Hepatocellular carcinoma (HCC) is the most common liver malignancy worldwide and a major cause of cancer-related mortality for which liver resection is an important curative-intent treatment option. However, many pati...Hepatocellular carcinoma (HCC) is the most common liver malignancy worldwide and a major cause of cancer-related mortality for which liver resection is an important curative-intent treatment option. However, many patients present with advanced disease and with underlying chronic liver disease and/or cirrhosis, limiting the proportion of patients who are surgical candidates. In addition, the development of recurrent or de novo cancers following surgical resection is common. These issues have led investigators to evaluate the benefit of neoadjuvant and adjuvant treatment strategies aimed at improving resectability rates and decreasing recurrence rates. While high-level evidence to guide treatment decision making is lacking, recent advances in locoregional and systemic therapies, including antiviral treatment and immunotherapy, raise the prospect of novel approaches that may improve the outcomes of patients with HCC. In this review, we evaluate the evidence for various neoadjuvant and adjuvant therapies and discuss opportunities for future clinical and translational research.展开更多
BACKGROUND Hypoxia-inducible factor 1α(HIF-1α) is a gene that regulates tumor survival,neovascularization and invasion. Overexpression of HIF-1α correlates with poor prognosis in hepatocellular carcinoma(HCC). RO70...BACKGROUND Hypoxia-inducible factor 1α(HIF-1α) is a gene that regulates tumor survival,neovascularization and invasion. Overexpression of HIF-1α correlates with poor prognosis in hepatocellular carcinoma(HCC). RO7070179 is a HIF-1α inhibitor that decreases HIF-1α mRNA and its downstream targets, it could be a potential treatment in HCC.AIM To evaluate safety and preliminary activity of RO7070179 in patients with previously treated HCC, with focus on a patient with prolonged response to RO7070179.METHODS In the preclinical study of RO7070179 in a HCC xenograft model, the mice wereseparated into 4 groups with each group received doses of 0, 3, 10 and 30 mg/kg for total 10 doses. HCC patients who failed at least one line of systemic treatment,received RO7070179 as a weekly infusion, each cycle is 6 wk. We evaluated the safety and HIF-1α mRNA levels of RO7070179.RESULTS Preclinical evaluation of RO7070179 in orthotopic HCC xenograft model showed no significant differences in HCC tumor weight between the 3 and 10 mg/kg groups. However, dose of 10 mg/kg of RO7070179, has shown 76% reduction of the amount of HIF-1α mRNA in HCC tissue. In the phase 1 b study of RO7070179 in previously treated HCC patients, 8 out of 9 were evaluable: 1 achieved PR and1 SD. The patient with PR responded after 2 cycles treatments, which has been maintained for 12 cycles. This patient also showed reduction in perfusion of dynamic contrast-enhanced magnetic resonance imaging(DCE-MRI) after 1 cycle of treatment. After 1 cycle of treatment, both patients with PR and SD showed decrease in HIF-1α mRNA at the root of biopsies(each biopsy was divided into 2 specimens, the tip and the root).CONCLUSION RO7070179 can reduce HIF-1α mRNA level in HCC patients with SD or PR. It is well tolerated at 10 mg/kg, with transaminitis as the dose of increased toxicity.This study indicates that RO7070179 might benefit HCC patients, and an early signal for clinical benefit can potentially be predicted through changes in either m RNA level or DCE-MRI within 1 cycle of therapy.展开更多
Pancreatic ductal adenocarcinoma(PDAC)is a lethal disease with limited therapeutic options.Despite extensive clinical research over the past several decades,meaningful improvements in care standards have been challeng...Pancreatic ductal adenocarcinoma(PDAC)is a lethal disease with limited therapeutic options.Despite extensive clinical research over the past several decades,meaningful improvements in care standards have been challenging to achieve.Research efforts are underway on several fronts,including cytotoxic chemotherapy combinations,immunotherapy,and targeted therapy.In this review,we chose to focus less on mainstream avenues of clinical research in PDAC and highlight some novel and innovative research efforts that are typically outside the spotlight of therapies.Examples of these novel approaches include pharmacologic vitamin C and electromagnetic fields.This review’s scope is to present the biological basis of the anti-cancer potential and the early clinical data,as well as the future landscape of these agents,including ongoing clinical trials in these therapeutic avenues.展开更多
文摘Hepatocellular carcinoma (HCC) is the most common liver malignancy worldwide and a major cause of cancer-related mortality for which liver resection is an important curative-intent treatment option. However, many patients present with advanced disease and with underlying chronic liver disease and/or cirrhosis, limiting the proportion of patients who are surgical candidates. In addition, the development of recurrent or de novo cancers following surgical resection is common. These issues have led investigators to evaluate the benefit of neoadjuvant and adjuvant treatment strategies aimed at improving resectability rates and decreasing recurrence rates. While high-level evidence to guide treatment decision making is lacking, recent advances in locoregional and systemic therapies, including antiviral treatment and immunotherapy, raise the prospect of novel approaches that may improve the outcomes of patients with HCC. In this review, we evaluate the evidence for various neoadjuvant and adjuvant therapies and discuss opportunities for future clinical and translational research.
文摘BACKGROUND Hypoxia-inducible factor 1α(HIF-1α) is a gene that regulates tumor survival,neovascularization and invasion. Overexpression of HIF-1α correlates with poor prognosis in hepatocellular carcinoma(HCC). RO7070179 is a HIF-1α inhibitor that decreases HIF-1α mRNA and its downstream targets, it could be a potential treatment in HCC.AIM To evaluate safety and preliminary activity of RO7070179 in patients with previously treated HCC, with focus on a patient with prolonged response to RO7070179.METHODS In the preclinical study of RO7070179 in a HCC xenograft model, the mice wereseparated into 4 groups with each group received doses of 0, 3, 10 and 30 mg/kg for total 10 doses. HCC patients who failed at least one line of systemic treatment,received RO7070179 as a weekly infusion, each cycle is 6 wk. We evaluated the safety and HIF-1α mRNA levels of RO7070179.RESULTS Preclinical evaluation of RO7070179 in orthotopic HCC xenograft model showed no significant differences in HCC tumor weight between the 3 and 10 mg/kg groups. However, dose of 10 mg/kg of RO7070179, has shown 76% reduction of the amount of HIF-1α mRNA in HCC tissue. In the phase 1 b study of RO7070179 in previously treated HCC patients, 8 out of 9 were evaluable: 1 achieved PR and1 SD. The patient with PR responded after 2 cycles treatments, which has been maintained for 12 cycles. This patient also showed reduction in perfusion of dynamic contrast-enhanced magnetic resonance imaging(DCE-MRI) after 1 cycle of treatment. After 1 cycle of treatment, both patients with PR and SD showed decrease in HIF-1α mRNA at the root of biopsies(each biopsy was divided into 2 specimens, the tip and the root).CONCLUSION RO7070179 can reduce HIF-1α mRNA level in HCC patients with SD or PR. It is well tolerated at 10 mg/kg, with transaminitis as the dose of increased toxicity.This study indicates that RO7070179 might benefit HCC patients, and an early signal for clinical benefit can potentially be predicted through changes in either m RNA level or DCE-MRI within 1 cycle of therapy.
文摘Pancreatic ductal adenocarcinoma(PDAC)is a lethal disease with limited therapeutic options.Despite extensive clinical research over the past several decades,meaningful improvements in care standards have been challenging to achieve.Research efforts are underway on several fronts,including cytotoxic chemotherapy combinations,immunotherapy,and targeted therapy.In this review,we chose to focus less on mainstream avenues of clinical research in PDAC and highlight some novel and innovative research efforts that are typically outside the spotlight of therapies.Examples of these novel approaches include pharmacologic vitamin C and electromagnetic fields.This review’s scope is to present the biological basis of the anti-cancer potential and the early clinical data,as well as the future landscape of these agents,including ongoing clinical trials in these therapeutic avenues.
