Combination percutaneous and intraarterial therapy for the treatment of hepatocellular carcinoma: a review.
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ABSTRACT:
SUBMITTER: Carmi L
PROVIDER: S-EPMC3324189 | biostudies-other | 2010 Sep
REPOSITORIES: biostudies-other
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Project description:Management of advanced hepatocellular carcinoma (HCC), one of the most lethal cancers worldwide, has presented a therapeutic challenge over past decades. Most patients with advanced HCC and a low possibility of surgical resection have limited treatment options and no alternative but to accept local or palliative treatment. In the new era of cancer therapy, increasing numbers of molecular targeted agents (MTAs) have been applied in the treatment of advanced HCC. However, mono-targeted therapy has shown disappointing outcomes in disease control, primarily because of tumor heterogeneity and complex cell signal transduction. Because incapacitation of a single target is insufficient for cancer suppression, combination treatment for targeted therapy has been proposed and experimentally tested in several clinical trials. In this article, we review research studies aimed to enhance the efficacy of targeted therapy for HCC through combination strategies. Combination treatments involving targeted therapy for advanced HCC are compared and discussed.
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Project description:Hepatocellular carcinoma (HCC) is the sixth most common primary cancer with an unsatisfactory long-term survival. Gain of function mutations of PIK3CA occur in a subset of human HCC. Alpelisib, a selective PIK3CA inhibitor, has been approved by the FDA to treat PIK3CA mutant breast cancers. In this manuscript, we evaluated the therapeutic efficacy of alpelisib, either alone or in combination, for the treatment of HCC. We tested alpelisib in mouse HCC induced by hydrodynamic injection of c-Met/PIK3CA(H1047R) (c-Met/H1047R), c-Met/PIK3CA(E545K) (c-Met/E545K), and c-Met/sgPten gene combinations. Alpelisib slowed down the growth of c-Met/H1047R and c-Met/E545K HCC but was ineffective in c-Met/sgPten HCC. Mechanistically, alpelisib inhibited p-ERK and p-AKT in c-Met/H1047R and c-Met/E545K HCC progression but did not affect the mTOR pathway or genes involved in cell proliferation. In human HCC cell lines transfected with PIK3CA(H1047R), alpelisib synergized with the mTOR inhibitor MLN0128 or the CDK4/6 inhibitor palbociclib to suppress HCC cell growth. In c-Met/H1047R mice, alpelisib/MLN0128 or alpelisib/palbociclib combination therapy caused tumor regression. Our study demonstrates that alpelisib is effective for treating PIK3CA-mutated HCC by inhibiting MAPK and AKT cascades. Furthermore, combining alpelisib with mTOR or CDK4/6 inhibitors has a synergistic efficacy against PIK3CA-mutated HCC, providing novel opportunities for precision medicine against HCC.
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Project description:ObjectiveHepatocellular carcinoma (HCC) is the most common type of primary liver cancer with limited treatment options. Cabozantinib, an orally bioavailable multikinase inhibitor is now approved by Food and Drug Administration (FDA) for HCC patients. We evaluated the therapeutic efficacy of cabozantinib, either alone or in combination, in vitro and in vivo.DesignHuman HCC cell lines and HCC mouse models were used to assess the therapeutic efficacy and targeted molecular pathways of cabozantinib, either alone or in combination with the pan-mTOR inhibitor MLN0128 or the checkpoint inhibitor anti-PD-L1 antibody.ResultsCabozantinib treatment led to stable disease in c-Met/β-catenin and Akt/c-Met mouse HCC while possessing limited efficacy on Akt/Ras and c-Myc liver tumours. Importantly, cabozantinib effectively inhibited c-MET and ERK activity, leading to decreased PKM2 and increased p21 expression in HCC cells and in c-Met/β-catenin and Akt/c-Met HCC. However, cabozantinib was ineffective in inhibiting the Akt/mTOR cascade. Intriguingly, a strong inhibition of angiogenesis by cabozantinib occurred regardless of the oncogenic drivers. However, cabozantinib had limited impact on other tumour microenvironment parameters, including tumour infiltrating T cells, and did not induce programmed death-ligand 1 (PD-L1) expression. Combining cabozantinib with MLN0128 led to tumour regression in c-Met/β-catenin mice. In contrast, combined treatment with cabozantinib and the checkpoint inhibitor anti-PD-L1 antibody did not provide any additional therapeutic benefit in the four mouse HCC models tested.Conclusionc-MET/ERK/p21/PKM2 cascade and VEGFR2-induced angiogenesis are the primary targets of cabozantinib in HCC treatment. Combination therapies with cabozantinib and mTOR inhibitors may be effective against human HCC.
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Project description:The liver tumor immune microenvironment has been thought to possess a critical role in the development and progression of hepatocellular carcinoma (HCC). Despite the approval of immune checkpoint inhibitors (ICIs), such as programmed cell death receptor 1 (PD-1)/programmed cell death ligand 1 (PD-L1) and cytotoxic T lymphocyte associated protein 4 (CTLA-4) inhibitors, for several types of cancers, including HCC, liver metastases have shown evidence of resistance or poor response to immunotherapies. Radiation therapy (RT) has displayed evidence of immunosuppressive effects through the upregulation of immune checkpoint molecules post-treatment. However, it was revealed that the limitations of ICIs can be overcome through the use of RT, as it can reshape the liver immune microenvironment. Moreover, ICIs are able to overcome the RT-induced inhibitory signals, effectively restoring anti-tumor activity. Owing to the synergetic effect believed to arise from the combination of ICIs with RT, several clinical trials are currently ongoing to assess the efficacy and safety of this treatment for patients with HCC.
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Project description:Advanced hepatocellular carcinoma (HCC) is a severe malignancy that poses a serious threat to human health. Owing to challenges in early diagnosis, most patients lose the opportunity for radical treatment when diagnosed. Nonetheless, recent advancements in cancer immunotherapy provide new directions for the treatment of HCC. For instance, monoclonal antibodies against immune checkpoint inhibitors (ICIs) such as programmed cell death protein 1/death ligand-1 inhibitors and cytotoxic t-lymphocyte associated antigen-4 significantly improved the prognosis of patients with HCC. However, tumor cells can evade the immune system through various mechanisms. With the rapid development of genetic engineering and molecular biology, various new immunotherapies have been used to treat HCC, including ICIs, chimeric antigen receptor T cells, engineered cytokines, and certain cancer vaccines. This review summarizes the current status, research progress, and future directions of different immunotherapy strategies in the treatment of HCC.
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Project description:PurposeTo test the hypothesis that antitumoral immunity can be induced after cryoablation (cryo) of hepatocellular carcinoma (HCC) through coadministration of the immunostimulant CpG and an immune checkpoint (programmed cell death 1 [PD-1]) inhibitor.Materials and methodsSixty-three immunocompetent C57BL/6J mice were generated with 2 orthotopic HCC tumor foci: 1 for treatment and 1 to observe for antitumoral immunity. Tumors were treated with incomplete cryo alone or intratumoral CpG and/or a PD-1 inhibitor. The primary endpoint was death or when the following criteria for sacrifice were met: tumor > 1 cm (determined using ultrasound) or moribund state. Antitumoral immunity was assessed using flow cytometry and histology (tumor and liver) as well as enzyme-linked immunosorbent assay (serum). Analysis of variance was used for statistical comparisons.ResultsAt 1 week, the nonablated satellite tumor growth was reduced by 1.9-fold (P = .047) in the cryo + CpG group and by 2.8-fold (P = .007) in the cryo + CpG + PD-1 group compared with that in the cryo group. Compared with cryo alone, the time to tumor progression to endpoints was also prolonged for cryo + CpG + PD-1 and cryo + CpG mice, with log-rank hazard ratios of 0.42 (P = .031) and 0.27 (P < .001), respectively. Flow cytometry and histology showed increased cytotoxic T-cell infiltration (P = .002) and serum levels of the proinflammatory cytokine interferon-γ (P = .015) in tumors and serum of cryo + CpG mice compared with those in tumors and serum of mice treated with cryo alone. High serum levels of the anti-inflammatory cytokine tumor growth factor-β and the proangiogenesis chemokine C-X-C motif chemokine ligand 1 were correlated with a shorter time to endpoints and faster tumor growth.ConclusionsCryo combined with the immunostimulant CpG promoted cytotoxic T-cell infiltration into tumors, slowed tumor growth, and prolonged the time to progression to endpoints in an aggressive murine HCC model.
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Project description:Hepatocellular carcinoma (HCC) is one of the most common malignancies, with an increasing incidence. With advances in surgical techniques and instrumentation and the development of molecular-target drugs, a number of potentially curative treatments have become available. Management of HCC patients depends on the stage of their tumor. Liver resection remains the first choice for very early-stage HCC, but it is being challenged by local ablative therapy. For early-stage HCC that meet the Milan criteria, liver transplantation still offers a better outcome; however, local ablative therapy can be a substitute when transplantation is not feasible. Local ablation is also used as a bridging therapy toward liver transplantation. HCC recurrence is the main obstacle to successful treatment, and there is currently no effective means of preventing or treating HCC recurrence. Transarterial therapy is considered suitable for intermediate-stage HCC, while sorafenib is recommended for advanced-stage HCC. This stage-based approach to therapy not only provides acceptable outcomes but also improves the quality of life of HCC patients. Because of the complexity of HCC, therapeutic approaches must be adapted according to the characteristics of each individual patient. This review discusses the current standards and trends in the treatment of HCC.
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Project description:Background and aims: Synthetic cyclin-dependent kinase (CDK) 4/6 inhibitors exert antitumor effects by forcing RB1 in unphosphorylated status, causing not only cell cycle arrest but also cellular senescence, apoptosis, and increased immunogenicity. These agents currently have an indication in advanced breast cancers and are in clinical trials for many other solid tumors. HCC is one of promising targets of CDK4/6 inhibitors. RB family dysfunction is often associated with the initiation of HCC; however, this is revivable, as RB family members are not frequently mutated or deleted in this malignancy. Approach and results: Loss of all Rb family members in transformation related protein 53 (Trp53)-/- mouse liver resulted in liver tumor reminiscent of human HCC, and re-expression of RB1 sensitized these tumors to a CDK4/6 inhibitor, palbociclib. Introduction of an unphosphorylatable form of RB1 (RB7LP) into multiple liver tumor cell lines induced effects similar to palbociclib. By screening for compounds that enhance the efficacy of RB7LP, we identified an I kappa B kinase (IKK)β inhibitor Bay 11-7082. Consistently, RB7LP expression and treatment with palbociclib enhanced IKKα/β phosphorylation and NF-κB activation. Combination therapy using palbociclib with Bay 11-7082 was significantly more effective in hepatoblastoma and HCC treatment than single administration. Moreover, blockade of IKK-NF-κB or AKT pathway enhanced effects of palbociclib on RB1-intact KRAS Kirsten rat sarcoma viral oncogene homolog mutated lung and colon cancers. Conclusions: In conclusion, CDK4/6 inhibitors have a potential to treat a wide variety of RB1-intact cancers including HCC when combined with an appropriate kinase inhibitor.
2021-05-26 | GSE153123 | GEO
Project description:Hepatocellular carcinoma (HCC) is estimated to be the fourth leading cause of cancer-related deaths globally, and its overall prognosis is dismal because most cases are diagnosed at a late stage and are unamenable to curative treatment. The emergence of immune checkpoint inhibitors (ICIs) has dramatically improved the therapeutic efficacy for advanced hepatocellular carcinoma; however, their response rates remain unsatisfactory, partly because >50% of HCC exhibit an ICI-nonresponsive tumor microenvironment characterized by a paucity of cytotoxic T cells (immune-cold), as well as difficulty in their infiltration into tumor sites (immune excluded). To overcome this limitation, combination therapies with locoregional therapies, including ablation, transarterial embolization, and radiotherapy, which are usually used for early stage HCCs, have been actively explored to enhance ICI efficacy by promoting the release of tumor-associated antigens and cytokines, and eventually accelerating the so-called cancer-immunity cycle. Various combination therapies have been investigated in early- to late-phase clinical trials, and some have shown promising results. This comprehensive article provides an overview of the immune landscape for HCC to understand ICI efficacy and its limitations and, subsequently, reviews the status of combinatorial therapies of ICIs with locoregional therapy for HCC.
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