Current status of ctDNA in precision oncology for hepatocellular carcinoma.
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ABSTRACT:
SUBMITTER: Li Y
PROVIDER: S-EPMC8074474 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Hepatocellular carcinoma (HCC) is the fifth most common cancer and the second leading cause of cancer related deaths world-wide. Liver transplantation, surgical resection, trans-arterial chemoembolization, and radio frequency ablation are effective strategies to treat early stage HCC. Unfortunately, HCC is usually diagnosed at an advanced stage and there are not many treatment options for late stage HCC. First-line therapy for late stage HCC includes sorafenib and lenvatinib. However, these treatments provide only an approximate three month increase in survival. Besides, they cannot specifically target cancer cells that lead to a wide array of side effects. Patients on these drugs develop resistance within a few months and have to rely on second-line therapy that includes regorafenib, pembrolizumab, nivolumab, and cabometyx. These disadvantages make gene therapy approach to treat HCC an attractive option. The two important questions that researchers have been trying to answer in the last 2-3 decades are what genes should be targeted and what delivery systems should be used. The objective of this review is to analyze the changing landscape of HCC gene therapy, with a focus on these two questions.
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Project description:Hepatocellular carcinoma (HCC) is the second most common cause of cancer death worldwide. This cancer commonly arises against a background of chronic liver disease. As a result, a patient with HCC requires multidisciplinary care. Treatment options vary widely based on tumor burden and metastases. The most widely utilized staging system is the Barcelona Clinic Liver Cancer staging system, which recommends treatments based on tumor size and the underlying liver disease and functional status of the patient. Treatment options range from surgical resection or transplantation to locoregional therapies with modalities such as radiofrequency ablation and transarterial chemoembolization to systemic chemotherapies. Future care involves the development of combination therapies that afford the best tumor response, further clarification of the patients best suited for therapies and the development of new oral chemotherapeutic agents.
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Project description:The discovery of the immune checkpoint mechanism has contributed greatly to recent advances in cancer treatment. The anticytotoxic T lymphocyte-associated protein 4 antibody ipilimumab was first approved as a therapeutic drug for malignant melanoma in the USA in 2011; since then, antiprogrammed cell death 1 (PD-1) antibody and antiprogrammed death-ligand 1 (PD-L1) antibody have also been approved and clinically introduced and are indicated for the treatment of various cancers. Numerous clinical studies are now underway to evaluate the efficacy of immune checkpoint inhibitors for patients with many kinds of cancer, including hepatocellular carcinoma (HCC), and the outcomes of these trials are highly anticipated. Synergic effects of immune checkpoint inhibitors used in combination with molecular targeted agents or local therapy have also been suggested, resulting in expectations regarding the use of these drugs in combination with existing standard treatment methods for HCC. Thus, the treatment of HCC is now entering an age of significant innovation triggered by the clinical introduction of immune checkpoint inhibitors.
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Project description:The management of hepatocellular carcinoma (HCC) has substantially changed in the past few decades, the introduction of novel therapies (such as sorafenib) have improved patient survival. Nevertheless, HCC remains the third most common cause of cancer-related deaths worldwide. Decision-making largely relies on evidence-based criteria, as showed in the US and European clinical practice guidelines, which endorse five therapeutic recommendations:resection; transplantation; radiofrequency ablation; chemoembolization; and sorafenib. Many molecularly targeted agents that inhibit angiogenesis, epidermal growth factor receptor, and mammalian target of rapamycin are at different stages of clinical development in advanced HCC. Future research should continue to unravel the mechanism of hepatocarcinogenesis and to identify key relevant molecular targets for therapeutic intervention. Identification and validation of potential surrogate and predictive biomarkers hold promise to individualize patient's treatment to maximize clinical benefit and minimize the toxicity and cost of targeted agents.
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Project description:Radiofrequency ablation (RFA) is widely accepted as a first-line interventional oncology approach for hepatocellular carcinoma (HCC) and has the advantages of high treatment efficacy and low complication risk. Local control rates equivalent to hepatic resection can be reached by RFA alone when treating small HCCs (<2?cm) in favorable locations. However, local tumor progression and recurrence rates with RFA monotherapy increase sharply when treating larger lesions (>3?cm). To address this clinical problem, recent efforts have focused on multimodel management of HCC by combining RFA with different techniques, including percutaneous ethanol injection, transarterial chemo-embolization, targeted molecular therapy, nanoparticle-mediated therapy, and immunotherapy. The combination strategy indeed leads to better outcomes in comparison to RFA alone. In this article, we review the current status of RFA-combined multimodal therapies in the management of HCC.
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Project description:Pancreatic cancer remains one of the major causes of cancer-related mortality. The majority of pancreatic cancer patients are diagnosed at the advanced stage with unresectable and drug resistant tumors. The new treatments with the combination of chemotherapy, molecular targeted therapy, and immunotherapy have shown modest effects on therapeutic efficacy and survival of the patients. Therefore, there is an urgent need to develop effective therapeutic approaches targeting highly heterogeneous pancreatic cancer cells and tumor microenvironments. Recent advances in biomarker targeted cancer therapy and image-guided drug delivery and monitoring treatment response using multifunctional nanoparticles, also referred to as theranostic nanoparticles, offer a new opportunity of effective detection and treatment of pancreatic cancer. Increasing evidence from preclinical studies has shown the potential of applications of theranostic nanoparticles for designing precision oncology approaches for pancreatic cancer therapy. In this review, we provide an update on the current understanding and strategies for the development of targeted therapy for pancreatic cancer using nanoparticle drug carriers. We address issues concerning drug delivery barriers in stroma rich pancreatic cancer and the potential approaches to improve drug delivery efficiency, therapeutic responses and tumor imaging. Research results presented in this review suggest the development of an integrated therapy protocol through image-guided and targeted drug delivery and therapeutic effect monitoring as a promising precision oncology strategy for pancreatic cancer treatment.
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Project description:To develop diagnostic and prognostic biomarkers, we compared methylation profiles of HCC tissues and normal blood by analyzing 485,000 CpG markers and identified a HCC enriched methylation marker panel compared to that of normal blood. We found there was a highly correlation of methylation profiles between DNA from HCC cancer tissue and matched plasma ctDNA within the same patient. We then selected 10 markers from this panel and created a combined diagnosis score (cd-score) which showed high diagnostic specificity and sensitivity in both a training cohort and an independent validation cohort. We also showed the cd-score correlate highly with tumor load, treatment response and stage and is superior to that by AFP. We also showed the cd-score correlate highly with tumor load, treatment response and stage and is superior to that by AFP. Additional, we generated 8 markers from unicox and LASSO-cox analysis and created a combined prognosis score (cp-score) which could predict prognosis and survival. Together, these findings demonstrated the utility of ctDNA methylation markers in the diagnosis, treatment evaluation and prognosis of HCC.
2019-01-01 | GSE93203 | GEO
Project description:Immune checkpoint inhibitors (ICIs) represent a promising treatment for many kinds of cancers, including hepatocellular carcinoma (HCC). The rationale for using ICIs in HCC is based on the immunogenic background of hepatitis and cirrhosis and on the observation of high programmed death-ligand 1 (PD-L1) expression and tumor-infiltrating lymphocytes in this cancer. Promising data from phase?I/II studies in advanced HCC, showing durable objective response rates (~20% in first- and second-line settings) and good safety profile, have led to phase III studies with ICIs as single agents or in combination therapy, both in first and second line setting. While the activity of immunotherapy agents as single agents seems to be limited to an "ill-defined" small subset of patients, the combination of the anti PD-L1 atezolizumab and anti-vascular endothelial growth factor bevacizumab revealed a benefit in the outcomes when compared to sorafenib in the first line. In addition, the activity and efficacy of the combinations between anti-PD-1/anti-PD-L1 antibody and other ICIs, tyrosine kinase inhibitors, or surgical and locoregional therapies, has also been investigated in clinical trials. In this review, we provide an overview of the role of ICIs in the management of HCC with a critical evaluation of the current status and future directions.
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Project description:A growing body of literature highlights the cross-talk between tumor cells and the surrounding peri-tumoral stroma as a key modulator of the processes of hepatocarcinogenesis, epithelial mesenchymal transition (EMT), tumor invasion and metastasis. The tumor microenvironment can be broadly classified into cellular and non-cellular components. The major cellular components include hepatic stellate cells, fibroblasts, immune, and endothelial cells. These cell types produce the non-cellular components of the tumor stroma, including extracellular matrix (ECM) proteins, proteolytic enzymes, growth factors and inflammatory cytokines. The non-cellular component of the tumor stroma modulates hepatocellular carcinoma (HCC) biology by effects on cancer signaling pathways in tumor cells and on tumor invasion and metastasis. Global gene expression profiling of HCC has revealed that the tumor microenvironment is an important component in the biologic and prognostic classification of HCC. There are substantial efforts underway to develop novel drugs targeting tumor-stromal interactions. In this review, we discuss the current knowledge about the role of the tumor microenvironment in pathogenesis of HCC, the role of the tumor microenvironment in the classification of HCC and efforts to develop treatments targeting the tumor microenvironment.
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