HCC Therapy Research Articles

LncRNA OIP5-AS1 interacts with miR-363-3p to contribute to hepatocellular carcinoma progression through up-regulation of SOX4.

Long noncoding RNA OIP5-AS1 has been observed to be increased in several cancers, however, its role and biological mechanism was poorly understood in HCC. Currently, we found OIP5-AS1 expression was upregulated in HCC cells compared with normal human liver cells. Knockdown of OIP5-AS1 suppressed HCC cell proliferation, induced cells cycle arrest and cells apoptosis. In addition, HCC cell migration and invasion capacity in vitro were also inhibited by OIP5-AS1 inhibition. Bioinformatics analysis revealed OIP5-AS1 could interact with miR-363-3p, thereby repressing HCC development. We also observed miR-363-3p was significantly decreased in HCC cells and overexpression of miR-363-3p repressed HCC progression. The correlation between OIP5-AS1 and miR-363-3p was confirmed by performing RIP assay and RNA pull-down assay. Subsequently, SOX4 was predicted as a target of miR-363-3p and miR-363-3p modulated SOX4 levels negatively in vitro. Apart from these, in vivo experiments established that OIP5-AS1 can suppress HCC development through regulating miR-363-3p and SOX4. Collectively, these demonstrated that OIP5-AS1 was involved in HCC progression via targeting miR-363-3p and SOX4. OIP5-AS1 can act as a novel candidate for HCC diagnosis, prognosis, and therapy.

IGF-1 Child-Turcotte-Pugh score as a predictor of overall survival to therapy in CTP-A, BCLC stage C patients with advanced hepatocellular carcinoma.

488 Background: Child-Turcotte-Pugh (CTP) A is the standard population for active HCC therapy. The IGF-CTP score, comprises levels of type 1 insulin-like growth factor (IGF-1), bilirubin, INR, and albumin, significantly improved the prediction of overall survival (OS) in recently published studies. Our current study aimed to investigate the accuracy of the IGF-CTP score in predicting OS in HCC Child-Pugh A patients (pts) treated with local and/or systemic therapies (tx). The overall hypothesis is that the IGF-CTP score can further distinguish CP-A pts in terms of overall survival, PFS. Methods: Between 2014 and 2018, a total of 274 pts with new advanced HCC BCLC stage who had available baseline plasma IGF-1 level were retrospectively enrolled. Clinicopathologic features and treatment history were collected. We calculated IGF-CTP scores, used Kaplan-Meier method and log rank test to estimate and compare time to event outcomes between subgroups of patients. Results: 198 pts were CTP Class A, 209 patient underwent systemic tx, 65 underwent local tx [see table]; 161 were re-classified as IGF-CTP-A with a median OS of 16.09 months (95% CI = 13.06 to 23.29 months) (p <0.0001), whereas 37 patients were reclassified as intermediate risk (IGF-CTP-B) and had significantly shorter OS of 10.66 months (95% CI = 5.49 to 26.51) (p <0.0001). Conclusions: The results of this study support our biologically-driven hypothesis that IGF-CTP score is predictive of overall survival to therapy in advanced HCC treated with local and/or systemic therapy. Among HCC pts with CTP-A class, some are reclassified as IGF-CP-B/C and were found to have significantly poorer prognosis in terms of shorter OS. Future validation of the predictive ability of our IGF-1 score may lead to adopting it as a stratification tool in clinical trials as well as to predict HCC outcome and guide therapy decision in routine practice. [Table: see text]

Targeted Therapy for Hepatocellular Carcinoma: Co-Delivery of Sorafenib and Curcumin Using Lactosylated pH-Responsive Nanoparticles.

PurposeHepatocellular carcinoma (HCC) is a leading cancer worldwide. In the present investigation, sorafenib (SFN) and curcumin (CCM) were co-delivered using pH-sensitive lactosylated nanoparticles (LAC-NPs) for targeted HCC treatment.MethodspH-responsive lactosylated materials were synthesized. SFN and CCM co-delivered, pH-responsive lactosylated nanoparticles (LAC-SFN/CCM-NPs) were self-assembled by using the nanoprecipitation technique. The nanoparticles were characterized in terms of particle size, charge and drug release profile. The anti-cancer effects of the nanoparticles were evaluated in human hepatic carcinoma cells (HepG2) cells and HCC tumor xenograft models.ResultsLAC-SFN/CCM-NPs are spherical particles with light coats on the surface. The size and zeta potential of LAC-SFN/CCM-NPs were 115.5 ± 3.6 nm and −34.6 ± 2.4, respectively. The drug release of LAC-SFN/CCM-NPs in pH 5.5 was more efficient than in pH 7.4. LAC-SFN/CCM-NPs group exhibited the smallest tumor volume (239 ± 14 mm3), and the inhibition rate of LAC-SFN/CCM-NPs was 77.4%.ConclusionIn summary, LAC-SFN/CCM-NPs was proved to be a promising system for targeted HCC therapy.

Phase Ib/II study of sorafenib (SOR) and pembrolizumab (PEM) in advanced hepatocellular cancer (HCC).

TPS596 Background: SOR has been the backbone of advanced HCC therapy with poor outcome. Anti-PD-1 therapy is approved as a second-line treatment option in HCC due to its promising efficacy and safety. Our preclinical work showed that SOR is immunomodulatory and may be synergistic when combined with anti-PD-1 therapy. Guided by this data, we initiated this multicenter study of SOR and PEM in advanced HCC patients (pts). Methods: Pts who have Child-Pugh Class A, ECOG PS of 0/1, biopsy-proven measurable HCC that is unresectable or metastatic, are included. Pts must not receive either SOR or anti-PD-1 therapy before. A total of 27 pts will be enrolled from 2 sites. Pts must have the following lab values: ANC ≥ 1,500/ mc; Hgb ≥ 8.5 g/dL; Plts ≥75,000/ mcL; serum total bilirubin ≤ 2.0 mg/dL; AST/ALT ≤ 5 X ULN; serum creatinine ≤ 1.5 X ULN. Pts with active hep B must be on antiviral therapy. Pts would be on a 4-week run-in of SOR alone at 400mg BID to ensure tolerability and stable dose (minimum 200 BID) before beginning PEM 200mg IV q3 weeks. Both drugs would be administered until progression or unacceptable toxicity with response assessment q6 weeks by RECIST 1.1 criteria. Primary endpoint: response rate. Secondary endpoints: safety, overall survival, and progression-free survival. Correlative Endpoints: Pre-treatment levels of immunosuppressive cells and the functional activity of effector T cells would be compared to post-treatment blood and tumor samples. The first 6 pts who completed 4 weeks of SOR-only treatment and began the combination therapy (addition of PEM at a fixed dose of 200 mg Q3W) would comprise the safety lead-in. Pts who withdrew before initiation of combination therapy (for reasons other than DLT) would be replaced. Dose-Limiting toxicity was defined as any ≥ grade 3 clinically significant toxicity, which is deemed possibly treatment-related and occurs within the first cycle of combination therapy. Toxicity would be assessed by NCI CTCAEV4.0. Status: First patient enrollment on 12/19/2017. On 11/28/2018, our 6th patient completed the SOR lead-in phase and began combination treatment with SOR and PEM. As of Sept 12, 2019, thirteen pts have enrolled, and 9 pts have received combination treatment. Support: Merck. Clinical trial information: NCT03211416.

Efficacy and Safety of Lenvatinib as a Conversion Therapy for HCC

Efficacy and Safety of Lenvatinib as a Conversion Therapy for HCC

Small interfering RNA targeting alpha7 nicotinic acetylcholine receptor sensitizes hepatocellular carcinoma cells to sorafenib

AimsIt has been demonstrated that reduced expression of alpha7 nicotinic acetylcholine receptor (α7nAChR) led to reduced chemotherapeutic drugs resistance in various cancer cells. However, whether small interfering RNA (siRNA) mediated knockdown of α7nAChR can reduce sorafenib (SOR) resistance in HCC cells remains to be determined. Materials and methodsThe effects of α7nAChR-siRNA in combination with SOR treatment was analyzed in human (HepG2) and mouse (Hepa 1–6) HCC cell lines. The MTT, DAPI staining and flow cytometry assays were applied to measure the cell viability, apoptosis and cell cycle progression of the cells. Also, the changes in the mRNA and protein levels of the α7nAChR were measured by quantitative real-time PCR and western blot analysis, respectively. Key findingsThe results revealed that SOR increased both mRNA and protein levels of α7nAChR in HCC cells. Treatment with α7nAChR-siRNA abolished these effects. Also, SOR treatment in combination with α7nAChR-siRNA significantly sensitizes HCC cells to SOR cytotoxicity. This combination therapy significantly induced HCC cells apoptosis compared to SOR alone. SignificanceThese experimental results indicate that knockdown of α7nAChR by siRNA increased the SOR antitumor activity of HCC cells and suggests that this additive combination is a promising drug candidate for HCC therapy.

Knockdown of LINC00473 Enhances Radiosensitivity in Hepatocellular Carcinoma via Regulating the miR-345-5p/FOXP1 Axis.

BackgroundHepatocellular carcinoma (HCC) is the most common form of liver cancer. Radioresistance is a significant obstacle in HCC therapy. Long non-coding RNA 473 (LINC00473) has been found to impair the effect of radiotherapy. This study aimed to explore the function and molecular basis of LINC00473 in the radiosensitivity of HCC cells.MethodsThe levels of LINC00473, miR-345-5p and Forkhead Box P1 (FOXP1) were determined by quantitative real-time polymerase chain reaction. Cell viability was assessed by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay. Survival fraction was calculated by colony survival assay after exposure to different doses of radiation. Cell apoptosis was evaluated by flow cytometry. The interaction among LINC00473, miR-345-5p and FOXP1 was confirmed by dual-luciferase reporter assay. The protein level of FOXP1 was detected by Western blot assay.ResultsLINC00473 and FOXP1 were up-regulated, while miR-345-5p was down-regulated in HCC tissues and cells. Radiation elevated LINC00473 expression in a dose- and time-dependent manner. Depletion of LINC00473 inhibited proliferation and heightened radiosensitivity and apoptosis in HCC cells. In addition, LINC00473 was a sponge of miR-345-5p. Also, miR-345-5p overexpression sensitized HCC cells to radiation. Moreover, miR-345-5p directly targeted FOXP1. MiR-345-5p inhibition or FOXP1 up-regulation reversed the enhanced radiosensitivity caused by LINC00473 knockdown.ConclusionLINC00473 contributed to radioresistance in HCC via modulating the miR-345-5p/FOXP1 axis, which might provide a promising diagnostic marker for HCC radiotherapy.

LncRNA SNHG11 Promotes Proliferation, Migration, Apoptosis, and Autophagy by Regulating hsa-miR-184/AGO2 in HCC.

BackgroundThe most common malignant tumor of the digestive system is HCC. However, the mechanism and pathogenesis of HCC occurrence and progress are still unknown. LncRNA is closely related to the occurrence and progress of HCC. It is important to investigate the effect and role of lncRNA in HCC.Materials and MethodsLncRNA microarray assay was used to screen the differential expression profile of lncRNA. SNHG11, miR-184 and GO2 expression was analyzed by RT-PCR. The ability of SNHG11 to serve as a sponge for miRNA and the fact that miR-184 directly targets mRNA were revealed by dual luciferase assay and RIP. Apoptosis and autophagy related proteins were detected by Western blot. Cell proliferation, invasion, migration, and apoptosis were detected by CCK-8 assay, wound healing assay, transwell assay, and flow cytometry.ResultsLncRNA microarray assay and RT-PCR results revealed that the expression of SNHG11 was increased in HCC tumor tissues and also upregulated in HCC cells. SNHG11 had a connection with poor survival rate in HCC. In addition, dual luciferase assay and RIP results revealed that SNHG11 serves as a sponge for miR-184 and miR-184 directly targets AGO2. Pearson correlation analysis showed that SNHG11 with miR-184 and miR-184 with AGO2 were negative correlations, and SNHG11 with AGO2 was a positive correlation. Cell function assay and Western blot showed SNHG4/miR-184/AGO2 regulatory loop was critical for HCC cell proliferation, migration, apoptosis, and autophagy.ConclusionOur study demonstrated that the expression of SNHG11 is higher in HCC; moreover, SNHG11 promotes proliferation, migration, apoptosis, and autophagy by regulating AGO2 via miR-184 in HCC. Our verification of the role of SNHG11 may provide a novel biomarker for the diagnosis, therapy, and prognosis of HCC.

Upregulation of musashi1 increases malignancy of hepatocellular carcinoma via the Wnt/\u03b2-catenin signaling pathway and predicts a poor prognosis

BackgroundHepatocellular carcinoma (HCC) is a common human malignant cancer due to a high metastatic capacity and the recurrence rate is also high. This study is aim to investigate the role of musashi1 as a potential biomarker for therapy of HCC.MethodsThe mRNA and protein expression levels of musashi1 were detected in HCC samples and cell lines. The malignant properties of HCC cells, including proliferation, invasion and migration were measured by overexpressing or knocking down expression of musashi1. Additionally, the correlation between musashi1 and clinicopathological indexes and prognosis were analyzed. The expression of CD44 was measured and the correlation between CD44 and musashi1 was analyzed.ResultsIn vitro cytological experiments demonstrated that musashi1 was elevated in HCC samples and cell lines and this increased expression affected cancer cell viability, migration and invasive capacity by activating of the Wnt/β-catenin signaling pathway. Analysis of clinicopathological characteristics suggested that up-regulation of musashi1 was related to metastasis potential and a poor prognosis. Besides, there was a positive correlation between CD44 and musashi1 expression. Upregulation of musashi1 in malignant liver tumors may have contributed to the maintenance of stem-cell like characteristics of HCC cells.ConclusionsUpregulation of musashi1 could enhance malignant development of HCC cells and thus might be a novel marker for HCC therapy.

The Current Landscape of Systemic Therapies for Advanced Hepatocellular Carcinoma

As the global burden of HCC continues to rise, there is an overwhelming need for new systemic therapies for the treatment of advanced-stage HCC. In this review, we explore the current landscape of approved therapies for intermediate-stage HCC after progression with locoregional therapy or in those who present with advanced-stage HCC not amenable to curative options. In the last 10 years, several agents have been studied in the first and second-line treatment of HCC but failed to show clinical benefit. Between 2008 and 2016, sorafenib was the sole agent used in the treatment of advanced-stage HCC. Recent strides have shown success with lenvatinib as an alternative agent for first-line treatment, and regorafenib, cabozantinib, ramucirumab, nivolumab, and pembrolizumab as second- and thrid-line agents in advanced HCC. The next series of HCC trials are appropriately directed at combination therapies—combining targeted therapy with immunomodulators in the hopes of improving overall survival and ultimately getting closer to finding a cure.

133P - Prognostic and predictive factors from the phase III CELESTIAL trial of cabozantinib (C) versus placebo (P) in previously treated advanced hepatocellular carcinoma (aHCC)

BackgroundC improved overall survival (OS) and progression-free survival (PFS) vs P in the phase 3 CELESTIAL trial (NCT01908426). Median OS was 10.2 mo with C vs 8.0 mo with P (HR 0.76, 95% CI 0.63–0.92; p = 0.005), and median PFS was 5.2 mo vs 1.9 mo (HR 0.44, 95% CI 0.36–0.52; p < 0.001) (Abou-Alfa, NEJM 2018). Here, retrospective univariate (UV) and multivariate (MV) analyses were done to identify prognostic and predictive factors for OS from CELESTIAL. Methods707 patients (pts) were randomized 2:1 to receive C (60 mg qd) or P. Pts were Child-Pugh grade A and ECOG PS ≤ 1 and must have received prior sorafenib and could have received up to 2 prior lines of systemic therapy for HCC. UV and MV analyses of OS were done using the Cox proportional hazard regression model to compare subgroups defined by baseline variables within each treatment group (Bruix, J Hepatol 2017). MV analyses used backward selection with cutoffs of p ≤ 0.1 for inclusion and p ≤ 0.05 for retention of prognostic factors in the final model. Variables with p ≤ 0.05 for treatment-subgroup interaction were considered possible predictive factors for treatment benefit. ResultsAge, sex, race, region, and etiology were not significant covariates in stepwise UV and MV analyses of OS. Nine baseline variables related to disease status, laboratory values, or prior therapy were identified as possible prognostic factors for OS in one or both treatment groups (Table). No covariates were found to be predictive of an OS benefit with C.Table133PTableMV analysis of OSCabozantinibPlacebop-valueHRp-valueHRECOG PS [≥1 vs 0]0.00201.430.961.01Macrovascular invasion (MVI) [yes vs no]0.00231.470.161.28Number of sites [2 vs 1]0.0471.330.00241.84Number of sites [3 vs 1]<0.00011.820.0101.70Alpha-fetoprotein (AFP) [≥400 vs < 400 ng/mL]<0.00011.72<0.00011.95Albumin-bilirubin (ALBI) grade [≥2 vs 1]0.00051.570.0221.48Neutrophil to lymphocyte ratio [≥median vs <median]0.0121.340.0251.45Alkaline phosphatase [≥median vs <median]0.00091.50<0.00012.15Prior transarterial chemoembolization (TACE) [yes vs no]0.340.900.0280.69 ConclusionsExploratory UV and MV analyses identified high baseline values of AFP, alkaline phosphatase, ALBI grade, neutrophil to lymphocyte ratio, and number of disease sites as possible prognostic factors for shorter OS in previously treated aHCC. Disease etiology and demographic factors such as race and region were not found to be prognostic for OS. Clinical trial identificationNCT01908426 (Other Study ID Numbers: XL184-309). Editorial acknowledgementDavid Markby (Exelixis). Legal entity responsible for the studyExelixis. FundingExelixis. DisclosureT. Yau: Advisory / Consultancy: Exelixis; Honoraria (self): Ipen, Exelixis. T. Meyer: Advisory / Consultancy: BMS, BAYER, EISAI, BTG, AZ, BEIGENE, TARVEDA, MSD; Research grant / Funding (self): BTG BAYER. R.K. Kelley: Research grant / Funding (institution), Funding to institution: Agios, AstraZeneca, Bayer, BMS; Research grant / Funding (self), Funding to self: IDMC: Genentech/Roche; Research grant / Funding (institution): Agios, AstraZeneca, Bayer, BMS, Eli Lilly, Exelixis, EMD Serono, Medimmune, Merck, Novartis, QED, Taiho. M. Mangeshkar: Full / Part-time employment: Exelixis; Shareholder / Stockholder / Stock options: Exelixis. A-L. Cheng: Advisory / Consultancy, Advisory: Bayer Schering Pharma, Bristol-Myers Squibb, Eisai, Merck Serono, Novartis, Ono Pharmaceutical, Exelixis, Nucleix Ltd., Roche/Genentech, and IQVIA; Advisory / Consultancy, Consultancy: Bayer Schering Pharma, Bristol-Myers Squibb, Eisai, Merck Serono, Novartis, Ono Pharmaceutical, Exelixis, Nucleix Ltd., Roche/Genentech, and IQVIA; Honoraria (self): Bayer, Eisai, and Merck Sharp Dohme, Merck Serono, Novartis, Ono Pharmaceutical, Roche/Genentech, and IQVIA. A.B. El-Khoueiry: Advisory / Consultancy: Bayer, BMS, Agenus, Merck, EISAI, Pieris, EMD Serono, Exelixis, Roche/Genentech, Apeiron; Research grant / Funding (self): AstraZeneca, Astex. G.K. Abou-Alfa: Research grant / Funding (institution): ActaBiologica, Agios, Array, AstraZeneca, Bayer, Beigene, BMS, Casi, Celgene, Exelixis, Genentech, Halozyme, Incyte, Lilly, Mabvax, Novartis, OncoQuest, Polaris Puma, QED, Roche; Advisory / Consultancy: 3DMedcare, Agios, Alignmed, Amgen, Antengene, Aptus, Aslan, Astellas, AstraZeneca, Bayer, Beigene, Bioline, BMS, Boston Scientifc, Bridgebio, Carsgen, Celgene, Casi, Cipla, CytomX, Daiichi, Debio, Delcath, Eisai, Exelixis, Flatiron, Genoscience, Halozyme.

340TiP - A multicenter, randomized, controlled, phase II trial exploring adjuvant combined therapy of apatinib and SHR-1210 (anti-PD-1), in patients with hepatocellular carcinoma at high risk of recurrence after radical resection

BackgroundHepatocellular carcinoma (HCC) is the most common malignancy with high rates of recurrence and metastasis after radical resection. Vascular invasion, including portal vein tumor thrombus (PVTT) and microvascular invasion (MVI), and microsatellite lesions are two significant risk factors of postoperative recurrence and metastasis for HCC. Therefore, it is necessary to discover adjuvant therapies for patients with these risk factors. Anti-angiogenesis therapy combined with immunotherapy has demonstrated clinical benefits in multiple advanced solid neoplasms, including HCC. An exploratory phase Ib study (NCT02942329) proved that combined therapy of apatinib (250mg QD) and anti-PD-1 drug, SHR-1210 (200mg Q2W) was well tolerated and had preliminary efficacy in advanced HCC. Trial designThis multicenter, randomized, controlled, phase II study will evaluate the safety and efficacy of adjuvant combined therapy of apatinib and anti-PD-1 drug, SHR-1210, compared with hepatic arterial infusion (HAI) chemotherapy, in patients with HCC at high risk of recurrence after radical resection. 200 patients, aged >18 years, Child-Pugh score 0 or 1, with histologically confirmed primary HCC, BCLC stage A or B diseases that are radical resected without other prior therapy for HCC and who are found to have microsatellite lesions, microvascular invasion or PVTT involved in second-order branch or above by preoperative imaging examination or postoperative pathological findings will be recruited and randomized (1:1) to receive apatinib (250mg QD) and SHR-1210 (200mg Q2W) for 6 months, or 2 times of standard HAI treatments (epirubicin 80-100mg or epirubicin 50mg+oxaliplatin 50mg). The primary endpoint is to compare recurrence-free survival and secondary endpoints include overall survival, safety, 1,2,3-year recurrence rate and Quality of Life score (QoL). Survival follow-up will continue for up to 3 years. The study is ongoing. Clinical trial identificationNCT 03839550. Legal entity responsible for the studyNational Cancer Center/Cancer Hospital. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Randomized phase II trial of sorafenib, capecitabine and oxaliplatin (SECOX) vs sorafenib in patients with advanced HCC

Abstract We aimed to compare the efficacy and tolerability of SECOX regimen with sorafenib alone as first-line treatment of advanced HCC in a multicenter, open-label and randomized setting. Patients not suitable for surgery or loco-regional therapies and no prior systemic therapy for advanced HCC were recruited in 3 centres. Eligible patients were randomly assigned to receive either SECOX (sorafenib 400 mg BD continuously, oxaliplatin 85 mg/m2 on D1, and capecitabine 1700 mg/m2 on D1-7 q2w) or sorafenib alone in 1:1 ratio. Primary endpoint was time-to-progression (TTP). Secondary endpoints were tolerability, ORR, OS and PFS. 46 patients (pts) were randomized and treated, of whom 22 were in the SECOX arm. Median age was 64 years and majority were male (72%). 40 pts (87%) were HBV carrier, and 42 pts (91%) had Child-Pugh A liver function. 30 pts (65%) had received prior non-systemic treatment for HCC. Median duration of follow-up was 7.8 months (mos) (range 0.3-25.8). At the time of analysis, 1 pt in the SECOX arm is still receiving treatment. Median TTP was 3.2 mos (95% CI 1.7-5.8) for SECOX vs 2.8 mos (95% CI 1.8-4.0) for sorafenib. The hazard ratio (HR) for TTP was 0.91 (95% CI 0.5-1.7; p = 0.77; predetermined futility boundary HR ≥ 0.86). Median OS was 7.1 mos (95% CI 3.0-15.3) for SECOX vs 12.5 mos (95% CI 7.2-15.4) for sorafenib (p = 0.29). Median PFS was 3.1 mos (95% CI 1.6-5.8) for SECOX vs 2.7 mos (95% CI 1.8-4.0) for sorafenib. 2 pts (9%) and no pts achieved PR in the SECOX and sorafenib arms, respectively. The clinical benefit rate (CR+PR+SD) was 36% for the SECOX arm and 21% for the sorafenib arm (p = 0.50). Incidence of treatment-related AEs (trAEs) was common in both SECOX and sorafenib arms (64% and 71% respectively, p = 0.75). The most common grade 3-4 trAE was ALP increase (14%) for SECOX and hand-foot skin reaction (25%) for sorafenib. Conclusions: The addition of capecitabine and oxaliplatin to sorafenib did not result in significant improvement in TTP.

749P - Prognostic and predictive factors from the phase III CELESTIAL trial of cabozantinib (C) versus placebo (P) in previously treated advanced hepatocellular carcinoma (aHCC)

749P - Prognostic and predictive factors from the phase III CELESTIAL trial of cabozantinib (C) versus placebo (P) in previously treated advanced hepatocellular carcinoma (aHCC)

Abernethy Malformation – a Rare but Important Diagnosis Prior to Liver-Directed Therapy for Hepatocellular Carcinoma

A 45-year-old man with incidentally discovered, unresectable HCC were treated with TACE to the left hepatic lobe and TARE to the right hepatic lobe. Upon retrospective review, he was found to have a congenital extrahepatic portosystemic shunt with the absence of the portal vein (Abernethy malformation). This case report discusses variant splanchnic and portal anatomy in the setting of rare, congenital portosystemic shunts and evaluates types of liver-directed therapies for HCC in this setting.

Immune checkpoint blockade therapies for HCC: current status and future implications

Hepatoma Research is an open access journal and focuses on all topics related to hepatoma. The following articles are especially welcome: pathogenesis, clinical examination and early diagnosis of hepatoma, complications of hepatoma, and their preventions and treatments, etc.

Ultrasound-Triggered Nanodroplets for Targeted Co-Delivery of Sorafenib/Doxorubicin for Hepatocellular Carcinoma Therapy

The clinical treatment of hepatocellular carcinoma has been hindered due to the drug resistance and heterogeneity of tumor cells. A new therapy strategy combined chemo drugs and molecular-targeted drugs is considered to be promising for conquering these challenges. However, the different pharmacokinetic profiles, hydrophobicity and systemic toxicity of these drugs may still cause serious challenges to the clinical applications of this combination therapy. In this study, smart sorafenib (SF) and doxorubicin (DOX)-loaded nanodroplets (SF/DOX-NDs) were fabricated to solve the above issues. The liquid-to-gas phase transition of SF/DOX-NDs could function as a cavitation nucleus to boost drug release and increase cellular uptake after exposure to therapeutic ultrasound (TUS) irradiation. Additionally, this strategy has a therapeutic effect to induce apoptosis and inhibit the proliferation, migration, and invasion of hepatoma cells. Furthermore, the intense cavitation of SF/DOX-NDs at the tumor site could disrupt microvessels, which is beneficial for tissue-penetrating drug delivery inside tumors. Consequently, tumor angiogenesis was reduced, and tumor growth was remarkably inhibited by SF/DOX-NDs. These results indicated that combination therapy using SF/DOX-NDs may offer a promising approach to achieve effective HCC therapy with low side effects.

Targeting p53/TRAIL/caspase-8 signaling by adiponectin reverses thioacetamide-induced hepatocellular carcinoma in rats

Given the enormous impact of HCC on the patients' quality of life and healthcare economics, the current study was conducted to investigate the potential ability of adiponectin to reverse established HCC and to investigate the underlying mechanisms which control the chemotherapeutic and hepatoprotective effects. HCC was induced in Male Sprague Dawely rats by I.P. injection of thioacetamide(200 mg/kg) 3 times/week for 14 weeks.HCC development was confirmed by histopathological examination and assessment of serum levels of α-fetoprotein (AFP). Adiponectin was administered (5 μg/kg, I.P.) starting from week 13 of the experiment and for further 4 weeks. Adiponectinadministration revealed a significant antitumor activity with significant improvement in liver functions and oxidative status. Nevertheless, pathological features as cirrhosis, dysplastic changes, and tumoral nodules were significantly attenuated with significant enhancement in hepatic caspase-3 immunostaining. Mechanistically, adiponectin administration was associated with significant restoration of p53 activity; which increased by 133%, with a reduction in HCC-induced expression of-JNK which decreased by 53%as well as a significant enhancement of hepatic TRAIL and caspase-8 activities which increased by 27% and 20% respectively. In conclusion; Adiponectin can be proposed as a promising therapy for HCC. Adiponectin's tumoricidal activity can be partially mediated by blocking HCC-induced reduction in p53 expression as well as reactivation of TRAIL signaling and induction of apoptotic pathway providing more protection for the body against the tumor.

Abstract 1255: Identification of mutational landscape predicting efficacy of immune checkpoint blockades and recurrent mutations related to high tumor mutational burden in hepatocellular carcinoma by next generation sequencing

Abstract Introduction: HCC is an aggressive and genetic heterogeneous disease. Several disrupted signaling pathways have been identified, though actionable targets are limited. The majority of systemic chemotherapy and targeted therapy (tyrosine kinase inhibitors (TKIs) or monoclonal antibodies) have demonstrated minimal to no clinical activity. Immunotherapy has emerged as a potentially transformative strategy with attractive and long-lasting responses in HCC. However, the clinical efficacy of immune check point blockades (ICB) is limited to a select subset of patients and is hampered by drug resistance. Methods: In this study, we focused on tumor cell intrinsic factors and conducted a hybridization-capture methodology and targeted 1 Mb of genomic coding sequence ( Gene Plus1021 Panel). Analysis of 81 HCC tumors and matching plasma normal samples was performed to characterize the landscape of somatic mutations especially those related to the sensitivity, resistance and hyper progression of ICB therapy in HCC. For genes identified in our study significantly correlated with tumor mutational burden (TMB), We further did the verification in The Cancer Genome Atlas (TCGA)-LIHC. 363 HCC tumor samples were included in the cohort and the data was downloaded from cBioPortal website (http://www.cbioportal.org/). Results: We analyzed 81 HCC tumor samples accepted in Peking University International Hospital from January 2015 to Jun 2018 who did not receive ICB therapy at the time of taking specimen. The top quartile (7 muts/Mb) of TMB distribution was used as the cutoff value to define high tumor mutational burden (TMB-H). There were 26 cases (32.10%) with high TMB. Among all the 81 samples analyzed we detected no mismatch repair deficiency (dMMR), but identified five gene mutations having a significant correlation with high TMB including TP53, CTNNB1, ARID1A, MLL and NCOR1, p=0.0439, 0.0196, 0.0023, 0.0247 and 0.0076, retrospectively. We further did the verification in The Cancer Genome Atlas (TCGA)-LIHC. Gene mutations of TP53, CTNNB1, and MLL were proved to be highly associated with TMB-H status, p=0.0009, 0.0016 and 0.0013, retrospectively. Moreover, gene mutations of ARID1A, TP53 and MLL were proved to implicate poor overall survival. We detected 2 mutations (2.47%) in POLE, 2 mutations (2.47%) in PTEN, 1 mutation (1.23%) in DNMT3A, and 1 sample (1.23%) with high microsatellite instability (MSI-H). TMB value for the only one sample in MSI-H status was 9 muts/Mb (TMB-H). Instead of dMMR, one TP53 mutation and one ARID1A mutation were detected in this sample. Conclusions: TMB-high and crucial driver gene mutations associated with high mutation load should be evaluated as potential predictive biomarkers in datasets of HCC patients treated with ICB therapy. Note: This abstract was not presented at the meeting. Citation Format: Li Li, Zhaohong Wen, Michael J. Overman, Xiaosong Rao, Yuting Yi, Yanfang Guan, Jun Liang. Identification of mutational landscape predicting efficacy of immune checkpoint blockades and recurrent mutations related to high tumor mutational burden in hepatocellular carcinoma by next generation sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1255.

Abstract 1940: Comparison of anti-hepatocellular carcinoma efficacy between regorafenib and sorafenib using multimodality molecular imaging: A preclinical study

Abstract Purpose: Sorafenib has been used as a targeted therapy for HCC for more than a decade, and regorafenib has recently been approved for HCC treatment and shown to prolong survival for advanced HCC patients after treatment failure with sorafenib. However, there has been no systematic study to directly compare the therapeutic effects of regorafenib and sorafenib against HCC. In this study, we systematically compared the therapeutic effects of sorafenib and regorafenib against HCC in vitro and in vivo using multimodality molecular imaging. Experimental Design: we systemically investigated and compared the anti-tumorigenic and anti-angiogenic efficacy of regorafenib and sorafenib in vitro and in vivo using multi-modality molecular imaging as bioluminescence imaging (BLI), bioluminescence tomography (BLT), fluorescence molecular imaging (FMI), and computer tomography angiography (CTA) etc. Moreover, the safety and side effects of two drugs were simultaneously systemically evaluated. Results: The results showed that compared with sorafenib treatment, regorafenib exerted stronger antitumor and antiangiogenic effects and significantly increased the survival rate of HCC model mice. Although both drugs caused side effects, their severity was usually higher with sorafenib, except that regorafenib caused hypertension, which was not observed with sorafenib. Conclusions: The study suggests that multimodality molecular imaging can help sensitively evaluate the drug treatment efficacy against HCC before tumor anatomical changes occur and also helps understand the underlying antitumor mechanism of a drug at the molecular and cellular levels. Our data may provide an experimental basis for clinical application of HCC targeted treatment with regorafenib and sorafenib. Citation Format: Yang Du, Jie Tian. Comparison of anti-hepatocellular carcinoma efficacy between regorafenib and sorafenib using multimodality molecular imaging: A preclinical study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1940.