Multikinase Inhibitor Sorafenib Research Articles

Evaluation of Serum voltage gated calcium channel α2δ1 as a novel Marker for diagnosis of Hepatocellular Carcinoma in Cirrhotic Egyptian Patient

Abstract Background Hepatocellular carcinoma (HCC) is the most common primary liver tumor and represents the third-leading cause of cancer-related death in the world. The incidence of HCC continues to increase worldwide, with a unique geographic, age, and sex distribution. The most important risk factor associated with HCC is liver cirrhosis, with the majority of cases caused by chronic infection with hepatitis B (HBV) and C (HCV) viruses and alcohol abuse, although nonalcoholic fatty liver disease is emerging as an increasingly important cause. Primary prevention in the form of HBV vaccination has led to a significant decrease in HBV-related HCC, and initiation of antiviral therapy appears to reduce the incidence of HCC in patients with chronic HBV or HCV infection. Additionally, the use of ultrasonography enables the early detection of small liver tumors and forms the backbone of recommended surveillance programs for patients at high risk for the development of HCC. Cross-sectional imaging studies, including computed tomography and magnetic resonance imaging, represent further noninvasive techniques that are increasingly employed to diagnose HCC in patients with cirrhosis. The mainstay of potentially curative therapy includes surgery – either resection or liver transplantation. However, most patients are ineligible for surgery, because of either advanced disease or underlying liver dysfunction, and are managed with locoregional and/or systemic therapies. Randomized controlled trials have demonstrated a survival benefit with both local therapies, either ablation or embolization, and systemic therapy in the form of the multikinase inhibitor sorafenib. Despite this, median survival remains poor and recurrence rates significant. Further advances in our understanding of the molecular pathogenesis of HCC hold promise in improving the diagnosis and treatment of this highly lethal cancer. Objectives Evaluation of Serum voltage gated calcium channel α2δ1 as a novel Marker for diagnosis of Hepatocellular Carcinoma in Cirrhotic Egyptian Patients. Patients and Methods This study had been carried out on 90 subjects, age range 21-73 year selected from Internal medicine and Hepatology outpatient clinics and inpatient wards at Ain shams university hospitals. Subjects were divided as follow: Group A(Case): 40 patients with liver cirrhosis without Hepatocellular carcinoma and group B (Control): 40 patients with liver cirrhosis and Hepatocellular carcinoma and group C: 10 normal population for detecting normal value of the marker with exclusion criteria including age < 18 years old and Patients diagnosed with malignancy other than HCC. Results The study subjects are classified into three groups: Group A cirrhotic patients without HCC, Group B cirrhotic patients with HCC and Group C normal individual subjects. Conclusion Serum voltage gated calcium channel levels were significantly higher in patients with HCC and mildly elevated in patients with liver cirrhosis compared to the control group. Thus it can be used as a tumor marker for HCC.

How Immunotherapy Has Changed the Continuum of Care in Hepatocellular Carcinoma.

Simple SummaryHCC is a very aggressive disease and patients diagnosed in an advanced/metastatic setting obtain poor survival outcomes with standard treatments. In recent years, the introduction of immunotherapy strategies, such as immune checkpoint inhibitors as single agents and in combination with already approved local and systemic treatments, has strongly changed the therapeutic landscape of HCC. Soon, the discovery of novel potential immune targets, together with the understanding of potential biomarkers of resistance, will help to better define novel treatment opportunities for patients with HCC.Hepatocellular carcinoma (HCC) is one of the leading causes of death worldwide. The use of local treatment, such as surgical resection, liver transplant, and local ablation, has improved the survival of patients with HCC detected at an early stage. Until recently, the treatment of patients with metastatic disease was limited to the use of the multikinase inhibitor (MKI) sorafenib with a marginal effect on survival outcome. New target approaches, such as the oral MKI lenvatinib in first-line treatment and regorafenib, ramucirumab, and cabozantinib in later lines of therapy, have demonstrated efficacy in patients with preserved liver function (Child–Pugh class A) and good performance status. On the other hand, the implementation of immune checkpoint inhibitors directed against PD-1 (nivolumab and pembrolizumab), PD-L1 (atezolizumab), and anti-CTLA4 (ipilimumab) in the management of advanced HCC has strongly changed the continuum of care of HCC. Future research should include the evaluation of molecular biomarkers that can help patient selection and provide new insight on potential combined approaches. In this review, we provide an overview of the clinical evidence of the use of immune checkpoint inhibitors in HCC, and discuss how immunotherapy has been implemented into the continuum of HCC care.

The development of multi-kinase inhibitors as pancreatic cancer therapeutics

Pancreatic cancer is an almost incurable malignancy whose incidence has increased over the past 30 years. Instead of pursuing the development of modalities utilizing 'traditional' cytotoxic chemotherapeutic agents, we have explored the possibilities of developing novel multi-kinase inhibitor drug combinations to kill this tumor type. Several approaches using the multi-kinase inhibitors sorafenib, regorafenib, and neratinib have been safely translated from the bench to the bedside, with objective anti-tumor responses. This review will discuss our prior preclinical and clinical studies and discuss future clinical opportunities in this disease.

Targeting Na+ /K+ -ATPase by berbamine and ouabain synergizes with sorafenib to inhibit hepatocellular carcinoma.

The multikinase inhibitor sorafenib is a first-line drug for advanced hepatocellular carcinoma. The response to sorafenib varies among hepatocellular carcinoma patients and many of the responders suffer from reduced sensitivity after long-term treatment. This study aims to explore a novel strategy to potentiate or maximize the anti-hepatocellular carcinoma effects of sorafenib. We used hepatocellular carcinoma cell lines, western blotting, various antagonists, siRNA and tumour xenografts mouse model to determine the anti- hepatocellular carcinoma effects of sorafenib in combination with berbamine or other Na+ /K+ -ATPase ligands. Berbamine and the cardiotonic steroid, ouabain, synergize with sorafenib to inhibit hepatocellular carcinoma cells growth. Mechanistically, berbamine induces Src phosphorylation in Na+ /K+ -ATPase-dependent manner, leading to the activation of p38MAPK and EGFR-ERK pathways. The Na+ /K+ -ATPase ligand ouabain also induces Src, EGFR, type I insulin-like growth factor receptor, ERK1/2 and p38MAPK phosphorylation in hepatocellular carcinoma cells. Treatment of hepatocellular carcinoma cells with Src or EGFR inhibitor inhibits the induction of ERK1/2 phosphorylation by berbamine. Moreover, sorafenib inhibits the induction of Src, p38MAPK, EGFR and ERK1/2 phosphorylation by berbamine and ouabain. Importantly, combination of sorafenib with berbamine or ouabain synergistically inhibits both sorafenib-naïve and sorafenib-resistant hepatocellular carcinoma cells growth. Co-treatment of hepatocellular carcinoma cells with berbamine and sorafenib significantly induces cell death and significantly inhibits hepatocellular carcinoma xenografts growth in vivo. Berbamine or other Na+ /K+ -ATPase ligands have a potential for improving sorafenib responsiveness in hepatocellular carcinoma. Targeting Na+ /K+ -ATPase represents a novel strategy to potentiate the anti- hepatocellular carcinoma effects of sorafenib.

Longitudinal Circulating Levels of miR-23b-3p, miR-126-3p and lncRNA GAS5 in HCC Patients Treated with Sorafenib.

Human hepatocellular carcinoma (HCC) is the most frequent primary tumor of the liver and the third cause of cancer-related deaths. The multikinase inhibitor sorafenib is a systemic drug for unresectable HCC. The identification of molecular biomarkers for the early diagnosis of HCC and responsiveness to treatment are needed. In this work, we performed an exploratory study to investigate the longitudinal levels of cell-free long ncRNA GAS5 and microRNAs miR-126-3p and -23b-3p in a cohort of 7 patients during the period of treatment with sorafenib. We used qPCR to measure the amounts of GAS5 and miR-126-3p and droplet digital PCR (ddPCR) to measure the levels of miR-23b-3p. Patients treated with sorafenib displayed variable levels of GAS5, miR-126-3p and miR-23b-3p at different time-points of follow-up. miR-23b-3p was further measured by ddPCR in 37 healthy individuals and 25 untreated HCC patients. The amount of miR-23b-3p in the plasma of untreated HCC patients was significantly downregulated if compared to healthy individuals. The ROC curve analysis underlined its diagnostic relevance. In conclusion, our results highlight a potential clinical significance of circulating miR-23b-3p and an exploratory observation on the longitudinal plasmatic levels of GAS5, miR-126-3p and miR-23b-3p during sorafenib treatment.

USP29-mediated HIF1\u03b1 stabilization is associated with Sorafenib resistance of hepatocellular carcinoma cells by upregulating glycolysis

Understanding the mechanisms underlying evasive resistance in cancer is an unmet medical need to improve the efficacy of current therapies. In hepatocellular carcinoma (HCC), aberrant expression of hypoxia-inducible factor 1 α (HIF1α) and increased aerobic glycolysis metabolism are drivers of resistance to therapy with the multi-kinase inhibitor Sorafenib. However, it has remained unknown how HIF1α is activated and how its activity and the subsequent induction of aerobic glycolysis promote Sorafenib resistance in HCC. Here, we report the ubiquitin-specific peptidase USP29 as a new regulator of HIF1α and of aerobic glycolysis during the development of Sorafenib resistance in HCC. In particular, we identified USP29 as a critical deubiquitylase (DUB) of HIF1α, which directly deubiquitylates and stabilizes HIF1α and, thus, promotes its transcriptional activity. Among the transcriptional targets of HIF1α is the gene encoding hexokinase 2 (HK2), a key enzyme of the glycolytic pathway. The absence of USP29, and thus of HIF1α transcriptional activity, reduces the levels of aerobic glycolysis and restores sensitivity to Sorafenib in Sorafenib-resistant HCC cells in vitro and in xenograft transplantation mouse models in vivo. Notably, the absence of USP29 and high HK2 expression levels correlate with the response of HCC patients to Sorafenib therapy. Together, the data demonstrate that, as a DUB of HIF1α, USP29 promotes Sorafenib resistance in HCC cells, in parts by upregulating glycolysis, thereby opening new avenues for therapeutically targeting Sorafenib-resistant HCC in patients.

Abstract 1040: Imipridones exhibit synergy with sorafenib, HDAC inhibition, PARP inhibition, and proteasome inhibition in liver cancer cell lines

Abstract Liver cancer is a significant cause of cancer-related death worldwide. We previously showed that the imipridone class of small molecule therapeutics is active against hepatocellular malignancies. ONC201, the first imipridone to reach clinical trials, antagonizes the G protein-coupled receptor DRD2 and is an agonist of mitochondrial caseinolytic protease ClpP. ONC206 also antagonizes DRD2 and is a ClpP agonist. ONC212 is an agonist of both the orphan G protein-coupled receptor GPR132 and ClpP. We investigated the efficacy of ONC201, ONC206, and ONC212 in combination with histone deacetylase inhibition (HDACi), poly ADP ribose polymerase inhibition (PARPi), proteasome inhibition, and current standard of care multi-kinase inhibitor sorafenib. Liver cancer cell lines Hep3B and HepG2 were treated with ONC201, ONC206, and ONC212 to determine dose-response effect. Both cell lines were also treated with each imipridone in combination with sorafenib. Combination treatment effect was also tested between ONC201 and the HDACi vorinostat, PARPi nariparib, and the proteasome inhibitor marizomib. Cell viability was measured with CellTiter-Glo. Synergy was quantified using the combination index (CI). Protein expression was assessed using Western blot. As has been previously reported, both HepG2 and Hep3B cell lines were sensitive to ONC201 (Hep3B IC50 = 2.29μM; HepG2 IC50 = 2.69μM), ONC206 (Hep3B IC50 = 0.11μM; HepG2 IC50 = 0.15μM), and ONC212 (Hep3B IC50 = 0.07μM; HepG2 IC50 = 0.05μM) administered as single-agent therapy with ONC212 demonstrating the greatest potency. In combination with sorafenib, all three imipridones demonstrated synergy in both cell lines. ONC201 and ONC206 exhibited stronger synergy with CI < 0.3 at multiple dose combinations. ONC201 was also found to exert a synergistic reduction in cell viability when Hep3B and HepG2 cells were treated with vorinostat, nariparib, and marizomib. These results suggest that the imipridone family of small molecules is a novel therapy for liver cancer with efficacy as a single agent and in combination with existing targeted agents. Future studies will clarify the mechanisms of synergy and expand the findings into small animal models. Citation Format: Joshua N. Honeyman, Wen-I Chang, Varun V. Prabhu, Joshua E. Allen, Lanlan Zhou, Wafik S. El-Deiry. Imipridones exhibit synergy with sorafenib, HDAC inhibition, PARP inhibition, and proteasome inhibition in liver cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1040.

Identification of Effective Combinations of Targeted Drugs for DNMT3A and NPM1 Mutated Acute Myeloid Leukemia

Abstract Introduction: As the molecular heterogeneity underlying cancer becomes better understood, the capacity to define actionable targeted therapeutic strategies for patients appears essential to improving outcomes. These challenges are exemplified in patients with acute myeloid leukemia (AML), where a broad spectrum of driver mutations, emergence of genetically heterogeneous subclones, rescue signals in the microenvironment, and tumor-intrinsic feedback pathways frequently result in a lack of durable responses and rapid development of resistance to many single-agent targeted therapies. To identify biomarker-driven effective combination strategies for patients with AML, we built upon our previous ex vivo profiling of targeted drug combinations in primary patient specimens through integrated analysis of an expanded cohort of 133 AML patients. Methods: Freshly isolated primary mononuclear cells from patients were cultured in the presence of a panel of 48 drug combinations in fixed molar dose series encompassing different classes of targeted small-molecule inhibitors already approved by the FDA or in clinical development. For comparison, cells were also tested against graded concentrations of each single-agent, and sensitivity was assessed by MTS-based viability assay. IC50 and AUC values were derived using a probit regression model. Efficacy of each combination relative to its respective single-agents was calculated as a Combination Ratio (CR) value, defined as the combination IC50 or AUC divided by the lowest single-agent IC50 or AUC value, where a CR value Results: Analysis of our discovery cohort of 58 AML patients revealed several associations between molecular features and combination sensitivity. An intriguing finding was the significantly enhanced efficacy of combinations involving the bromodomain inhibitor, JQ1, in patients with mutations in NPM1 or DNMT3A. Specifically, the combination of JQ1 with the multi-kinase inhibitor sorafenib demonstrated superior efficacy compared to each inhibitor alone in patients with NPM1 mutations (median IC50 CR: 0.437; p=0.010). JQ1 paired with the CDK4/6 inhibitor, palbociclib, demonstrated superior efficacy compared with single-agents for patients with DNMT3A mutations (median IC50 CR: 0.119; p=0.017). These associations between the presence of NPM1 or DNTM3A mutations and increased JQ1-inclusive combination efficacy were also validated using our expanded AML cohort of 133 patients. For patients with NPM1 mutations, one-way ANOVA based comparison of AUC values for JQ1, sorafenib, and the combination showed JQ1 as the more effective of the two single agents, with the combination significantly reducing AUC beyond either drug alone (p Conclusions: Among the observed patterns of ex vivo drug combination efficacy associated with select, actionable diagnostic and genetic subsets in our study, our data suggest that AML patients harboring NPM1 or DNMT3A mutations demonstrate moderate sensitivity to the bromodomain inhibitor JQ1 and their viability is further inhibited by combinations of JQ1 with sorafenib or palbociclib, respectively. More broadly, these findings warrant clinical evaluation and highlight the utility of integrating drug sensitivity data with genomic information to identifying novel treatment strategies for improving disease control and patient outcomes. Disclosures Traer: ImmunoGen: Consultancy; Tolero: Consultancy; Notable Labs: Equity Ownership. Druker: Henry Stewart Talks: Patents & Royalties; MED-C: Membership on an entity's Board of Directors or advisory committees; MolecularMD: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Beta Cat: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; McGraw Hill: Patents & Royalties; Novartis: Research Funding; Bristol-Myers Squibb: Research Funding; Aptose Biosciences: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; The Leukemia & Lymphoma Society: Other: Joint Steering Committee of AML Master Protocol, Research Funding; Roche TCRC: Consultancy, Membership on an entity's Board of Directors or advisory committees; Third Coast Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Cylene: Consultancy, Membership on an entity's Board of Directors or advisory committees; ARIAD: Research Funding; Oregon Health & Science University: Patents & Royalties: #843 Mutated ABL Kinase Domains (licensed to various companies); #0996 Detection of Gleevec Resistant Mutations (licensed to various companies, including MolecularMD); #0606 Treatment of Gastrointestinal Stromal Tumors (exclusively licensed to Novartis); GRAIL: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Monojul: Consultancy; Millipore: Patents & Royalties: Royalties from Dana-Farber Cancer Institute, which has an exclusive commercial license with Millipore for monoclonal antiphosphotyrosine antibody 4G10, which I developed while employed at DFCI.; Baxalta US Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Tyner: Gilead: Research Funding; Incyte Corporation: Research Funding; Syros: Research Funding; Seattle Genetics: Research Funding; Leap Oncology: Consultancy; Aptose Biosciences: Research Funding; Array Biopharma: Research Funding; Constellation Pharmaceuticals: Research Funding; Agios Pharmaceuticals: Research Funding; Genentech: Research Funding; Takeda Pharmaceutical Company: Research Funding; Janssen Pharmaceutica: Research Funding; AstraZeneca: Research Funding.

Liver Field during Immunotherapy of Hepatocellular Carcinoma: Some Like It Hot

Liver Field during Immunotherapy of Hepatocellular Carcinoma: Some Like It Hot

Hepatocellular carcinoma with extrahepatic adrenal metastasis: an atypical case report

<p class="abstract">Hepatocellular carcinoma with extrahepatic metastasis are a threat to public health worldwide. Lung, bones and abdominal lymph nodes are the major sites of metastasis from liver primary, adrenal metastasis being a less common site. Here we present an old male presented with upper abdominal pain diagnosed as advanced, unresectable hepatocellular carcinoma with right adrenal metastasis. Patient was treated with multi-kinase inhibitor sorafenib and outcome was acceptable with good patient compliance.</p>

Retraction Note to: Differential modulatory effects of GSK-3b and HDM2 on sorafenib-induced AIF nuclear translocation (programmed necrosis) in melanoma

GSK-3β phosphorylates numerous substrates that govern cell survival. It phosphorylates p53, for example, and induces its nuclear export, HDM2-dependent ubiquitination, and proteasomal degradation. GSK-3β can either enhance or inhibit programmed cell death, depending on the nature of the pro-apoptotic stimulus. We previously showed that the multikinase inhibitor sorafenib activated GSK-3β and that this activation attenuated the cytotoxic effects of the drug in various BRAF-mutant melanoma cell lines. In this report, we describe the results of studies exploring the effects of GSK-3β on the cytotoxicity and antitumor activity of sorafenib combined with the HDM2 antagonist MI-319. MI-319 alone increased p53 levels and p53-dependent gene expression in melanoma cells but did not induce programmed cell death. Its cytotoxicity, however, was augmented in some melanoma cell lines by the addition of sorafenib. In responsive cell lines, the MI-319/sorafenib combination induced the disappearance of p53 from the nucleus, the down modulation of Bcl-2 and Bcl-xL, the translocation of p53 to the mitochondria and that of AIF to the nuclei. These events were all GSK-3β-dependent in that they were blocked with a GSK-3β shRNA and facilitated in otherwise unresponsive melanoma cell lines by the introduction of a constitutively active form of the kinase (GSK-3β-S9A). These modulatory effects of GSK-3β on the activities of the sorafenib/MI-319 combination were the exact reverse of its effects on the activities of sorafenib alone, which induced the down modulation of Bcl-2 and Bcl-xL and the nuclear translocation of AIF only in cells in which GSK-3β activity was either down modulated or constitutively low. In A375 xenografts, the antitumor effects of sorafenib and MI-319 were additive and associated with the down modulation of Bcl-2 and Bcl-xL, the nuclear translocation of AIF, and increased suppression of tumor angiogenesis. Our data demonstrate a complex partnership between GSK-3β and HDM2 in the regulation of p53 function in the nucleus and mitochondria. The data suggest that the ability of sorafenib to activate GSK-3β and alter the intracellular distribution of p53 may be exploitable as an adjunct to agents that prevent the HDM2-dependent degradation of p53 in the treatment of melanoma.

Anti-miR-518d-5p overcomes liver tumor cell death resistance through mitochondrial activity

Dysregulation of miRNAs is a hallmark of cancer, modulating oncogenes, tumor suppressors, and drug responsiveness. The multi-kinase inhibitor sorafenib is one of the first-line drugs for advanced hepatocellular carcinoma (HCC), although the outcome for treated patients is heterogeneous. The identification of predictive biomarkers and targets of sorafenib efficacy are sorely needed. Thus, selected top upregulated miRNAs from the C19MC cluster were analyzed in different hepatoma cell lines compared to immortalized liver human cells, THLE-2 as control. MiR-518d-5p showed the most consistent upregulation among them. Thus, miR-518d-5p was measured in liver tumor/non-tumor samples of two distinct cohorts of HCC patients (n = 16 and n = 20, respectively). Circulating miR-518d-5p was measured in an independent cohort of HCC patients receiving sorafenib treatment (n = 100), where miR-518d-5p was analyzed in relation to treatment duration and patient’s overall survival. In vitro and in vivo studies were performed in human hepatoma BCLC3 and Huh7 cells to analyze the effect of miR-518d-5p inhibition/overexpression during the response to sorafenib. Compared with healthy individuals, miR-518d-5p levels were higher in hepatic and serum samples from HCC patients (n = 16) and in an additional cohort of tumor/non-tumor paired samples (n = 20). MiR-518d-5p, through the inhibition of c-Jun and its mitochondrial target PUMA, desensitized human hepatoma cells and mouse xenograft to sorafenib-induced apoptosis. Finally, serum miR-518d-5p was assessed in 100 patients with HCC of different etiologies and BCLC-stage treated with sorafenib. In BCLC-C patients, higher serum miR-518d-5p at diagnosis was associated with shorter sorafenib treatment duration and survival. Hence, hepatic miR-518d-5p modulates sorafenib resistance in HCC through inhibition of c-Jun/PUMA-induced apoptosis. Circulating miR-518d-5p emerges as a potential lack of response biomarker to sorafenib in BCLC-C HCC patients.

A phase 1 study of neoadjuvant chemotherapy followed by concurrent chemoradiation with gemcitabine, sorafenib, and vorinostat in pancreatic cancer.

e16268 Background: The multi-kinase inhibitor sorafenib (S) and HDAC inhibitor vorinostat (V) demonstrated synergism against preclinincal pancreatic cancer (PaCa) models. The combination of S & V also potently radiosensitized pancreatic cancer cells and enhanced the activity of gemcitabine (G). This led to a phase 1 trial to determine the doses and schedule appropriate for phase 2 study of S & V with weekly G and intensity modulated radiotherapy (IMRT) as neoadjuvant treatment of PaCa following chemotherapy. Methods: Using a 3+3 dose-escalation design, adult patients with resectable, borderline resectable, unresectable, and lymph node positive PaCa were enrolled to 6 dose levels. Enrolled patients had completed at least 8w of neoadjuvant chemotherapy prior to IMRT. The schedule of administration was weekly 200mg/m2 G weekly during IMRT, S & V were dosed either 3x or 5x weekly during IMRT. Primary endpoint was to identify the dose and schedule for S & V with G based chemoradiation. Key secondary endpoints included antitumor activity, R0 resection rate, OS. Correlative studies to evaluate a variety of biomarkers and Nanostring expression analysis on pre- and post-therapy tumor specimens were also performed. Results: 22 patients were enrolled and 21 treated at 6 dose levels. Due to thrombocytopenia limiting drug exposure, the trial was modified to reduce G to 200mg/m2/wk and S & V to 3 d/wk instead of 5 d/wk. 13 patients were eligible for surgery, and 9 had R0 resections. Conclusions: Our findings indicate that the study regimen was well tolerated, typical toxicities of S (hand foot syndrome) were not observed with intermittent dosing. Uncomplicated cytopenias limited drug exposure, which was improved with intermittent S&V dosing. The RP2D of the combination is S (400mg po BID 3d/wk), V (200mg po qd 3d/wk), G 200mg/m2 IV weekly, with IMRT (50.4 Gy over 28 fractions, 5d/wk). Antitumor activity was observed across dose levels, with an encouraging R0 resection rate. These results warrant further investigation of combining S and V with G and IMRT as neoadjuvant treatment of PaCa following chemotherapy. Analyses of correlative studies and OS are underway. Clinical trial information: NCT02349867. [Table: see text]

Encorafenib and binimetinib with or without nivolumab in treating patients with metastatic radioiodine refractory BRAF V600 mutant thyroid cancer.

TPS6085 Background: Differentiated thyroid cancer is the most common endocrine malignancy and has a high frequency of actionable molecular aberrations including BRAF V600E mutations (45%), RET fusions (10%), and NTRK fusions ( < 2%). FDA approved systemic therapies for metastatic radioiodine refractory differentiated thyroid cancer (RR-DTC) include multikinase inhibitors (Lenvatinib and sorafenib), NTRK inhibitors (larotrectinib and entrectinib for NTRK fusion+ cancers), and RET inhibitors (selpercatinib and pralsetinib for RET fusion+ cancers). Previous phase II clinical trials showed clinical efficacy with first and second generation BRAF inhibitors in patients with BRAF mutant RR-DTC. BRAF inhibitors have not yet been FDA approved for treatment of BRAF mutant RR-DTC. Effective therapeutic options for patients with BRAF mutant RR-DTC remains an important unmet clinical need. BRAF mutant thyroid cancers often show elevated expression of PD-L1. Additionally, BRAF inhibition results in increased expression of PD-L1 in thyroid cancer. This clinical trial seeks to evaluate the safety and efficacy of encorafenib plus binimetinib with or without nivolumab in patients with BRAF mutant metastatic RR-DTC. Encorafenib and binimetinib are highly selective and potent oral inhibitors of BRAF and MEK, respectively. Nivolumab is a potent inhibitor of the immune co-inhibitory receptor programmed cell death protein 1 (PD-1). Methods: This is a phase II, single institution, open-label, randomized clinical trial evaluating the combinations of (Arm 1) encorafenib 450 mg/day + binimetinib 45 mg twice daily and (Arm 2) encorafenib 450 mg/day + binimetinib 45 mg twice daily + nivolumab 480 mg I.V. every 4 weeks in patients with metastatic BRAF mutant RR-DTC. The trial will enroll 20 patients in each arm and treatment will be given in 28 day cycles for up to 2 years. Eligible patients must have metastatic/unresectable BRAF mutant RR-DTC, an ECOG performance status of 0-1 and adequate bone marrow, liver and kidney function. Patients with CNS metastases are included if the metastases have been treated and remained stable or are asymptomatic and ≤10 mm in diameter. Patients may be systemic therapy naïve or have previously been treated with multikinase inhibitors. Prior therapy with BRAF, MEK or immune checkpoint inhibitors is exclusionary. The primary endpoint is confirmed objective response rate (ORR) determined by RECIST v1.1 with restaging imaging every 12 weeks. Secondary endpoints include progression free survival, overall survival, and safety/tolerability (CTCAE v5.0). Arms 1 and 2 will be evaluated independently and are not powered for direct comparison. The trial design includes continuous toxicity monitoring with a Pocock-type stopping boundary. This clinical trial is in progress and 3 patients have been enrolled. Clinical trial information: NCT04061980.

Desmoid-type fibromatosis: toward a holistic management.

Desmoid-type fibromatosis, a rare locally aggressive fibroblastic proliferation, is a treatment challenge. This review aimed to explore recent data about the management of desmoid-type fibromatosis. New data underline the role of kinases and ɣ-secretase in stimulating cell proliferation and invasiveness in desmoid-type fibromatosis. This explains the proven activity of multikinase inhibitors (sorafenib or pazopanib) in the management of desmoid-type fibromatosis or the emerging role of a ɣ-secretase inhibitor. An international guideline for management was recently published, and this guideline take into account patient point of view. Lastly, recent studies highlight the multidimensional burden of desmoid-type fibromatosis, particularly health-related quality of life (HRQoL). Active surveillance with planned MRI is the first-line management in desmoid-type fibromatosis. A site-specific and stepwise approach should be considered for progressive desmoid-type fibromatosis. Further, a risk-benefit analysis that considers the side effects and long-term sequelae should be conducted before deciding to start any treatment. A less aggressive approach should be considered. Multikinase inhibitors are effective, but their tolerability and side effects should be discussed with the patients. The symptoms and HRQoL should be integrated in decision-making. Desmoid-type fibromatosis patients should be offered support to address their needs supportive care.

Histone deacetylase inhibitor resminostat in combination with sorafenib counteracts platelet-mediated pro-tumoral effects in hepatocellular carcinoma

In hepatocellular carcinoma (HCC), blood platelets have been linked to tumor growth, epithelial-to-mesenchymal transition (EMT), extrahepatic metastasis and a limited therapeutic response to the multikinase inhibitor (MKi) sorafenib, the standard of care in advanced HCC for the last decade. Recent clinical data indicated an improved overall survival for sorafenib in combination with the HDAC inhibitor resminostat in a platelet count dependent manner. Here, the impact of platelets on the sorafenib and resminostat drug effects in HCC cells was explored. In contrast to sorafenib, resminostat triggered an anti-proliferative response in HCC cell lines independent of platelets. As previously described, platelets induced invasive capabilities of HCC cells, a prerequisite for extravasation and metastasis. Importantly, the resminostat/sorafenib drug combination, but not the individual drugs, effectively blocked platelet-induced HCC cell invasion. Exploration of the molecular mechanism revealed that the combined drug action led to a reduction of platelet-induced CD44 expression and to the deregulation of several other epithelial and mesenchymal genes, suggesting interference with cell invasion via EMT. In addition, the drug combination decreased phosphorylated ERK level, indicating inhibition of the mitogenic signaling pathway MEK/ERK. Taken together, the resminostat plus sorafenib combination counteracts platelet-mediated cancer promoting effects in HCC cells.

Histone Deacetylase Inhibitors in the Treatment of Hepatocellular Carcinoma: Current Evidence and Future Opportunities.

Hepatocellular carcinoma (HCC) remains a major health problem worldwide with a continuous increasing prevalence. Despite the introduction of targeted therapies like the multi-kinase inhibitor sorafenib, treatment outcomes are not encouraging. The prognosis of advanced HCC is still dismal, underlying the need for novel effective treatments. Apart from the various risk factors that predispose to the development of HCC, epigenetic factors also play a functional role in tumor genesis. Histone deacetylases (HDACs) are enzymes that remove acetyl groups from histone lysine residues of proteins, such as the core nucleosome histones, in this way not permitting DNA to loosen from the histone octamer and consequently preventing its transcription. Considering that HDAC activity is reported to be up-regulated in HCC, treatment strategies with HDAC inhibitors (HDACIs) showed some promising results. This review focuses on the use of HDACIs as novel anticancer agents and explains the mechanisms of their therapeutic effects in HCC.

In pursuit of a selective hepatocellular carcinoma therapeutic agent: Novel thalidomide derivatives with antiproliferative, antimigratory and STAT3 inhibitory properties.

Advanced stage liver cancer is predominantly treated with the multi-kinase inhibitor sorafenib; however, this therapeutic agent lacks selectivity in its cytotoxic actions and is associated with poor survival outcomes. Herein we report the design and preparation of several thalidomide derivatives, including a variety of novel thioether-containing forms that are especially rare in the literature. Importantly, two of the derivatives described are potent antiproliferative agents with dose-dependent selectivity for tumorigenic liver progenitor cells (LPC) growth inhibition (up to 36% increase in doubling time at 10μM) over non-tumorigenic cells (no effect at 10μM). Furthermore, these putative anti-liver cancer agents were also found to be potent inhibitors of tumorigenic LPC migration. This report also describes these derivatives' effects on several key signalling pathways in our novel liver cell lines by immunofluorescence and AlphaLISA assays. Aryl thioether derivative 7f significantly reduced STAT3 phosphorylation (23%) and its nuclear localisation (16%) at 10μM in tumorigenic LPCs, implicating the IL-6/JAK/STAT3 axis is central in the mode of action of our derivatives.

New 3-Aryl-2-(2-thienyl)acrylonitriles with High Activity Against Hepatoma Cells.

New 2-(thien-2-yl)-acrylonitriles with putative kinase inhibitory activity were prepared and tested for their antineoplastic efficacy in hepatoma models. Four out of the 14 derivatives were shown to inhibit hepatoma cell proliferation at (sub-)micromolar concentrations with IC50 values below that of the clinically relevant multikinase inhibitor sorafenib, which served as a reference. Colony formation assays as well as primary in vivo examinations of hepatoma tumors grown on the chorioallantoic membrane of fertilized chicken eggs (CAM assay) confirmed the excellent antineoplastic efficacy of the new derivatives. Their mode of action included an induction of apoptotic capsase-3 activity, while no contribution of unspecific cytotoxic effects was observed in LDH-release measurements. Kinase profiling of cancer relevant protein kinases identified the two 3-aryl-2-(thien-2-yl)acrylonitrile derivatives 1b and 1c as (multi-)kinase inhibitors with a preferential activity against the VEGFR-2 tyrosine kinase. Additional bioinformatic analysis of the VEGFR-2 binding modes by docking and molecular dynamics calculations supported the experimental findings and indicated that the hydroxy group of 1c might be crucial for its distinct inhibitory potency against VEGFR-2. Forthcoming studies will further unveil the underlying mode of action of the promising new derivatives as well as their suitability as an urgently needed novel approach in HCC treatment.

Oncopharmacogenomics of Hepatocellular Carcinoma - A Therapy Related Review

Hepatocellular carcinoma (HCC) remains a highly complex disease resistant to commonly used chemotherapy and radiotherapy. As the fifth most common cancer worldwide with the third highest mortality rate and very poorly understood molecular pathways driving hepatocarcinogenesis, new treatment strategies are urgently needed for this devastating disease. The multi kinase inhibitor Sorafenib was the first molecular targeted drug in HCC that led to significant survival benefit in patients with advanced tumors. It is the first drug to be considered standard of care for advanced HCC and supports the importance of molecular therapies in the treatment of this cancer. Analysis of genetic and epigenetic alterations as well as different molecular pathways involved in the development of HCC help to identify potential new druggable targets. A variety of novel compounds are already under preclinical or clinical investigation, and accumulating evidence suggests that combination therapy targeting different pathways will potentiate anti-tumoral effects and will become the future therapeutic approach. In addition, the establishment of a robust molecular classification will pave the way for a more personalized treatment scheme in HCC. In this article a review of the current knowledge of the molecular pathogenesis of HCC and an overview of molecular targeted therapies in the management of HCC are provided.