Drug development for hepatocellular carcinoma: knowing the past helps to understand the future.
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ABSTRACT:
SUBMITTER: Chan SL
PROVIDER: S-EPMC4221377 | biostudies-literature | 2014 Nov
REPOSITORIES: biostudies-literature
Publications
Drug development for hepatocellular carcinoma: knowing the past helps to understand the future.
The oncologist 20140915 11
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Project description:Hepatocellular carcinoma (HCC) is one of the most common causes of cancer related mortality worldwide. The incidence of HCC has been increasing annually. Viral infection, alcohol usage, and other causes of cirrhosis have been identified as major risk factors for HCC development. The underlying pathogenesis has not been as well defined. There have been multiple hypotheses to the specific mechanisms of hepatocarcinogenesis and they share the common theme of chronic inflammation, increase oxidative stress, and genomic alteration. Therapeutic options of HCC have been primarily local and/or regional including transplantation, resection, and radial frequency ablation, chemoembolization or radio-embolization. For unresectable or metastatic disease, the options are limited. Conventional chemotherapeutic options have been noted to have limited benefit. Sorafenib has been the one and only systemic therapy which has demonstrated modest overall survival benefit. This has led to more extensive research with focus on targeted therapy. Numerous pre-clinical and early phase clinical studies have been noted but failed to show efficacy in later phase clinical trials. In an effort to identify new potential therapeutic options, new understanding of underlying pathways to hepatocarcinogenesis should be one of the main focuses. This leads to development of more molecularly targeted agents to specific pathways, and immunotherapy. This article provides a review of major studies of molecular targeted agents which attempts to target these specific pathways in HCC.
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Project description:Hepatocellular carcinoma (HCC) is a common neoplasia which represents the second leading cause of cancer related death. Most cases occur in developing countries, but its incidence is rising in Western countries due to hepatitis C. Although hepatitis therapies have evolved and the HCC screening has increased in several areas, 40% present with advanced disease which is only amenable for palliative systemic treatment. HCC continues posing a challenge, in part due to the inherent chemoresistance of this neoplasia, the pharmacologic challenges due to an ill liver, difficulty in assessing radiological responses accurately, etc. Traditional chemotherapy have shown some responses without clear survival benefit, however, sorafenib demonstrated advantages in survival in advanced HCC when liver function is kept and recently immunotherapy seems to be a promising approach for some patients. This article will briefly expose the most relevant systemic treatment modalities to offer a general view from the past to the future.
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Project description:Systemic chemotherapy is one of the most important treatment modalities for advanced hepatocellular carcinoma (HCC). Before the introduction of sorafenib, cytotoxic agents, hormonal therapies, or many combinations of these were the mainly used modalities for systemic chemotherapy of advanced HCC. However, such regimens were of only limited value in clinical practice, because some randomized controlled studies comparing promising regimens with no treatment or doxorubicin alone failed to show any overall survival advantage. In two pivotal phase III placebo-controlled studies, the SHARP trial and the Asia-Pacific trial, sorafenib was demonstrated to significantly delay the time to progression and the overall survival time in patients with advanced HCC. Therefore, sorafenib therapy has come to be acknowledged as a standard therapy for advanced HCC worldwide. After the introduction of sorafenib, a number of phase III trials of various molecular-targeted agents vs. sorafenib as first-line chemotherapy and of various molecular-targeted agents vs. placebo as second-line chemotherapy have been conducted to determine if any of these agents could offer a survival benefit, however, none of the agents examined so far has been demonstrated to provide any survival benefit over sorafenib or placebo. Recently, favorable treatment efficacies have been reported in some clinical trials of molecular-targeted agents in the biomarker-enriched population. Development of individualized cancer treatments using molecular-targeted agents based on the results of genome-sequencing is aggressively ongoing. Furthermore, immune-oncologic agents, such as anti-CTLA-4 antibody and anti-PD-1/PD-L1 antibody, have been reported to provide promising outcomes. Thus, various novel systemic chemotherapeutic agents are currently under development, and further improvements in the treatment outcomes are expected.
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Project description:Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide, and is most commonly found in the setting of liver cirrhosis. Treatment of HCC must consider both the tumors present, as well as the remaining dysfunctional liver that both hinders treatment and can produce additional HCC over time. Ablation is an evolving part of the multimodality treatment approach to HCC that can effectively destroy tumors while preserving surrounding liver parenchyma. New technologies have made ablation an indispensable tool in the treatment of all stages of HCC. This review presents the history, present technologies and future potential of ablation in the treatment of HCC.
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Project description:BackgroundSorafenib, a multikinase inhibitor that targets angiogenesis in hepatocellular carcinoma (HCC), has become a standard treatment for advanced-stage HCC and has shown survival benefits in recent clinical trials. Transarterial chemoembolization (TACE) and sorafenib are currently standard treatments for intermediate and advanced-stage HCC, respectively. Combined locoregional therapy, including TACE and molecular targeted therapies such as sorafenib, is an issue under active investigation in an attempt to improve the outcomes of patients with unresectable HCC.SummaryVarious clinical trials of these combined strategies have been conducted; however, the designs of these studies are diverse in terms of treatment modalities and schedules; comparisons with controls, baseline tumor stages, and hepatic functional reserves; and outcome measures.Key messagesThis article reviews heterogeneity in the design of recent clinical trials of combined locoregional and molecular targeted therapies and briefly addresses future study directions.
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Project description:Model-informed drug development (MIDD) approaches have rapidly advanced in drug development in recent years. Additionally, the Prescription Drug User Fee Act (PDUFA) VI has specific commitments to further enhance MIDD. Tumor growth dynamic (TGD) modeling, as one of the commonly utilized MIDD approaches in oncology, fulfills the purposes to accelerate the drug development, to support new drug and biologics license applications, and to guide the market access. Increasing knowledge of TGD modeling methodologies, encouraging applications in clinical setting for patients' survival, and complementing assessment of regulatory review for submissions, together fueled promising potentials for imminent enhancement of TGD in oncology. This review is to comprehensively summarize the history of TGD, and present case examples of the recent advance of TGD modeling (mixture model and joint model), as well as the TGD impact on regulatory decisions, thus illustrating challenges and opportunities. Additionally, this review presents the future perspectives for TGD approach.
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Project description:BackgroundUnderstanding how endangered species respond to climatic changes is fundamental for their conservation. Due to its restricted geographic range, its sensitivity to the ongoing global warming and its continuing decline, the Southwestern-Alpine endemic wolf spider Vesubia jugorum is currently classified as Endangered in the IUCN Red List. Here, we combined species distribution modelling (SDM) and phylogeographic inference to describe the present, the past and the future of this species in light of the mtDNA genetic structure of extant populations.ResultsPhylogenetic and network analyses show a high level of genetic differentiation and a strong genetic structure of the populations, likely explicable by a long history of isolation and survival in separate refugia. The SDM projection into past climatic conditions supports these results by showing a smaller distribution range compared to present, mostly restricted to the Maritime and Ligurian Alps, which possibly served as main refugium. Future forecast shows a significant shift in the bioclimatic range towards higher altitudes and latitudes, with a drastic decrease of habitat suitability in the central and south-eastern parts of the range, with consequent general loss of haplotype diversity.ConclusionSDM and phylogeographic inference support the hypothesis that the current distribution and the genetic structure of the extant populations mirror the survival in situ of Vesubia jugorum across repeated glacial and interglacial phases, in line with the 'long-term stability hypothesis'. Future predictions show a significant shift in the bioclimatic range that V. jugorum will be likely unable to track, with profound impact on its long-term survival and its genetic diversity. Our considerations have implication for conservation genetics, highlighting the pivotal role of the transboundary protected areas of the SW-Alps in promoting conservation efforts for this species.
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Project description:Animals traversing different environments encounter both stable background stimuli and novel cues, which are thought to be detected by primary sensory neurons and then distinguished by downstream brain circuits. Here we show that each of the ~1000 olfactory sensory neuron (OSN) subtypes in the mouse harbors a distinct transcriptome whose content is precisely determined by interactions between its odorant receptor and the environment. This transcriptional variation is systematically organized to support sensory adaptation: expression levels of more than 70 genes relevant to transforming odors into spikes continuously vary across OSN subtypes, dynamically adjust to new environments over hours, and accurately predict acute OSN-specific odor responses. The sensory periphery therefore separates salient signals from predictable background via a transcriptional rheostat whose moment-to-moment state reflects the past and constrains the future; these findings suggest a general model in which structured transcriptional variation within a cell type reflects individual experience.
2021-12-06 | GSE173947 | GEO