Recent advances in systemic therapy for hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the most common and lethal malignant tumors in the world. Therapeutic options for advanced HCC are limited. Systemic treatment, especially with conventional cytotoxic drugs, is usually ineffective. For more than a decade, sorafenib has been the only systemic drug that has been proven to be clinically effective for treating advanced HCC. However, over the past three years, the rapid progress of molecular targeted therapies has dramatically changed the treatment landscape for advanced HCC. Immune checkpoint therapies are now being incorporated into HCC therapies, and their combination with molecular targeted therapy is emerging as a tool to enhance the immune response. In this review, we summarize the development and progress of molecular targeted agents and immunotherapies in HCC.

A Necroptosis-Related Gene Signature for Predicting Prognosis, Immune Landscape, and Therapy Sensitivity in Hepatocellular Carcinoma

Background: Hepatocellular carcinoma (HCC) remains a growing threat to global health. Necroptosis is a newly discovered regulated cell necrosis that plays a vital role in cancer development. Thus, we conducted this study to develop a predictive signature based on necroptosis-related genes.Methods: The tumor samples in The Cancer Genome Atlas (TCGA) Liver Hepatocellular Carcinoma (LIHC) cohort were subtyped using the consensus clustering algorithm. Univariate Cox regression and LASSO-Cox analysis were performed to construct a gene signature model from differentially expressed genes between tumor clusters. Then we integrated TNM stage and the prognostic model to build a nomogram. The gene signature and the nomogram were externally validated in the GSE14520 cohort from the gene expression omnibus (GEO) and LIRP-JP cohort from the International Cancer Genome Consortium (ICGC). Predictive performance evaluation was conducted using Kaplan-Meier plot, time-dependent receiver operating characteristic curve, principal components analysis, concordance index, and decision curve analysis. The tumor microenvironment was estimated using seven published methods. Finally, we also predicted the drug responses to immunotherapy, conventional chemotherapy and molecular-targeted therapy using two algorithms and two datasets. Results: We identified two necroptosis-related clusters and a ten-gene signature (MTMR2, CDCA8, S100A9, ANXA10, G6PD, SLC1A5, SLC2A1, SPP1, PLOD2, and MMP1). The gene signature and the nomogram had good predictive ability in TCGA, ICGC, and GEO cohorts. The risk score was positively associated with the degree of necroptosis and immune infiltration (especially immunosuppressive cells). The high-risk group could benefit more from immunotherapy. Chemotherapy and molecular-targeted therapy should be adapted to the molecular profiles of each patient.Conclusion: The necroptosis-related gene signature provides reliable evidence for prognosis prediction, comprehensive treatment, and new therapeutic targets for HCC patients. The nomogram can further improve predictive accuracy.

SPDR-1 HSP90 inhibition overcomes resistant to molecular targeted therapy in BRAFV600E mutant glioblastoma

The BRAFV600E mutation results in the constitutive activation of downstream mitogen activated protein kinase (MAPK) pathway that promotes tumor growth. Recently, molecular targeted therapy using BRAF/MEK inhibitor has been reported for BRAFV600E mutant high-grade glioma, but the therapeutic effect is limited by the emergence of drug resistance. Herein, we established paired BRAFV600E mutant glioblastoma (GBM) patient-derived xenograft (PDX) models, which were derived from tumors at prior to and recurrence after molecular targeted therapy. These PDX models were found to extensively recapitulate the histology, genetic abnormalities, and even the clinical course of the patients. Furthermore, BRAF/MEK inhibitor gradually caused resistance in cell lines derived from specimens that initially responded to molecular targeted therapy. In this study, genomic and epigenomic changes had little effect on the resistance mechanism. On the other hand, we found that hyperactivation of the MAPK pathway through c-Raf and the AKT/mTOR pathway primarily caused resistance to molecular targeted therapy in BRAFV600E mutant GBM. Through a high throughput drug screening, we find that HSP90 inhibitor with BRAF/MEK inhibitor coordinately deactivates MAPK pathway and AKT/mTOR pathway, and mediates potent toxicity in vitro and in vivo in refractory and acquired resistant models. These findings support that this therapeutic approach can overcome the limitation of current molecular targeted therapy in BRAFV600E mutant GBM.

ET-1 Translational research platform for malignant brain tumors

Introduction: The standard therapy for malignant brain tumors includes surgery and combination therapy with radiation and chemotherapy, but to provide individualized treatment based on the biological and molecular genetic background of the tumor, integrate genetic information with various functional data are required. In this study, we present an overview of our integrated approaches for translational research and clinical management. Methods: In glioma, pre-and intra-operative clinical information, including intraoperative genetic diagnosis, and intraoperative rapid immunohistochemistry is obtained, then a multidisciplinary treatment approach is started based on these integrated data. Specimens collected intraoperatively are cryopreserved for future analysis, and primary cultured cells are routinely collected. The cultured cells are transplanted into the brain of immunodeficient mice to establish patient-derived xenograft model (PDX). Genetic screening, such as IDH, TERT, BRAF, H3F3A mutation and MGMT methylation analysis are routinely assessed within a few days after surgery and used as information for integrated diagnosis. In case of PDX establishment or recurrence, we perform whole exon sequencing or comprehensive genomic assessment to identify genetic abnormalities. If genomic alterations for possible molecular targeted therapy are identified, we assess drug sensitivity test in vitro and in vivo, which are utilized for research to develop optimal molecular targeted therapy. The results, such as the therapeutic effects of molecular targeted drugs, are used for clinical applications. Results: Since the platform was established, we have treated a total of 286 patients, including 189 gliomas and 37 central nervous system lymphomas based on the integrated information. We are currently collecting clinical data to examine if this integrated approach could provide clinical benefit.Conclusion: The translational research system for malignant brain tumors plays an important role in the promotion of clinical and basic research.

BET protein inhibition evidently enhances sensitivity to PI3K/mTOR dual inhibition in intrahepatic cholangiocarcinoma

Intrahepatic cholangiocarcinoma (ICC), the second most common primary liver cancer, is a fatal malignancy with a poor prognosis and only very limited therapeutic options. Although molecular targeted therapy is emerged as a promising treatment strategy, resistance to molecular-targeted therapy occurs inevitably, which represents a major clinical challenge. In this study, we confirmed that mammalian target of rapamycin (mTOR) signaling is the most significantly affected pathways in ICC. As a novel phosphoinositide 3-kinase (PI3K)/mTOR dual inhibitor, BEZ235, exerts antitumour activity by effectively and specifically blocking the dysfunctional activation of the PI3K/serine/threonine kinase (AKT)/mTOR pathway. We generate the orthotopic ICC mouse model through hydrodynamic transfection of AKT and yes-associated protein (YAP) plasmids into the mouse liver. Our study confirmed that BEZ235 can suppress the proliferation, invasion and colony conformation abilities of ICC cells in vitro but cannot effectively inhibit ICC progression in vivo. Inhibition of PI3K/mTOR allowed upregulation of c-Myc and YAP through suppressed the phosphorylation of LATS1. It would be a novel mechanism that mediated resistance to PI3K/mTOR dual inhibitor. However, Bromo- and extraterminal domain (BET) inhibition by JQ1 downregulates c-Myc and YAP transcription, which could enhance the efficacy of PI3K/mTOR inhibitors. The efficacy results of combination therapy exhibited effective treatment on ICC in vitro and in vivo. Our data further confirmed that the combination of PI3K/mTOR dual inhibitor and BET inhibition induces M1 polarization and suppresses M2 polarization in macrophages by regulating the expression of HIF-1α. Our study provides a novel and efficient therapeutic strategy in treating primary ICC.

Clinical and Preclinical Outcomes of Combining Targeted Therapy With Radiotherapy

In the era of precision medicine, radiation medicine is currently focused on the precise delivery of highly conformal radiation treatments. However, the tremendous developments in targeted therapy are yet to fulfill their full promise and arguably have the potential to dramatically enhance the radiation therapeutic ratio. The increased ability to molecularly profile tumors both at diagnosis and at relapse and the co-incident progress in the field of radiogenomics could potentially pave the way for a more personalized approach to radiation treatment in contrast to the current ‘‘one size fits all’’ paradigm. Few clinical trials to date have shown an improved clinical outcome when combining targeted agents with radiation therapy, however, most have failed to show benefit, which is arguably due to limited preclinical data. Several key molecular pathways could theoretically enhance therapeutic effect of radiation when rationally targeted either by directly enhancing tumor cell kill or indirectly through the abscopal effect of radiation when combined with novel immunotherapies. The timing of combining molecular targeted therapy with radiation is also important to determine and could greatly affect the outcome depending on which pathway is being inhibited.