA methyltransferases (DNMTs) has emerged as a novel treatment strategy in solid tumors. Aberrant hypermethylation in promoters of critical tumor suppressor genes is the basis for the idea that treatment with hypomethylating agents may lead to the restoration of a "normal" epigenome and produce clinically meaningful therapeutic outcomes. The aim of this review article is to summarize the current state of knowledge of DNMT inhibitors in the treatment of genitourinary malignancies. The efficacy of these agents in genitourinary malignancies was reported in a number of studies and suggests a role of induced DNA hypomethylation in overcoming resistance to conventional cytotoxic treatments. The clinical significance of these findings should be further investigated.

Mevastatin blockade of autolysosome maturation stimulates LBH589-induced cell death in triple-negative breast cancer cells

Histone deacetylase inhibitors (HDACi) are promising anti-cancer agents, and combining a HDACi with other agents is an attractive therapeutic strategy in solid tumors. We report here that mevastatin increases HDACi LBH589-induced cell death in triple-negative breast cancer (TNBC) cells. Combination treatment inhibited autophagic flux by preventing Vps34/Beclin 1 complex formation and downregulating prenylated Rab7, an active form of the small GTPase necessary for autophagosome-lysosome fusion. This means that co-treatment with mevastatin and LBH589 activated LKB1/AMPK signaling and subsequently inhibited mTOR. Co-treatment also led to cell cycle arrest in G2/M phase and induced corresponding expression changes of proteins regulating the cell cycle. Co-treatment also increased apoptosis both in vitro and in vivo, and reduced tumor volumes in xenografted mice. Our results indicate that disruption of autophagosome-lysosome fusion likely underlies mevastatin-LBH589 synergistic anticancer effects. This study confirms the synergistic efficacy of, and demonstrates a potential therapeutic role for mevastatin plus LBH589 in targeting aggressive TNBC, and presents a novel therapeutic strategy for further clinical study. Further screening for novel autophagy modulators could be an efficient approach to enhance HDACi-induced cell death in solid tumors.

Macrophage-Secreted TNFα and TGFβ1 Influence Migration Speed and Persistence of Cancer Cells in 3D Tissue Culture via Independent Pathways.

The ability of a cancer cell to migrate through the dense extracellular matrix within and surrounding the solid tumor is a critical determinant of metastasis. Macrophages enhance invasion and metastasis in the tumor microenvironment, but the basis for their effects is not fully understood. Using a microfluidic 3D cell migration assay, we found that the presence of macrophages enhanced the speed and persistence of cancer cell migration through a 3D extracellular matrix in a matrix metalloproteinases (MMP)-dependent fashion. Mechanistic investigations revealed that macrophage-released TNFα and TGFβ1 mediated the observed behaviors by two distinct pathways. These factors synergistically enhanced migration persistence through a synergistic induction of NF-κB-dependent MMP1 expression in cancer cells. In contrast, macrophage-released TGFβ1 enhanced migration speed primarily by inducing MT1-MMP expression. Taken together, our results reveal new insights into how macrophages enhance cancer cell metastasis, and they identify TNFα and TGFβ1 dual blockade as an antimetastatic strategy in solid tumors. Cancer Res; 77(2); 279-90. ©2016 AACR.

Programmed cell death-1 pathway inhibition in myeloid malignancies: implications for myeloproliferative neoplasms.

Myeloproliferative neoplasms (MPNs) are clonal hematopoietic diseases that belong to the spectrum of myeloid malignancies (MyMs), which also include myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), and chronic myelogenous leukemia (CML). While hematopoietic stem cell transplantation (HSCT) is a potentially curative therapeutic approach to many MyMs, the associated morbidity and mortality have necessitated the development of non-HSCT therapeutics for symptom management and disease course modification. Immune checkpoint inhibition, in particular along the programmed cell death protein 1 (PD-1)/B7-H1 (PD-L1) axis, is an established strategy in solid tumors with potential as an adjunctive therapy in hematologic malignancies. Seminal studies suggest that the pro-inflammatory microenvironment of MyMs can suppress T lymphocyte-mediated immunity via PD-1 signaling and that response to mainstay epigenetic therapies for MyMs may be governed by PD-1 gene regulation. Although the role of PD-1 signaling in MPN pathogenesis and progression is as yet unclear, research in MPN patients has revealed expansion of myeloid-derived suppressor cells (MDSCs), which may effect host immune tolerance of tumor via temporally and spatially specific activation of PD-1/PD-L1 signaling. The current understanding of immune dysfunction in MPNs and analogous MyMs offers a compelling rationale to study PD-1/PD-L1 inhibition in patients as a novel treatment option.