Targeted therapy for hepatocellular carcinoma: Challenges and opportunities
Introduction
Liver cancer is the sixth most commonly diagnosed cancer, with about 841,000 newly diagnosed cases and 782,000 deaths annually [1]. Hepatocellular carcinoma (HCC), accounting for about 80% of primary liver cancer, is the major pathological type. According to CONCORD-3 data reported by the Lancet, for most cancers, the survival trends are generally increasing due to the access to early diagnosis and optimal treatment. However, in most countries, liver cancer survival has changed very little during the 20-year period (1995–2014). The five-year net survival rate of liver cancer was in the range of 5–30% throughout 2000–2014. Take China for an example, the survival rate was 11.7% during 2000–2004, only increased to 14.1% during 2010–2014 [2]. In fact, the majority of HCC patients are diagnosed in advanced-stage, at which point surgical treatments (resection and transplantation) and locoregional treatment (chemoembolization) have been disappointing in terms of patients' overall survival [3]. Meanwhile, traditional chemotherapies, such as 5-fluorouracil, cisplatin, doxorubicin, or gemcitabine, haven't shown promising outcomes. Therefore, the development of effective targeted therapy for advanced HCC is in urgent need.
In 2007, a multi-kinase inhibitor (MKIs), sorafenib, was approved as the first systemic agent for the treatment of advanced unresectable HCC as Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol (SHARP) trial had suggested a survival benefit of about 3 months [4]. Since then, a glimmer of hope for unresectable advanced HCC has attracted various clinical trials testing for candidate targeted drugs. Currently, three oral multi-kinase inhibitors, sorafenib, regorafenib and lenvatinib, have been approved as first-line or second-line therapy for advanced HCC [5]. For immunotherapy, an anti-PD-1 monoclonal antibody, Nivolumab, has been granted accelerated approval from Food and Drug Administration (FDA) to treat advanced HCC based on promising results from a phase II trial (Checkmate-040) [6]. Also, other targeted therapies, such as GPC3 based CAR-T and AMPK inhibitors are also under exploration [7,8].
Despite those promising data in clinical trials, targeted therapies still confronted with problems like low objective response rate (ORR) and adaptive or acquired resistance [4,[9], [10], [11]]. These unsatisfied outcomes mainly result from heterogeneity of HCC derived from its morphological diversity, signal transduction network and microenvironmental discrepancies etc [12,13]. Thus, researches on biomarkers of liver cancer classification, biomarkers of response and how to deal with cancer revolution within tumors during therapy are still expected. In this review, we summarized the recent targeted therapies for HCC, mechanisms on resistance and potential strategies to overcome low efficacy of current therapies, in hope of shedding light on precision medicine for HCC in future researches.
Section snippets
Introduction of multi-kinase inhibitors
Sorafenib, an oral multikinase inhibitor (MKI), which blocks tyrosine kinase receptor (VEGFR-2/3, PDGFR-β, c-Kit, FLT-3, RET), downstream pathway kinase (Ras/Raf/MEK/ERK, JAK/STAT) activities and other targets (c-Raf, B-Raf), is the first approved systemic agent for advanced liver cancer (Fig. 1) [[14], [15], [16]]. According to SHARP trial, sorafenib showed a 2.8-month prolonged survival for patients compared with the placebo group, with a median overall survival (OS) of 10.7 months versus 7.9
CAR-T
Cancer immunotherapy is named as Breakthroughs of the Year by Science in 2013 due to the progress made in two fields: chimeric antigen receptor (CAR)-modified T cells and checkpoint inhibitors. CAR-T have been heralded as a promising technology due to the substantial benefit observed in patients with relapsed or refractory B-cell malignancies [[84], [85], [86], [87]]. The success of CAR-T has encouraged many resources worldwide to recognize additional tumor-associated antigens aiming to extend
Perspectives
The development of HCC is a multistep process with a complex interaction of altered signaling pathways, tumor microenvironment, and varied genetic background, leading to high tumoral heterogeneity, which posed a great challenge to precision medicine. With the advancement in multi-omics and gene editing technology, precision medicine has brought hope to the previous “uncurable” patients. However, it's undeniable that we have faced with many bottleneck issues followed with the approval of the new
Acknowledgment
We gratefully acknowledge the support from the National Natural Science Foundation of China (81802878, 81722034, 81572896) and Shanghai Sailing Program (18YF1400200). It is also sponsored by National Major Scientific and Technological Special Project for “Significant New Drugs Development”& “Prevention and Control of Infectious Diseases” (2018ZX09101-002; 2017ZX100203205004).
Conflicts of interest
The authors have no conflict of interest to disclose.
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