Hepatocellular carcinoma (HCC) is a particularly lethal form of cancer, yet effective therapeutic options for advanced HCC are limited. The poly(ADP‐ribose) polymerases (PARPs) and histone ...deacetylases (HDACs) are emerging to be among the most promising targets in cancer therapy, and sensitivity to PARP inhibition depends on homologous recombination (HR) deficiency and inhibition of HDAC activity blocks the HR pathway. Here, we tested the hypothesis that cotargeting both enzymatic activities could synergistically inhibit HCC growth and defined the molecular determinants of sensitivity to both enzyme inhibitors. We discovered that HCC cells have differential sensitivity to the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) and PARP inhibitor olaparib, and identified one pair of cell lines, termed SNU‐398 and SNU‐449, with sensitive versus resistant phenotype to both enzyme inhibitors, respectively. Coadministration of SAHA and olaparib synergistically inhibited the growth of SNU‐398 but not SNU‐449 cells, which was associated with increased apoptosis and accumulated unrepaired DNA damage. Multiple lines of evidence demonstrate that the hepatic fibrosis/hepatic stellate cell activation may be an important genetic determinant of cellular sensitivity to both enzymatic inhibitors, and coordinate activation or inactivation of the aryl hydrocarbon receptor (AhR) and cyclic adenosine monophosphate (cAMP)‐mediated signaling pathways are involved in cell response to SAHA and olaparib treatment. Conclusion: These findings suggest that combination therapy with both enzyme inhibitors may be a strategy for therapy of sensitive HCC cells, and identification of these novel molecular determinants may eventually guide the optimal use of PARP and HDAC inhibitors in the clinic. (HEPATOLOGY 2012;55:1840–1851)
Background
Docetaxel is a taxane anticancer drug used in a wide variety of solid tumors. Liposomes are versatile drug carriers that may increase drug solubility, serve as sustained release systems, ...provide protection from drug degradation and toxicities, and help overcome multidrug resistance. This phase I study was conducted to determine the maximum tolerated dose, dose-limiting toxicities (DLTs), pharmacokinetics (PK), and clinical response of liposomal-encapsulated docetaxel (LE-DT) in patients with advanced solid tumor malignancies.
Methods
LE-DT was administered using a standard 3 + 3 dose escalation schema with dose levels of 50, 65, 85, 110, and 132 mg/m
2
IV on a 3-week cycle. Toxicities were assessed using the NCI-CTCAE version 3.0, and response was assessed using RECIST criteria (version 1.0). PK samples were drawn during cycle 1 and analyzed using a non-compartmental analysis.
Results
Twenty-four patients were treated for 1–30 cycles (median = 4). No DLTs were experienced through dose levels of 50, 65, 85, and 110 mg/m
2
. Two out of two patients experienced grade 4 neutropenia at the 132 mg/m
2
dose level. When an additional three patients were treated at the expanded 110 mg/m
2
dose level, two experienced grade 4 neutropenia. The 85 mg/m
2
dose level was reassessed with an expanded group of three additional patients, and only one of three patients experienced grade 4 neutropenia. The protocol was amended to allow G-CSF during cycle 1, and an additional three patients were treated at 110 mg/m
2
with no DLTs experienced. No patient experienced significant neuropathy, even patients treated for 19, 20, and 30 cycles. PK followed a two-compartment elimination pattern; there was no correlation between PK and toxicity. Two patients with thyroid and neuroendocrine cancer had partial responses (PR, 8 %), and one patient with non-small-cell lung cancer had an unconfirmed PR. Eight patients (33 %) had stable disease lasting more than 3 months, for a clinical benefit rate of 41 %.
Conclusion
LE-DT was well tolerated with expected toxicities of neutropenia, anemia, and fatigue, but without neuropathy or edema. Clinical benefit (SD + PR) was observed in 41 % of the patients. The recommended phase II dose of LE-DT is 85 mg/m
2
without G-CSF or 110 mg/m
2
with G-CSF.
Purpose
To determine the antitumor efficacy and tolerability of combination temozolomide (TMZ) and veliparib (ABT-888) in patients with advanced, sorafenib-refractory hepatocellular carcinoma (HCC).
...Methods
This single-arm phase II trial enrolled patients with pathologically confirmed, sorafenib-refractory HCC. All patients received 40 mg ABT-888 PO daily on days 1–7 and 150 mg/m
2
TMZ PO daily on days 1–5 of a 28-day cycle. The primary endpoint was objective response rate (ORR) at 2 months. Secondary endpoints included overall survival (OS), progression-free survival (PFS), and toxicity profile. Tumor response was assessed every 2 cycles using RECIST criteria, and toxicities were assessed using CTCAE v4.03.
Results
We enrolled 16 patients in the first phase of the trial, but the study was discontinued due to a poor ORR; only four patients (25 %) had SD after 2 cycles. Twelve patients (75 %) were taken off study after 2 months of treatment; 10 of these had disease progression. Two patients (13 %) were taken off study due to severe toxicity, and one patient (6 %) died from non-treatment-related liver failure. One patient had SD for 16 months, receiving 11 cycles of therapy before being taken off study. The most common grade 3 treatment-related toxicities included vomiting (
n
= 2), thrombocytopenia (
n
= 2), nausea (
n
= 1), and anemia (
n
= 1). The median PFS was 1.9 months, and median OS was 13.1 months.
Conclusion
The combination of TMZ and ABT-888 is well tolerated in patients with advanced HCC. However, the regimen failed to show survival benefit.
ClinicalTrials.gov Identifier
NCT01205828.
Overactivation of the ErbB protein family, which is comprised of 4 receptor tyrosine kinase members (ErbB1/epidermal growth factor receptor EGFR/HER1, ErbB2/HER2, ErbB3/HER3, and ErbB4/HER4), can ...drive the development and progression of a wide variety of malignancies, including colorectal, head and neck, and certain non-small cell lung cancers (NSCLCs). As a result, agents that target a specific member of the ErbB family have been developed for the treatment of cancer. These agents include the reversible EGFR tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib; the EGFR-targeting monoclonal antibodies cetuximab and panitumumab; and the HER2-targeting monoclonal antibody trastuzumab. Lapatinib is a dual TKI that targets both EGFR and HER2. In addition, TKIs that inhibit multiple members of the ErbB family and also bind their targets irreversibly are under evaluation for the treatment of cancer. Three such compounds have progressed into clinical studies: the EGFR, HER2, and HER4 inhibitors afatinib, dacomitinib, and neratinib. Phase I studies of these agents have shown clinical activity in NSCLC, breast cancer, and other malignancies. Currently, afatinib is approved for EGFR mutation-positive NSCLC and is in development for squamous NSCLC, and dacomitinib is in phase III of clinical development for NSCLC, neratinib is in phase III of clinical development for the treatment of breast cancer, and afatinib is also in phase III development in head and neck cancer. Final results from clinical trials may lead to the potential approval of these agents in a variety of solid tumor malignancies.
Background and Aims
In patients with surgically unresectable early and intermediate stage hepatocellular carcinoma (HCC), only liver transplant (LT) offers a cure. Locoregional therapies, such as ...transarterial chemoembolization (TACE), are widely used to bridge patients waiting for an LT or downstage tumors beyond Milan Criteria (MC). However, there are no formal guidelines on the number of TACE procedures patients should receive. Our study explores the extent to which repeated TACE might offer diminishing gains toward LT.
Approach
We retrospectively analyzed 324 patients with BCLC stage A and B HCC who had received TACE with the intention of disease downstaging or bridging to LT. In addition to baseline demographics, we collected data on LT status, survival, and the number of TACE procedures. Overall survival (OS) rates were estimated using the Kaplan‐Meier method, and correlative studies were calculated using chi‐square or Fisher's exact test.
Results
Out of 324 patients, 126 (39%) received an LT, 32 (25%) of whom had responded favorably to TACE. LT significantly improved OS: HR 0.174 (0.094‐0.322, P < .001). However, the LT rate significantly decreased if patients received ≥3 vs < 3 TACE procedures (21.6% vs 48.6%, P < .001). If their cancer was beyond MC after the third TACE, the LT rate was 3.7%.
Conclusions
An increased number of TACE procedures may have diminishing returns in preparing patients for LT. Our study suggests that alternatives to LT, such as novel systemic therapies, should be considered for patients whose cancers are beyond MC after three TACE procedures.
The ultimate goal in treating patients with early and intermediate stage HCC is liver transplantation; surgery is the only means of a cure in HCC. Locoregional therapies such as transarterial chemoembolization (TACE) has historically played a crucial role in optimizing patients for liver transplantation. However, we call into question whether these patients still derive the greatest benefit from repeated TACE procedures, particularly in the current landscape of new and effective systemic therapy options.
Hepatocellular carcinoma (HCC) is the third leading cause of cancer–related deaths worldwide, mainly because of its poor prognosis. A valid mechanism‐based prognostic biomarker is urgently needed. ...γ‐hydroxy‐1,N2‐propanodeoxyguanosine (γ‐OHPdG) is an endogenously formed mutagenic DNA adduct derived from lipid peroxidation. We examined the relationship of γ‐OHPdG with hepatocarcinogenesis in two animal models and its potential role as a prognostic biomarker for recurrence in HCC patients. Bioassays were conducted in xeroderma pigmentosum group A knockout mice and diethylnitrosamine‐injected mice, both prone to HCC development. γ‐OHPdG levels in the livers of these animals were determined. The effects of antioxidant treatments on γ‐OHPdG and hepatocarcinogenesis were examined. Using two independent sets of HCC specimens from patients, we examined the relationship between γ‐OHPdG and survival or recurrence‐free survival. γ‐OHPdG levels in liver DNA showed an age‐dependent increase and consistently correlated with HCC development in all three animal models. Theaphenon E treatment significantly decreased γ‐OHPdG levels in the liver DNA of xeroderma pigmentosum group A knockout mice and remarkably reduced HCC incidence in these mice to 14% from 100% in the controls. It also effectively inhibited HCC development in the diethylnitrosamine‐injected mice. Using clinical samples from two groups of patients, our study revealed that higher levels of γ‐OHPdG are strongly associated with low survival (P < 0.0001) and low recurrence‐free survival (P = 0.007). Conclusion: These results support γ‐OHPdG as a mechanism‐based, biologically relevant biomarker for predicting the risk of HCC and its recurrence. (Hepatology 2018;67:159‐170).
Circulating tumor cells (CTCs), a population of cancer cells that represent the seeds of metastatic nodules, are a promising model system for studying metastasis. However, the expansion of ...patient-derived CTCs ex vivo is challenging and dependent on the collection of high numbers of CTCs, which are ultra-rare. Here we report the development of a combined CTC and cultured CTC-derived xenograft (CDX) platform for expanding and studying patient-derived CTCs from metastatic colon, lung, and pancreatic cancers. The propagated CTCs yielded a highly aggressive population of cells that could be used to routinely and robustly establish primary tumors and metastatic lesions in CDXs. Differential gene analysis of the resultant CTC models emphasized a role for NF-κB, EMT, and TGFβ signaling as pan-cancer signaling pathways involved in metastasis. Furthermore, metastatic CTCs were identified through a prospective five-gene signature (
,
,
,
, and
). Whole-exome sequencing of CDX models and metastases further identified mutations in constitutive photomorphogenesis protein 1 (
) as a potential driver of metastasis. These findings illustrate the utility of the combined patient-derived CTC model and provide a glimpse of the promise of CTCs in identifying drivers of cancer metastasis.
Proglumide is an orally administered cholecystokinin receptor antagonist that was found to improve nonalcoholic steatohepatitis, reverse liver fibrosis, and decrease incidence of hepatocellular ...carcinoma (HCC) in animal models. The current investigation aimed to test the pharmacokinetics and safety of proglumide in subjects with hepatic impairment compared with healthy controls. In this translational study, subjects with confirmed cirrhosis, Child-Pugh stage A or B, or healthy controls were recruited for a single-dosing study. Baseline urine and blood samples were obtained before administration of proglumide and also collected after ingestion up to 24 h. Drug concentrations measured by mass spectroscopy revealed peak plasma concentrations (Cmax) of 7847, 9721, and 10,635 ng/mL at about 1 h (Tmax) for healthy controls, subjects with Child-Pugh A, and B cirrhosis, respectively. The serum elimination half time was 3 h. Maximum urine drug concentration (Cmax = ~411 µg/mL) was observed at 3 h, and urinary drug concentration declined at 5 h. There were no adverse events reported, and follow-up liver panels in cirrhosis subjects were unchanged or improved. This investigation demonstrated that proglumide is safe and has similar pharmacokinetic properties in subjects with cirrhosis as in healthy controls; therefore, it will be safe to test the efficacy of proglumide as a therapeutic agent in those subjects with cirrhosis or HCC.
We sought to report outcomes and toxicity in patients with hepatocellular carcinoma (HCC) who received resin yttrium-90 selective internal radiation therapy ((90)Y-SIRT) and to identify factors ...associated with declining liver function.
Patients treated with (90)Y-SIRT were retrospectively evaluated. Radiographic response was assessed using RECIST 1.1. Median liver progression-free survival (LPFS) and overall survival (OS) were calculated using the Kaplan-Meier method. Bivariate analysis was used to examine associations between change in Child-Pugh (CP) score/class and patient characteristics and treatment parameters.
Twenty-seven patients with unresectable HCC underwent SIRT, 52% were CP Class A, 48% were Class B, 11% were BCLC stage B, and 89% were stage C. Forty-four percent of patients had portal vein thrombus at baseline. One-third of patients received bilobar treatment. Median activity was 32.1 mCi (range 9.18-43.25) and median--absorbed dose to the liver was 39.6 Gy (range 13.54-67.70). Median LPFS and OS were 2.5 and 11.7 months, respectively. Three-month disease control rate was 63 and 52% in the target lesions and whole liver, respectively. New onset or worsened from baseline clinical toxicities were confined to Grade 1-2 events. However, new or worsened Grade 3-4 laboratory toxicities occurred in 38% of patients at 3 months and 43% of patients at 6 months following SIRT (six had lymphocytopenia, three had hypoalbuminemia, and two had transaminasemia). After 3 months, six patients had worsened in CP score and five had worsened in class from baseline. After 6 months, four patients had worsened in CP score and one had worsened in class from baseline. Pretreatment bilirubinemia was associated with a 2+ increase in CP score within 3 months (P = 0.001) and 6 months (P = 0.039) of (90)Y-SIRT. Pretreatment transaminasemia and bilirubinemia were associated with increased CP class within 3 months of SIRT (P = 0.021 and 0.009, respectively).
(90)Y-SIRT was well-tolerated in patients with unresectable HCC, with no Grade 3-4 clinical toxicities. However, Grade 3-4 laboratory toxicities and worsened CP scores were more frequent. HCC patients with pretreatment bilirubinemia or transaminasemia may be at higher risk of experiencing a decline in liver function following (90)Y-SIRT.
Patients exhibiting pancreatic cancer possess poor rates of survival. Therefore, the identification of a biomarker that can be measured non-invasively and be used to predict patient outcomes is ...required for the successful treatment of pancreatic cancer. The present study evaluated serum microRNA (miRNA/miR) profiles in patients exhibiting pancreatic cancer, who were treated with lapatinib and capecitabine in a phase II trial. Serum samples were collected for the measurement of a panel of miRNAs (miR-21, miR-210, miR-221 and miR-7) associated with the epidermal growth factor receptor (EGFR)1 and human epidermal growth factor receptor (HER)2 pathways. Preclinically, human pancreatic cancer PANC-1, MIA PaCa-2 and BXCP-3 cell lines were utilized for miRNA and drug resistance studies. In total, 6/17 patients treated experienced disease progression following 2 cycles of treatment non-responders (NRS), while another 6/17 patients exhibited a stable disease state and received >4 cycles of treatment responders (RS); range, 4-22 cycles. Five patients withdrew from the study due to severe toxicity or mortality. The mean overall survival time was 6.5 vs. 10.4 months for NRS and RS, respectively. Significant upregulation of serum miRNAs at earlier time points (3-6 weeks) was observed in NRS. miRNA levels increased with cancer progression, and lapatinib and 5-fluorouracil (5-FU; the active form of capecitabine) treatment increased the miRNA levels (specifically miR-210 and miR-221) in the treatment-resistant pancreatic cancer PANC-1 and MIA PaCa-2 cell lines. However, lapatinib and 5-FU treatment did not increase the miRNA levels in the treatment-sensitive BXPC-3 cell line. Inhibition of miR-221 increased the sensitivity of the PANC-1 cells to treatment. In conclusion, an increase in specific serum miRNAs was associated with resistance to lapatinib and capecitabine treatment. Additional investigation is required with regard to the application of the miRNA panel investigated in the present study as a potential predictor of patient responses to anti-EGFR/HER2 treatment.
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