Preclinical analysis of the anti-tumor and anti-metastatic effects of Raf265 on colon cancer cells and CD26(+) cancer stem cells in colorectal carcinoma.

BACKGROUND: In colorectal carcinoma (CRC), activation of the Raf/MEK/ERK signaling pathway is commonly observed. In addition, the commonly used 5FU-based chemotherapy in patients with metastatic CRC was found to enrich a subpopulation of CD26(+) cancer stem cells (CSCs). As activation of the Raf/MEK/ERK signaling pathway was also found in the CD26(+) CSCs and therefore, we hypothesized that an ATP-competitive pan-Raf inhibitor, Raf265, is effective in eliminating the cancer cells and the CD26(+) CSCs in CRC patients. METHODS: HT29 and HCT116 cells were treated with various concentrations of Raf265 to study the anti-proliferative and apoptotic effects of Raf265. Anti-tumor effect was also demonstrated using a xenograft model. Cells were also treated with Raf265 in combination with 5FU to demonstrate the anti-migratory and invasive effects by targeting on the CD26(+) CSCs and the anti-metastatic effect of the combined treatment was shown in an orthotopic CRC model. RESULTS: Raf265 was found to be highly effective in inhibiting cell proliferation and tumor growth through the inhibition of the RAF/MEK/ERK signaling pathway. In addition, anti-migratory and invasive effect was found with Raf265 treatment in combination with 5FU by targeting on the CD26(+) cells. Finally, the anti-tumor and anti-metastatic effect of Raf265 in combination with 5FU was also demonstrated. CONCLUSIONS: This preclinical study demonstrates the anti-tumor and anti-metastatic activity of Raf265 in CRC, providing the basis for exploiting its potential use and combination therapy with 5FU in the clinical treatment of CRC.

The use of single-agent sorafenib in the treatment of advanced hepatocellular carcinoma patients with underlying Child-Pugh B liver cirrhosis: a retrospective analysis of efficacy, safety, and survival benefits.

BACKGROUND: This study explored the efficacy, tolerability, and survival benefits of using sorafenib in patients with Child-Pugh class B (CPB) cirrhosis. METHODS: Patients with advanced hepatocellular carcinoma who were treated with sorafenib at Queen Mary Hospital, Hong Kong, China, were analyzed retrospectively. Treatment outcomes were analyzed according to their respective Child-Pugh status. Patients with CPB disease were further divided into CPB7 (those with a score of 7) and CPB8-9 (a score of 8 or 9) subgroups. RESULTS: The baseline demographic parameters were comparable between 108 patients with Child-Pugh class A (CPA) disease and 64 CPB patients. Both clinical benefit rate (21.3% vs 32.4% vs 14.8%; P = .23) and progression-free survival (median: 3.2 months vs 3.2 months vs 2.3 months; P = .26) were similar among CPA, CPB7, and CPB8-9 groups, respectively. The overall survival was different among these groups (P = .002) and showed a trend toward worse outcome in CPB patients: the median was 6.1, 5.4, and 2.7 months among CPA, CPB7, and CPB8-9 patients, respectively. The commonest grade 3/4 adverse events were hand-foot syndrome (13.5%), diarrhea (9.9%), and rash (7.0%). Grade 3/4 leukopenia, thrombocytopenia, and anemia occurred in 2.9%, 5.3%, and 8.8% of the patients, respectively. Overall, the 3 groups of patients experienced similar incidence of most of these adverse events. Nonetheless, CPB patients experienced more anemia (P = .01), gastrointestinal bleeding (P = .02), and hepatic encephalopathy (P = .02). CONCLUSIONS: CPA and CPB patients tolerated sorafenib similarly and derived similar clinical and progression-free survival benefit. Among CPB patients, most benefits were observed in patients with a score of 7. Nevertheless, CPB patients were more susceptible to developing cirrhotic complications, and thus more vigilant surveillance is needed.

The outcomes and safety of single-agent sorafenib in the treatment of elderly patients with advanced hepatocellular carcinoma (HCC).

BACKGROUND: With the aging population, hepatocellular carcinoma (HCC) in the elderly represents a significant health burden. We aimed to evaluate and compare the efficacy and tolerability of single-agent sorafenib in treating elderly patients with advanced HCC versus the younger population. METHODS: We retrospectively analyzed a consecutive cohort of advanced HCC patients with Child-Pugh A or B liver function and an Eastern Cooperative Oncology Group performance status score of 0-2 treated with sorafenib. The patients were categorized into older (age ≥70 years) and younger (age <70 years) groups. Treatment outcomes and related adverse events (AEs) were compared. RESULTS: In total, 172 patients, 35 in the older (median age, 73 years) and 137 in the younger (median age, 55 years) group, were analyzed. The median progression-free survival time was similar in the older and younger groups (2.99 months versus 3.09 months; p = .275), as was the overall survival time (5.32 months versus 5.16 months; p = .310). Grade 3 or 4 AEs were observed in 68.6% of older and 62.7% of younger patients (p = .560), with neutropenia (11.4% versus 0.7%; p = .007), malaise (11.4% versus 2.2%; p = .033), and mucositis (5.7% versus 0.0%; p = .041) being more frequently reported in the elderly cohort. CONCLUSIONS: The survival benefits and overall treatment-related AEs of sorafenib are comparable in elderly and younger advanced HCC patients. Nevertheless, more vigilant monitoring in the elderly is warranted because they are more susceptible to develop neutropenia, malaise, and mucositis.

The significance of early alpha-fetoprotein level changes in predicting clinical and survival benefits in advanced hepatocellular carcinoma patients receiving sorafenib.

BACKGROUND: he role of serum alpha-fetoprotein (AFP) changes in predicting the treatment outcomes of advanced hepatocellular carcinoma (HCC) patients to sorafenib remains unknown. METHODS: Serum AFP was collected prospectively at baseline and subsequent follow-up visits in parallel with clinical and survival outcomes. AFP response was defined as a relative drop of AFP >20% of the baseline level after 6 weeks of sorafenib. The relationship between AFP response and the treatment outcomes was first explored in patients who received sorafenib in a phase II study. Subsequently, an independent validation set of patients were obtained to validate the association of AFP response to clinical outcomes. RESULTS: Included in the exploration and validation sets for analysis were 41 and 53 patients, respectively, with baseline AFP level >20 µg/L. In the exploration cohort, AFP response was significantly associated with clinical benefit (CB) rate (relative chance 3.4, 95% confidence interval [CI], 1.1-11.1), and multivariate analysis indicated that AFP response was associated with significantly better progression-free survival (PFS) (hazard ratio [HR], 0.31; 95% CI, 0.13-0.76) and marginally better overall survival (OS) (HR, 0.30; 95% CI, 0.09-1.02). When applying AFP changes in the validation set, significant associations were again found between AFP response with CB rate (relative chance, 5.5; 95% CI, 2.3-13.6) and PFS (HR, 0.12; 95% CI, 0.04-0.30) but not OS (HR, 0.61; 95% CI, 0.27-1.26). CONCLUSION: Drop in AFP level at 6 weeks is an exploratory early surrogate for both CB and PFS in advanced HCC patients receiving sorafenib.

Molecular targeted therapy of advanced hepatocellular carcinoma beyond sorafenib.

IMPORTANCE OF THE FIELD: With the recent advances in the knowledge of molecular biology of hepatocellular carcinoma (HCC), there have been encouraging developments in targeted therapy for advanced HCC. AREAS COVERED IN THIS REVIEW: This review discusses the development of targeted therapy for advanced HCC patient since 2006. Among the newly identified targets, promising results have been shown in targeting the anti-angiogenic pathway. Pure anti-angiogenic agents such as bevacizumab and PTK 787 demonstrate modest activity in treating patients with advanced HCC. Sorafenib, a multi-targeted tyrosine kinase inhibitor with both anti-angiogenic and anti-proliferative effects, has been shown to prolong the overall survival of patients with advanced HCC in two Phase III randomized trials. Like sorafenib, other anti-angiogenic multi-targeted tyrosine kinase inhibitors, such as sunitinib, pazopanib, brivanib and linifanib, also show promising activity in various stages of clinical trials. Other on-going early-phase studies are exploring the activities of drugs targeting novel pathways, such as PI3K/AKT/m TOR, hepatocyte growth factor/mesenchymal epithelial transition factor and insulin-like growth factor. WHAT THE READER WILL GAIN: After reading this review, the reader should have an in-depth understanding of the latest developments in the molecular targeted therapy of advanced HCC. TAKE HOME MESSAGE: The development of sorafenib in the treatment of advanced HCC proves the concept that molecular targeted therapies, especially anti-angiogenic agents, play a pivotal role in the treatment of this otherwise chemoresistant neoplasm. Future progress depends on further unraveling more molecular mechanisms of HCC for therapeutic intervention.

A subpopulation of CD26+ cancer stem cells with metastatic capacity in human colorectal cancer.

Recent evidence suggests that a subpopulation of cancer cells, cancer stem cells (CSCs), is responsible for tumor growth in colorectal cancer. However, the role of CSCs in colorectal cancer metastasis is unclear. Here, we identified a subpopulation of CD26(+) cells uniformly present in both the primary and metastatic tumors in colorectal cancer patients with liver metastasis. Furthermore, in patients without distant metastasis at the time of presentation, the presence of CD26(+) cells in their primary tumors predicted distant metastasis on follow-up. Isolated CD26(+) cells, but not CD26(-) cells, led to development of distant metastasis when injected into the mouse cecal wall. CD26(+) cells were also associated with enhanced invasiveness and chemoresistance. Our findings have uncovered a critical role of CSCs in metastatic progression of cancer. Furthermore, the ability to predict metastasis based on analysis of CSC subsets in the primary tumor may have important clinical implication as a selection criterion for adjuvant therapy.

Epidemiology of colorectal cancer in Asia.

The prevalence of colorectal cancer is increasing in Asia. However, the age-standardized rate has reached a plateau in some countries. Some studies have shown a male predominance difference and increasing risk in the elderly, but not in the younger population. 'Right shifting' of colorectal cancer, not accountable by difference in age or the indications for endoscopic examination, has also been noted. Westernized diet is associated with colorectal cancer, but controversy remains on how it causes colorectal cancer. Alcohol consumption, obesity, diabetes mellitus, consumption of red and processed meat and cigarette smoking are linked to bowel cancer epidemiologically. Only high dietary calcium has a consistent negative (or 'protective') effect. The efficacy of fish oil, vitamin D, soy, phytoestrogens, folate, methionine, riboflavin and vitamin B6 has not been established. Aspirin and non-steroidal anti-inflammatory drugs use decrease risk of colorectal cancer after 5-10 years of use. There is no evidence for a detrimental effect of proton pump inhibitors or benefit of statins in colorectal cancer. In conclusion, there is a rising trend and prevalence of colorectal cancer in Asia. Dietary modification or supplementation may not be effective in preventing colorectal cancer. Surveillance of colorectal cancer in high-risk groups, according to current recommendation, is probably most effective.

Peroxisome proliferator-activated receptor-gamma contributes to the inhibitory effects of Embelin on colon carcinogenesis.

Down-regulation of XIAP (X-linked inhibitor of apoptosis protein) sensitizes colon cancer cells to the anticancer effect of peroxisome proliferator-activated receptor-gamma (PPARgamma) ligands in mice. The aims of this study were to evaluate the effect of embelin (2,5-dihydroxy-3-undecyl-1,4-benzoquinone), an antagonist of XIAP, on colon cancer, with a particular focus on whether PPARgamma is required for embelin to exert its effect. A dominant-negative PPARgamma was used to antagonize endogenous PPARgamma in HCT116 cells. Cells were treated with or without embelin. Cell proliferation, apoptosis, and nuclear factor-kappaB (NF-kappaB) activity were measured. For in vivo studies, 1,2-dimethylhydrazine dihydrochloride (DMH) was s.c. injected to induce colon cancer in PPARgamma(+/+) and PPARgamma(+/-) mice. Mice were fed embelin daily for 10 days before DMH injection, and continued for 30 more weeks. Embelin inhibited proliferation and induced apoptosis in HCT116 cells with marked up-regulation of PPARgamma. In addition, embelin significantly inhibited the expressions of survivin, cyclin D1, and c-Myc. These effects were partially dependent on PPARgamma. PPARgamma(+/-) mice were more susceptible to DMH-induced colon carcinogenesis than PPARgamma(+/+) mice, and embelin significantly reduced the incidence of colon cancer in PPARgamma(+/+) mice but not in PPARgamma(+/-) mice. Embelin inhibited NF-kappaB activity in PPARgamma(+/+) mice but marginally so in PPARgamma(+/-) mice. Thus, reduced expression of PPARgamma significantly sensitizes colonic tissues to the carcinogenic effect of DMH. Embelin inhibits chemical carcinogen-induced colon carcinogenesis, but this effect is partially dependent on the presence of functional PPARgamma, indicating that PPARgamma is a necessary signaling pathway involved in the antitumor activity of normal organisms.

A phase I/II trial of chemoembolization for hepatocellular carcinoma using a novel intra-arterial drug-eluting bead.

BACKGROUND & AIMS: To assess the safety and efficacy of transarterial chemoembolization (TACE) using doxorubicin-eluting beads (DEB) for hepatocellular carcinoma (HCC). METHODS: Patients with incurable HCC and Child-Pugh class A cirrhosis were considered eligible for this phase I/II trial. Two courses of TACE using DEB were given at an interval of 2 months, and tumor response was assessed by computerized tomography scan. The phase I trial was a dose-escalating study starting from 25 mg to 150 mg doxorubicin in cohorts of 3 patients. The 150-mg doxorubicin dose was used for the phase II study. Primary end points were treatment-related complications and deaths. Secondary end points included tumor response and pharmacokinetics of doxorubicin. RESULTS: In the phase I study involving 15 patients, no dose-limiting toxicity was observed for up to 150 mg doxorubicin, which was used for 20 patients in the phase II study. The pharmacokinetic study showed a low peak plasma doxorubicin concentration (49.4 +/- 23.7 ng/mL), and no systemic toxicity was observed. The treatment-related complication rate was 11.4%. There was no treatment-related death. Among 30 patients who completed 2 courses of TACE, the partial response rate and the complete response rates were 50% and 0%, respectively, by response evaluation criteria in solid tumors (RECIST) criteria at computerized tomography scan 1 month after the second TACE. By modified RECIST criteria, taking into account the extent of tumor necrosis, 19 (63.3%) patients had a partial response and 2 (6.7%) had a complete response. CONCLUSIONS: This study shows that TACE using DEB is a safe and effective treatment for HCC, supporting a phase III randomized trial to compare this novel treatment with conventional TACE using doxorubicin-Lipiodol emulsion.