Development Of Targeted Therapies Research Articles

Development of a Fundamental Technology to Seek Drug Targets, and Its Application to Cancer Targeting Therapy

Human epidermal growth factor receptor 2 (Her2)-targeting antibodies and anti-hormone therapy are effective for most breast cancer patients. However, such approaches are not viable with resistant cases or in triple-negative breast cancer (TNBC) patients, given the lack of Her2 and estrogen and progesterone receptors in these patients. Thus, new drug targets are urgently required. From this perspective, we searched for novel drug targets using proteomic analysis, and identified Eph receptor A10 (EphA10), which is elevated in breast cancer cells as compared to normal breast tissue. Here, we evaluated the potential of EphA10 as a drug target by analyzing its protein expression profile/function in cancer cells, and then by using an anti-EphA10 antibody to treat EphA10-expressing tumor-bearing mice. Protein expression profile analysis showed that EphA10 was expressed in various breast cancer subtypes, including TNBCs, with no expression observed in normal tissues, apart from the testes. Moreover, functional analysis of the cancer cells revealed that ligand-dependent proliferation was observed in EphA10-expressed cancer cells. Thus, we developed our novel anti-EphA10 antibody, which binds to EphA10 with high specificity and affinity at the nanomolar level. Finally, therapeutic analysis indicated that tumor growth was significantly suppressed in the mAb-treated mice in a dose-dependent manner. These results suggest that the EphA10-targeting therapy may be a novel therapeutic option for the management of breast cancer, including in TNBCs which aren't currently treated with molecular-targeted agents. Consequently, we hope that these findings will contribute to the development of a new targeting therapy for refractory breast cancer patients.

Complexes formed by mutant p53 and their roles in breast cancer.

Breast cancer is the most frequently diagnosed malignancy in women, and mutations in the tumor suppressor p53 are commonly detected in the most aggressive subtypes. The majority of TP53 gene alterations are missense substitutions, leading to expression of mutant forms of the p53 protein that are frequently detected at high levels in cancer cells. P53 mutants not only lose the physiological tumor-suppressive activity of the wild-type p53 protein but also acquire novel powerful oncogenic functions, referred to as gain of function, that may actively confer a selective advantage during tumor progression. Some of the best-characterized oncogenic activities of mutant p53 are mediated by its ability to form aberrant protein complexes with other transcription factors or proteins not directly related to gene transcription. The set of cellular proteins available to interact with mutant p53 is dependent on cell type and extensively affected by environmental signals, so the prognostic impact of p53 mutation is complex. Specific functional interactions of mutant p53 can profoundly impact homeostasis of breast cancer cells, reprogramming gene expression in response to specific extracellular inputs or cell-intrinsic conditions. The list of protein complexes involving mutant p53 in breast cancer is continuously growing, as is the number of oncogenic phenotypes in which they could be involved. In consideration of the functional impact of such complexes, key interactions of mutant p53 may be exploited as potential targets for development of therapies aimed at defusing the oncogenic potential of p53 mutation.

High incident of EGFR mutant for lung cancer brain metastases patients and low risk of brain metastases in hippocampus.

e21200Background: Whole brain radiotherapy is one of main treatments for brain metastases, but it will induce neurotoxicity. As the development of target therapy, epidermal growth factor receptor (...

Clinical targeted next-generation sequencing to identify potentially actionable alterations in the majority of Asian cancer patients.

e24163Background: Clinically innovative genomic diagnostics may expedite the development of effective targeting therapies if the patient can be stratified correctly based on their unique cancer dri...

Research Progress of KRAS Mutation in Non-small Cell Lung Cancer

肺癌是全球癌症相关死亡的主要原因。非小细胞肺癌（non-small cell lung cancer, NSCLC）占所有肺癌患者中的80%-85%，大多数肺癌患者在确诊时已处于晚期阶段。目前，基于驱动基因的靶向治疗的发展改变了晚期NSCLC患者的治疗模式。在NSCLC中，表皮生长因子受体突变（epidermal growth factor receptor, EGFR）和棘皮动物微管相关蛋白和间变性淋巴瘤激酶（echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase, EML4-ALK）融合已被验证为强大的生物标志物。众所周知KRAS也是NSCLC中最常见的突变致癌基因之一，尽管20多年前在NSCLC中发现了KRAS突变，迄今为止用于治疗KRAS突变的NSCLC患者的药物有很多，但目前还没有针对直接消除KRAS活性的选择性和特异性抑制剂。此外具有KRAS突变的NSCLC患者对大多数系统性治疗的反应性差。然而使用靶向药物针对活化的信号通路个体化治疗对KRAS突变的NSCLC患者的预后有很好疗效。此外KRAS突变在NSCLC中的预后和预测作用尚不清楚。在这篇综述中，我们重点讨论了KRAS突变的NSCLC的研究进展，包括分子生物学、临床病理特征、KRAS突变的预后和预测等方面，进而有助于提高临床工作者对KRAS突变的NSCLC的认知。。

Progress of BRAF gene mutation in children with langerhans cell histiocytosis

Langerhans cell histiocytosis(LCH) is a rare disease characterized by clonal proliferation and aggregation of LCH cells(Langerhans cells, LCs), and there has been controversy about its pathogenesis.In recent years, BRAF mutations have been detected repeatedly in LCH patients, suggesting that the BRAF gene mutation may drive the occurrence and development of LCH, and may be associated with clinical chemotherapy and prognosis.These findings not only provide evidence for LCH as a tumor disease, but also lay a molecular genetic basis for the development of targeted therapy for LCH. Key words: Langerhans cell histiocytosis; BRAF gene; Mutation; Children

Identification of microRNA expression patterns in cutaneous and uveal melanoma cell lines.

microRNA (miRNA)-mediated epigenetic regulation of tumor suppressor genes and oncogenes has been shown to play a central role in melanomagenesis. Here, we focused on the identification of miRNA signatures in the cutaneous melanoma cell line G361 and the uveal melanoma cell line OCM-1. We carried out genome-wide miRNA expression profiling using a human miRNA microarray platform (Agilent Sanger miRBase, release 10.1) in both cell lines. Our screening revealed significant alteration of miRNA expression profiles in melanoma cell lines compared with normal human epidermal melanocytes. We defined 208 differentially expressed miRNAs in OCM-1 and 112 in G361. By comparison analysis between the resulting miRNA expression profiles, we identified 96 miRNAs that were modified in both cell models. Among these commonly modified miRNAs, 65 were downregulated, 28 upregulated, and 3 exhibited a different expression trend. Although preliminary, our analysis identified new melanoma-associated miRNAs providing novel miRNA candidates for the development of anticancer target therapy.

Considerations for Developing Targeted Therapies in Low‐Frequency Molecular Subsets of a Disease

Advances in our understanding of the molecular underpinnings of disease have spurred the development of targeted therapies and the use of precision medicine approaches in patient care. While targeted therapies have improved our capability to provide effective treatments to patients, they also present additional challenges to drug development and benefit-risk assessment such as identifying the subset(s) of patients likely to respond to the drug, assessing heterogeneity in response across molecular subsets of a disease, and developing diagnostic tests to identify patients for treatment. These challenges are particularly difficult to address when targeted therapies are developed to treat diseases with multiple molecular subtypes that occur at low frequencies. To help address these challenges, the US Food and Drug Administration recently published a draft guidance entitled "Developing Targeted Therapies in Low-Frequency Molecular Subsets of a Disease." Here we provide additional information on specific aspects of targeted therapy development in diseases with low-frequency molecular subsets.

Cyclophilin J PPIase Inhibitors Derived from 2,3-Quinoxaline-6 Amine Exhibit Antitumor Activity.

Cyclophilin J (CyPJ), also called peptidylprolyl isomerase like 3, has been identified as a novel member of the cyclophilin family. Our previous research has resolved the three-dimensional structure of CyPJ and demonstrated the peptidylprolyl cis–trans isomerase (PPIase) activity of CyPJ, which can be inhibited by the common immunosuppressive drug cyclosporine A (CsA). Importantly, CyPJ is upregulated in hepatocellular carcinoma (HCC) and promotes tumor growth; CyPJ inhibition by CsA- or siRNA-based knockdown results in a remarkable suppression of HCC. These findings suggest that CyPJ may be a potential therapeutic target for HCC, and discovery of relevant inhibitors may facilitate development of a novel CyPJ-based targeting therapy. However, apart from the common inhibitor CsA, CyPJ has yet to be investigated as a target for cancer therapy. Here, we report structure-based identification of novel small molecule non-peptidic CyPJ inhibitors and their potential as antitumor lead compounds. Based on computer-aided virtual screening, in silico, and subsequently surface plasmon resonance analysis, 19 potential inhibitors of CyPJ were identified and selected for further evaluation of PPIase CyPJ inhibition in vitro. Thirteen out of 19 compounds exhibited notable inhibition against PPIase activity. Among them, the compound ZX-J-19, with a quinoxaline nucleus, showed potential for tumor inhibition; thus, we selected it for further structure–activity optimization. A total of 22 chemical derivatives with 2,3-substituted quinoxaline-6-amine modifications were designed and successfully synthesized. At least 2 out of the 22 derivatives, such as ZX-J-19j and ZX-J-19l, demonstrated remarkable inhibition of tumor cell growth, comparable to CsA but much stronger than 5-fluorouracil. These results indicate that these two small molecules represent novel potential lead compounds for CyPJ-based antitumor drug development.

Histone modification aberrations in acute myeloid leukemia and the target therapy development in clinical settings

Histone modification aberrations in acute myeloid leukemia and the target therapy development in clinical settings

Abstract B16: Prognostic evaluation of components associated with epithelium-mesenchymal transition in women with serous carcinoma of high ovary grade

Abstract Introduction: High-grade serous ovarian carcinoma (HGSOC) is a heterogeneous disease with high mortality. Initially most women respond to platinum chemotherapy, but rapidly many become resistant to the drug and progress to relapse and death. Better knowledge of the pathways responsible for the mechanisms of invasion and metastasis in women with HGSOC may help in the identification of prognostic biomarkers and in the development of new target therapies. The epithelial-mesenchymal transition (EMT) is an important cellular process related to invasion and metastasis. Some protein components such as the receptor tyrosine kinase, discoidin domain receptor 2 (DDR2), acting on the signal-regulated kinase 1/2 (ERK1/2) extracellular pathway, and the transcriptional co-activator yes-associated protein (YAP), acting in Hippo, are associated with EMT. In such pathways, microRNAs, such as miR-182, miR-96, and miR-9 are described as post-transcriptional regulators. Objective: To evaluate the expression of DDR2, YAP and miR-182, miR-96 and miR-9 in formalin-fixed, paraffin-embedded blocks with HGSOC, and its association with clinical, tumor, platinum response, and survival characteristics. Methods: 63 women with HGSOC stages III and IV, who underwent platinum chemotherapy from 1996 until 2013, followed up until 2016 at the Women's Hospital Prof. Dr. José Aristodemo Pinotti, Brazil, were included. All women had paraffin blocks and complete clinical data on the chart. DDR2 and YAP expression were assessed by immunohistochemistry on tissue microarray (TMA) slides and the microRNAs were evaluated by real-time polymerase chain reaction (rtPCR). For the comparison of DDR2 and YAP expression with age, CA125 serum level, post-surgery residual stage disease, and platinum response, Mann-Whitney and Fisher tests were used. Progression-free survival (PFS) and overall survival (OS) were calculated by Cox regression. The PFS and OS curves were estimated by the Kaplan-Meier method and compared by the Log-Rank test. Expression of miR and DDR2 and YAP levels were compared by the t-test. Results: DDR2 expression was high in 8 (13.7%) women. There was no association between DDR2 expression and age, stage, CA125, residual post-surgery disease, and response to platinum-based chemotherapy. PFS was significantly worse in women whose tumors had high DDR2 expression (p=0.03), but not OS (p=0.49). MiR-182 level expression was lower in the group with high DDR2 expression (p<0.001), but not the expression level of miR-96 (p=0.067). High nuclear expression of YAP with low cytoplasmic expression was found in 15 (24.5%) women. There was no association between the expression of YAP and the characteristics of the disease or evolution of the women. MiR-9 level expression was not associated with YAP expression. Conclusions: Low levels of miR-182 expression were associated with high expression of DDR2, which was associated with poorer DFS. These findings suggest that the ERK1/2 signaling pathway was relevant to the EMT of these HGSOCs. The role of Hippo remained indeterminate. Citation Format: Susana Oliveira Ramalho, Luis Otávio Sarian, Rodrigo Natal, Liliana Andrade, Amanda Ferracini, Marina Pavanello, Cassio Cardoso Filho, Sophie Derchain. Prognostic evaluation of components associated with epithelium-mesenchymal transition in women with serous carcinoma of high ovary grade [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr B16.

Abstract B075: Evolving molecular prescreening program to identify genomic alterations in the NOTCH pathway

Abstract Introduction: Over 2 years we have adapted our VHIO molecular prescreening program (PreScr) to identify genomic alterations in tumors of patients (pt) eligible for phase 1 clinical trials (Ph1) testing NOTCH inhibitors. This retrospective study aims to assess the prevalence of NOTCH pathway alterations in tumors and how this information was used to select therapies and to develop the PreScr. Methods: From Jan/2015 to Dec/2016, 1,832 pt had formalin-fixed, paraffin-embedded tumor samples (TS) analyzed for mutations (mut) using a customized developed Amplicon-Seq panel of 61 cancer-related genes (including FBXW7 [50% exon coverage], NOTCH1 [hotspots 5% exon coverage], NOTCH4 [hotspots 3% exon coverage]) run in Illumina MiSeq; 191 (TS) for Copy Number Alterations (CNAs) using a panel of 59 genes (including NOTCH1-4) run in NanoString NCounter; and 481 (TS) for gene expression using a panel of 26 genes (including NOTCH 1-4) run in Nanostring NCounter. NOTCH1-2 gene amplifications (ampl) were validated by FISH. Results: Tumor types samples were colorectal (CRC) n=468 (25%), lung (LC) n=273 (15%), breast (BC) n=176 (10%), gynecologic (GYNC) n= 111 (6%), head and neck (H&N) n=95 (5%), urinary (UC) n=91 (5%), brain primary tumors n= 34 (2%), and others n=513 (28%). Overall, FBXW7 mut were detected in 28 cases (GYNC 4.5%, CRC 3.7%, UC 2.2%, H&N 1%, others 0.6%). Most frequent co-occurring mut were TP53 (n=15) and APC (n=11). We found no mutations in NOTCH1 or NOTCH4. NOTCH2ampl (≥ 6 copies) were found in 3 cases (biliary tract 20%, BC 4.3%). We found no CNAs in NOTCH1/3/4. Outlier high expression (normalized z-score > 4) of NOTCH family genes was detected in a variety of tumor types, including LC (NOTCH2/3), CRC (NOTCH1/2), BC (NOTCH3/4), UC (NOTCH3/4), and salivary gland (NOTCH1). Five pt were treated with Notch Gamma-secretase inhibitors in clinical trials (4 pt with FBXW7 mut and 1 pt with NOTCH2 ampl). Conclusion: We found a low prevalence of NOTCH pathway alterations in metastatic pt for Ph1 clinical trials. In order to increase the sensitivity for NOTCH mut detection, we will increase exon coverage of NOTCH genes. In parallel, outlier high expression data will be used to guide enrichment in future clinical trials. Our results reveal the challenges faced in an evolving PreScr to the NOTCH targeted therapy development. Citation Format: Analia Azaro, Susana Aguilar, Rodrigo Dienstmann, Irene Braña, Cinta Hierro, María Ochoa de Olza, Juan Martin-Liberal, María Vieito, Ignacio Matos, Paolo Nuciforo, Josep Tabernero, Jordi Rodon, Ana Vivancos, Elena Garralda. Evolving molecular prescreening program to identify genomic alterations in the NOTCH pathway [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B075.

Aptamer: A potential oligonucleotide nanomedicine in the diagnosis and treatment of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common cancers with a high mortality rate. Late diagnosis and poor prognosis are still a major drawback since curative therapies such as liver resection and liver transplantation are effective only for an early stage HCC. Development of novel molecular targeting therapies against HCC may provide new options that will improve the efficiency of the diagnosis and the success of the therapy, thus ameliorating the life expectancy of the patients. The aptamer is an oligonucleotide nanomedicine that has high binding affinity and specificity to small and large target molecules in the intracellular and extracellular environment with agonist or antagonist function. Currently, several aptamers for diagnostic and therapeutic purposes are under development to recognize different molecules of HCC. In in vitro models, the aptamer has been shown to be able to reduce the growth of HCC cells and increase the sensitivity to conventional chemotherapies. In in vivo mouse models, aptamer could induce cell apoptosis with antitumor activity. Overall data had shown that aptamer has limited toxicity and might be safe in clinical application. This review summarizes recent information of aptamer as a potential oligonucleotide nanomedicine tool, in diagnostics, targeted therapy, and as drug delivery nano-vehicles.

Transcriptome profiling identifies regulators of pathogenesis in collagen VI related muscular dystrophy.

ObjectivesThe collagen VI related muscular dystrophies (COL6-RD), Ullrich congenital muscular dystrophy (UCMD) and Bethlem myopathy (BM) are among the most common congenital muscular dystrophies and are characterized by distal joint laxity and a combination of distal and proximal joint contractures. Inheritance can be dominant negative (DN) or recessive depending on the type and location of the mutation. DN mutations allow incorporation of abnormal chains into secreted tetramers and are the most commonly identified mutation type in COL6-RD. Null alleles (nonsense, frameshift, and large deletions) do not allow incorporation of abnormal chains and act recessively. To better define the pathways disrupted by mutations in collagen VI, we have used a transcriptional profiling approach with RNA-Seq to identify differentially expressed genes in COL6-RD individuals from controls.MethodsRNA-Seq allows precise detection of all expressed transcripts in a sample and provides a tool for quantification of expression data on a genomic scale. We have used RNA-Seq to identify differentially expressed genes in cultured dermal fibroblasts from 13 COL6-RD individuals (8 dominant negative and 5 null) and 6 controls. To better assess the transcriptional changes induced by abnormal collagen VI in the extracellular matrix (ECM); we compared transcriptional profiles from subjects with DN mutations and subjects with null mutations to transcriptional profiles from controls.ResultsDifferentially expressed transcripts between COL6-RD and control fibroblasts include upregulation of ECM components and downregulation of factors controlling matrix remodeling and repair. DN and null samples are differentiated by downregulation of genes involved with DNA replication and repair in null samples.ConclusionsDifferentially expressed genes identified here may help identify new targets for development of therapies and biomarkers to assess the efficacy of treatments.

Therapy of primary CNS lymphoma: role of intensity, radiation, and novel agents.

Primary central nervous system (CNS) lymphomas represent a subgroup of malignancies with specific characteristics, an aggressive course, and unsatisfactory outcome in contrast with other lymphomas comparable for tumor burden and histological type. Despite the high sensitivity to conventional chemotherapy and radiotherapy, remissions are frequently short lasting. Treatment efficacy is limited by several factors, including the biology and microenvironment of this malignancy and the "protective" effect of the blood-brain barrier, which limits the access of most drugs to the CNS. Patients who survive are at high risk of developing treatment-related toxicity, mainly disabling neurotoxicity, raising the question of how to balance therapy intensification with the control of side effects. Recent therapeutic progress and effective international cooperation have resulted in a significantly improved outcome over the past 2 decades, with a higher proportion of patients receiving treatment with curative intent. Actual front-line therapy consists of high-dose methotrexate-based polychemotherapy. Evidence supporting the addition of an alkylating agent and rituximab is growing, and a recent randomized trial demonstrated that the combination of methotrexate, cytarabine, thiotepa, and rituximab (MATRix regimen) is associated with a significantly better overall survival. Whole-brain irradiation and high-dose chemotherapy supported by autologous stem cell transplantation are 2 effective consolidation strategies in patients with a disease responsive to induction chemotherapy. Different strategies such as alkylating maintenance, conservative radiotherapy, and nonmyeloablative consolidation are being addressed in large randomized trials and a more accurate knowledge of the molecular and biological characteristics of this malignancy are leading to the development of target therapies in refractory/relapsing patients, with the overall aim to incorporate new active agents as part of first-line treatment. The pros and cons of these approaches together with the best candidates for each therapy are outlined in this article.

Targeted therapy for acute myeloid leukemia: which drugs really improve the prognosis of patients?

Acute myeloid leukemia (AML) is a highly heterogeneous blood cancer. The risk stratification and treatment decisions are mainly based on recurrent genetic and molecular biologic characteristics, which represent the natural targets of targeted therapies of AML. In recent years, new targeted agents have been rapidly developed. However, the majority of existed targeted agents have been failed to show survival improvement in multicenter randomized clinical trials. Drugs with promising effects on overall survival (OS) or event-free survival (EFS) mainly comprise all-trans retinoic acid, arsenic trioxide, midostaurin, enasidenib, decitabine, azacitidine and gemtuzumab. This article reviews the necessity, limitations and development of targeted therapy for AML and the agents which have the potential to improve the prognosis of AML. Key words: Leukemia, myeloid, acute; Targeted therapy; Survival

INCB040093 Is a Novel PI3Kδ Inhibitor for the Treatment of B Cell Lymphoid Malignancies.

Phosphatidylinositol 3-kinase delta (PI3Kδ) is a critical signaling molecule in B cells and is considered a target for development of therapies against various B cell malignancies. INCB040093 is a novel PI3Kδ small-molecule inhibitor and has demonstrated promising efficacy in patients with Hodgkin's lymphoma in clinical studies. In this study, we disclose the chemical structure and the preclinical activity of the compound. In biochemical assays, INCB040093 potently inhibits the PI3Kδ kinase, with 74- to >900-fold selectivity against other PI3K family members. In vitro and ex vivo studies using primary B cells, cell lines from B cell malignancies, and human whole blood show that INCB040093 inhibits PI3Kδ-mediated functions, including cell signaling and proliferation. INCB040093 has no significant effect on the growth of nonlymphoid cell lines and was less potent in assays that measure human T and natural killer cell proliferation and neutrophil and monocyte functions, suggesting that the impact of INCB040093 on the human immune system will likely be restricted to B cells. INCB040093 inhibits the production of macrophage-inflammatory protein-1β (MIP-1beta) and tumor necrosis factor-β (TNF-beta) from a B cell line, suggesting a potential effect on the tumor microenvironment. In vivo, INCB040093 demonstrates single-agent activity in inhibiting tumor growth and potentiates the antitumor growth effect of the clinically relevant chemotherapeutic agent, bendamustine, in the Pfeiffer cell xenograft model of non-Hodgkin's lymphoma. INCB040093 has a favorable exposure profile in rats and an acceptable safety margin in rats and dogs. Taken together, data presented in this report support the potential utility of orally administered INCB040093 in the treatment of B cell malignancies.

SY9-2 - Treatment strategy for advanced soft tissue sarcoma

Soft tissue sarcoma (STS) is a rare tumor with more than 50 histologic subtypes. Many types of STS are not sensitive to chemotherapy, so patients with advanced diseases have poor prognosis. Development of novel anticancer therapy is in urgent need. Doxorubicin monotherapy is currently the standard first line treatment of advanced STS, but there is no standard for second line therapy. Recently, three new drugs: pazopanib, trabectedin, and eribulin have been approved for the second line treatment of patients with advanced STS, but the best treatment sequence of those drugs are not known. Sensitivity of STS to each drug seems to vary by histologic subtypes. For instance, liposarcoma seems be more sensitive to eribulin and less sensitive to pazopanib. Translocation related sarcoma (TRS) such as myxoid liposarcoma seems to be sensitive to trabectedin. Furthermore, these drugs have different safety profiles, so subtypes and patient characteristics must be considered for treatment selection. Development of specific molecular target therapy for each type of STS is necessary. There are specific chromosome translocations in 20-30% of STS, but their products are mostly transcriptional factors, and target therapy for those factors are difficult to develop. Trabectedin inhibits function of transcriptional factors, and shows higher efficacy for TRS. As molecular target therapies for gene mutations, success in molecular target therapy for c-kit and PDGFR mutation in gastrointestinal stromal tumor was followed by efficacy for rare sarcomas such as inflammatory myofibroblastic tumor or dermatofibrosarcoma protuberans, but there are few developments in other sarcomas. STS are associated with angiogenesis to a greater or lesser extent, so angiogenesis inhibitors such as pazopanib show good efficacy in some subtypes. Immune checkpoint inhibitors also have been developed for STS and show some efficacy in subtypes such as undifferentiated pleomorphic sarcoma.

Molecular targeted therapy in glioblastoma

Glioblastomas is the most common malignant primary brain tumors and the prognosis is very poor. With the development of tumor molecular biology, molecular targeted therapy for glioblastomas has become an integral part of its comprehensive treatment. Targeted therapy drugs of glioblastomas are emerging, including tyrosine kinase inhibitors, histone deacetylase inhibitors, phosphatidylinositol 3-kinase inhibitors, hypoxia inducible factor-1α inhibitors, sodium-potassium pump inhibitors, et al. With the development of new molecular targeted therapy, more effective or even treatment measures of glioblastomas might be found, which can provide a new approach for the individualized treatment of glioblastomas. Key words: Glioma; Targeted therapy

Serum IL-6 and IL-8 Correlate with Prognostic Factors in Ovarian Cancer

ABSTRACTThe aim of the study was to correlate serum levels of IL-2, IL-5, IL-6, IL-8, IL-10, and TNF-α with clinical, laboratory, and pathological prognostic factors in patients with primary ovarian malignancy. Patients treated at the Pelvic Mass Ambulatory of the Discipline of Gynecology and Obstetrics/Oncology Research Institute (IPON) of the UFTM with confirmed diagnosis of malignant ovarian neoplasia (n = 26) were evaluated. Serum collection was performed preoperatively for the determination of tumor markers. The cytokines IL-2, IL-5, IL-6, IL-8, IL-10, and TNF-α were assayed by enzyme-linked immunosorbent assay (ELISA). The prognostic factors were compared using the Mann-Whitney test, with significance level lower than 0.05. When evaluating IL6, it was observed that higher serum levels were associated with overall survival less than 60 months (p = 0.0382). In the evaluation of IL8, higher serum levels were associated with neutrophil-to-lymphocyte ratio (NLR) ≥ 4 and platelet-to-lymphocyte ratio (PLR) ≥ 200 (p = 0.0198 and p = 0.0072, respectively), altered values of serum CA125 (p = 0.0457), and stage IIIC (p = 0.0486). Therefore, increased levels of IL-6 and IL-8 are associated with factors of worse prognosis in ovarian cancer. Additional studies with a larger sample of patients are needed to confirm the role of cytokines as prognostic factors, in the definition of treatment, and in the development of future target therapies.