Glypican-3: A molecular marker for the detection and treatment of hepatocellular carcinoma☆.
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ABSTRACT:
SUBMITTER: Shih TC
PROVIDER: S-EPMC7771890 | biostudies-literature | 2020 Dec
REPOSITORIES: biostudies-literature
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Glypican-3: A molecular marker for the detection and treatment of hepatocellular carcinoma<sup>☆</sup>.
Shih Tsung-Chieh TC Wang Lijun L Wang Hsiao-Chi HC Wan Yu-Jui Yvonne YY
Liver research (Beijing, China) 20201111 4
Hepatocellular carcinoma (HCC) is a malignant tumor with a fairly poor prognosis (5-year survival of less than 50%). Using sorafenib, the only food and drug administration (FDA)-approved drug, HCC cannot be effectively treated; it can only be controlled at most for a couple of months. There is a great need to develop efficacious treatment against this debilitating disease. Glypican-3 (GPC3), a member of the glypican family that attaches to the cell surface by a glycosylphosphatidylinositol ancho ...[more]
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Project description:Hepatocellular carcinoma (HCC) has a high morbidity and mortality rate worldwide, with limited treatment options. Glypican-3 (GPC3) is a glycosylphosphatidylinositol-anchored glycoprotein that is overexpressed in most HCC tissues but not in normal tissues. GPC3-targeting antibody therapy shows limited response in a clinical trial due to the lack of a tumor-specific cytotoxic T lymphocyte (CTL) response. Here, in C57/B6 mice, we demonstrated that intravenous infusion of GPC3-coupled lymphocytes (LC/GPC3+) elicited robust GPC3-specific antibody and CTL responses, which effectively restricted proliferation and lysed cultured-HCC cells. Treatment with LC/GPC3+ induced durable tumor regression in HCC-bearing C57/B6 mice. Administration of LC/GPC3+ induced elevated levels of the cytotoxic T cell bioactive factors tumor necrosis factor alpha (TNF-α), interferon-γ (IFN-γ), granzyme B, and perforin, and substantially increased the number of infiltrating CD8+ T cells in tumor tissues. Moreover, immune responses elicited by LC/GPC3+ selectively suppressed GPC3+ tumors, but didn't affect the GPC3- tumors in BALB/c mice. Our findings provide the first preclinical evidence that intravenous infusion of the LC/GPC3+ complex can induce a strong anti-HCC effect through regulating systemic and local immune responses. These results indicate that the LC/GPC3+ complex could be developed as precision therapeutics for HCC patients in the future.
| S-EPMC5628867 | biostudies-literature
Project description:BackgroundGlypican-3 (GPC3) expression is investigated as a promising target for tumor-specific immunotherapy of hepatocellular carcinoma (HCC). This study aims to determine whether GPC3 alters the viscoelastic properties of HCC and whether tomoelastography, a multifrequency magnetic resonance elastography (MRE) technique, is sensitive to it.MethodsNinety-five participants (mean age, 58 ± 1 years; 78 men and 17 women) with 100 pathologically confirmed HCC lesions were enrolled in this prospective study from July 2020 to August 2021. All patients underwent preoperative multiparametric MRI and tomoelastography. Tomoelastography provided shear wave speed (c, m/s) representing tissue stiffness and loss angle (φ, rad) relating to viscosity. Clinical, laboratory, and imaging parameters were compared between GPC3-positive and -negative groups. Univariable and multivariable logistic regression were performed to determine factors associated with GPC3-positive HCC. The diagnostic performance of combined biomarkers was established using logistic regression analysis. Area-under-the-curve (AUC) analysis was done to assess diagnostic performance in detecting GPC3-positive HCC.FindingsGPC3-positive HCCs (n=72) had reduced stiffness compared with GPC3-negative HCCs (n=23) while viscosity was not different (c: 2.34 ± 0.62 versus 2.72 ± 0.62 m/s, P=0.010, φ: 1.11 ± 0.21 vs 1.18 ± 0.27 rad, P=0.21). Logistic regression showed c and elevated serum alpha-fetoprotein (AFP) level above 20 ng/mL were independent factors for GPC3-positive HCC. Stiffness with a cutoff of c = 2.8 m/s in conjunction with an elevated AFP yielded a sensitivity of 80.3%, specificity of 70.8%, and AUC of 0.80.InterpretationReduced stiffness quantified by tomoelastography may be a mechanical signature of GPC3-positive HCC. Combining reduced tumor stiffness and elevated AFP level may provide potentially valuable biomarker for GPC3-targeted immunotherapy.
| S-EPMC9744252 | biostudies-literature
Project description:Glypican-3 (GPC3) is an oncofetal glycoprotein attached to the cell membrane by a glycophosphatidylinositol anchor. GPC3 is overexpressed in some kinds of tumors, particularly hepatocellular carcinoma (HCC). The prognostic significance of serum GPC3 levels and GPC3 immunoreactivity in tumor cells has been defined in patients with HCC. In addition to its usefulness as a biomarker, GPC3 has attracted attention as a novel therapeutic target molecule, and clinical trials targeting GPC3 are in progress. The major mechanism of anti-GPC3 antibody (GPC3Ab) against cancer cells is antibody-dependent cellular cytotoxicity and/or complement-dependent cytotoxicity. Since GPC3Ab is associated with immune responses, a combination of protocols with immune checkpoint inhibitors has also been investigated. Moreover, some innovative approaches for GPC3-targeting therapy have emerged in recent years. This review introduces the results of recent clinical trials targeting GPC3 in HCC and summarizes the latest knowledge regarding the role of GPC3 in HCC progression and clinical application targeting GPC3.
| S-EPMC6770328 | biostudies-literature
Project description:Glypican-3 (GPC3) is a tumor associated antigen expressed by hepatocellular carcinoma (HCC) cells. This preclinical study evaluated the efficacy of a theranostic platform using a GPC3-targeting antibody αGPC3 conjugated to zirconium-89 (89Zr) and yttrium-90 (90Y) to identify, treat, and assess treatment response in a murine model of HCC. A murine orthotopic xenograft model of HCC was generated. Animals were injected with 89Zr-labeled αGPC3 and imaged with a small-animal positron emission/computerized tomography (PET/CT) imaging system (immuno-PET) before and 30 days after radioimmunotherapy (RIT) with 90Y-labeled αGPC3. Serum alpha fetoprotein (AFP), a marker of tumor burden, was measured. Gross tumor volume (GTV) and SUVmax by immuno-PET was measured using fixed intensity threshold and manual segmentation methods. Immuno-PET GTV measurements reliably quantified tumor burden prior to RIT, strongly correlating with serum AFP (R2 = 0.90). Serum AFP was significantly lower 30 days after RIT in 90Y-αGPC3 treated animals compared to those untreated (p = 0.01) or treated with non-radiolabeled αGPC3 (p = 0.02). Immuno-PET GTV measurements strongly correlated with tumor burden after RIT (R2 = 0.87), and GTV of animals treated with 90Y-αGPC3 was lower than in animals who did not receive treatment or were treated with non-radiolabeled αGPC3, although this only trended toward statistical significance. A theranostic platform utilizing GPC3 targeted 89Zr and 90Y effectively imaged, treated, and assessed response after radioimmunotherapy in a GPC3-expressing HCC xenograft model.
| S-EPMC7881163 | biostudies-literature
Project description:Hepatocellular carcinoma (HCC) is the most prevalent form of primary liver cancer and the second leading cause of cancer-related mortality globally. Despite advancements in current HCC treatment, it remains a malignancy with poor prognosis. Therefore, developing novel treatment options for patients with HCC is urgently needed. Chimeric antigen receptor (CAR)-modified natural killer (NK) cells have demonstrated potent anti-tumor effects, making them as a promising immunotherapy strategy for cancer treatment. Glypican-3 (GPC3), a cell surface oncofetal glycoprotein, is highly expressed in most HCC tissues, but not in normal tissues, and functions as a key driver of carcinogenesis. Given its high expression level on the cell surface, GPC3 is considered as an attractive immunotherapy target for HCC. In this study, two GPC3-specific CAR-NK cells, NK92MI/HN3 and NK92MI/HS20, were established using NK92MI cells, a modified IL-2-independent NK cell line. These cell lines were engineered with third generation GPC3-specific CARs, and their activities were subsequently evaluated in the treatment of HCC. We found that NK92MI/HN3 cells, rather than NK92MI/HS20 cells, exhibited a significant cytotoxicity effect against GPC3+ HepG2 cells in vitro and efficiently suppressed tumor growth in a xenograft model using NSG mice. In addition, irradiated NK92MI/HN3 cells displayed similar anti-tumor efficacy to unirradiated NK92MI/HN3 cells. Furthermore, we observed that NK92MI/HN3 cells showed higher killing activity against the GPC3 isoform 2 overexpression cell line (Sk-Hep1-v2) than those with GPC3 isoform 1 overexpression cell line (Sk-Hep1-v1). This suggest that the presence of different GPC3 isoforms in HCC may impact the cytotoxicity activity of NK92MI/HN3 cells and potentially influence therapeutic outcomes. These findings highlight the effective anti-HCC effects of NK92MI/HN3 cells and reveal the role of GPC3 isoforms in influencing therapy outcomes, suggesting that isoform analysis should be considered to optimize CAR-NK therapies to improve patient outcomes.
| S-EPMC11753693 | biostudies-literature
Project description:Predicting the risk of hepatocellular carcinoma (HCC) recurrence before treatment is necessary for developing subsequent treatment policies. Several tumor markers found in blood, such as alpha-fetoprotein (AFP) and protein induced by vitamin K absence or antagonist-II (PIVKA-II), are presently used to determine the occurrence and recurrence of HCC and to predict patient prognosis. However, these markers are insufficient for these purposes as certain patients have HCC recurrence despite exhibiting negative AFP and PIVKA-II. The present study identified glypican-3 (GPC3), an embryonal carcinoma antigen that is expressed specifically in HCC and is secreted into blood. Although the N-terminal domain of GPC3 in sera may be a potential prognostic factor for HCC, its biological role remains unclear. By contrast, full-length GPC3 (FL-GPC3) is reported to serve important roles in cell differentiation, proliferation and signaling events that cause HCC. Given the biological roles of FL-GPC3 in HCC progression, the present study evaluated its potential as a predictive marker of HCC recurrence. In the present study, a novel measurement system was constructed to specifically measure plasma FL-GPC3. Subsequently, its ability to predict recurrence after radical surgery in 39 HCC patients was evaluated. The results revealed that preoperative FL-GPC3 levels in patients with recurrence were significantly higher than those in patients without recurrence, suggesting that FL-GPC3 could be a better predictive maker of risk of recurrence than AFP or PIVKA-II. Furthermore, it was determined that the combination of FL-GPC3, AFP and PIVKA-II could predict recurrence within one year of radical surgery with high sensitivity and specificity. Based on these results, the validation of FL-GPC3 as a predictive marker of HCC recurrence in a larger population is warranted.
| S-EPMC7068289 | biostudies-literature
Project description:UnlabelledHepatocellular carcinoma (HCC) is a devastating malignancy in which imperfect imaging plays a primary role in diagnosis. Glypican-3 (GPC3) is an HCC-specific cell surface proteoglycan overexpressed in most HCCs. This paper presents the use of (89)Zr-conjugated monoclonal antibody against GPC3 ((89)Zr-αGPC3) for intrahepatic tumor localization using PET.MethodsPolymerase chain reaction confirmed relative GPC3 expression in cell lines. In vitro binding, in vivo biodistribution, and small-animal PET studies were performed on GPC3-expressing HepG2 and non-GPC3-expressing HLF and RH7777 cells and orthotopic xenografts.Results(89)Zr-αGPC3 demonstrated antibody-dependent, antigen-specific tumor binding. HepG2 liver tumors exhibited high peak uptake (836.6 ± 86.6 percentage injected dose [%ID]/g) compared with background liver (27.5 ± 1.6 %ID/g). Tumor-to-liver contrast ratio was high and peaked at 32.5. The smallest HepG2 tumor (<1 mm) showed lower peak uptake (42.5 ± 6.4 %ID/g) and tumor-to-liver contrast (1.57) but was still clearly visible on PET. Day 7 tissue activity was still substantial in HepG2 tumors (466.4 ± 87.6 %ID/g) compared with control RH7777 tumors (3.9 ± 1.3 %ID/g, P < 0.01), indicating antigen specificity by (89)Zr-αGPC3. HepG2 tumor treated with unlabeled αGPC3 or heat-denatured (89)Zr-αGPC3 demonstrated tumor activity (2.1 %ID/g) comparable to that of control xenografts, confirming antibody dependency.ConclusionThis study demonstrated the feasibility of using (89)Zr-αGPC3 to image HCC in the liver, as well as the qualitative determination of GPC3 expression via small-animal PET. The ability to clarify the identity of small liver lesions with an HCC-specific PET probe would provide clinicians with vital information that could significantly alter patient management, warranting further investigation for clinical translation.
| S-EPMC4116087 | biostudies-literature
Project description:Glypican-3 (GPC3) is expressed in 75% of hepatocellular carcinoma (HCC), but not normal liver, making it a promising HCC therapeutic target. GC33 is a full-length humanized monoclonal IgG1 specific to GPC3 that can localize to HCC in vivo. GC33 alone failed to demonstrate therapeutic efficacy when evaluated in patients with HCC; however, we posit that cytotoxic functionalization of the antibody with therapeutic radionuclides, may be warranted. Alpha particles, which are emitted by radioisotopes such as Actinium-225 (Ac-225) exhibit high linear energy transfer and short pathlength that, when targeted to tumors, can effectively kill cancer and limit bystander cytotoxicity. Macropa, an 18-member heterocyclic crown ether, can stably chelate Ac-225 at room temperature. Here, we synthesized and evaluated the efficacy of [225Ac]Ac-Macropa-GC33 in mice engrafted with the GPC3-expressing human liver cancer cell line HepG2. Following a pilot dose-finding study, mice (n = 10 per group) were treated with (1) PBS, (2) mass-equivalent unmodified GC33, (3) 18.5 kBq [225Ac]Ac-Macropa-IgG1 (isotype control), (4) 9.25 kBq [225Ac]Ac-Macropa-GC33, and (5) 18.5 kBq [225Ac]Ac-Macropa-GC33. While significant toxicity was observed in all groups receiving radioconjugates, the 9.25 kBq [225Ac]Ac-Macropa-GC33 group demonstrated a modest survival advantage compared to PBS (p = 0.0012) and 18.5 kBq [225Ac]Ac-IgG1 (p = 0.0412). Hematological analysis demonstrated a marked, rapid reduction in white blood cells in all radioconjugate-treated groups compared to the PBS and unmodified GC33 control groups. Our studies highlight a significant disadvantage of using directly-labeled biomolecules with long blood circulation times for TAT. Strategies to mitigate such treatment toxicity include dose fractionation, pretargeting, and using smaller targeting ligands.
| S-EPMC7792624 | biostudies-literature
Project description:Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related death in the world. Therapeutic outcomes of HCC remain unsatisfactory, and novel treatments are urgently needed. GPC3 (glypican-3) is an emerging target for HCC, given the findings that 1) GPC3 is highly expressed in more than 70% of HCC; (2) elevated GPC3 expression is linked with poor HCC prognosis; and (3) GPC3-specific therapeutics, including immunotoxin, bispecific antibody and chimeric antigen receptor T cells. have shown promising results. Here, we postulate that GPC3 is a potential target of antibody-drug conjugates (ADCs) for treating liver cancer. To determine the payload for ADCs against liver cancer, we screened three large drug libraries (> 9,000 compounds) against HCC cell lines and found that the most potent drugs are DNA-damaging agents. Duocarmycin SA and pyrrolobenzodiazepine dimer were chosen as the payloads to construct two GPC3-specific ADCs: hYP7-DC and hYP7-PC. Both ADCs showed potency at picomolar concentrations against a panel of GPC3-positive cancer cell lines, but not GPC3 negative cell lines. To improve potency, we investigated the synergetic effect of hYP7-DC with approved drugs. Gemcitabine showed a synergetic effect with hYP7-DC in vitro and in vivo. Furthermore, single treatment of hYP7-PC induced tumor regression in multiple mouse models. Conclusion: We provide an example of an ADC targeting GPC3, suggesting a strategy for liver cancer therapy.
| S-EPMC6482108 | biostudies-literature
Project description:Glypican-3 (GPC3) is a developmentally-regulated oncofetal protein that has been established as a clinically-relevant biomarker for early hepatocellular carcinoma (HCC). It is one of the first transcripts to appear during malignant hepatocyte transformation, and is expressed at the protein level in approximately half of high-grade dysplastic macronodules in cirrhotic liver. Several studies show it is expressed in most (75 to 100%) of HCCs confirmed by histopathology. The protein is anchored to the hepatocyte membrane by a glycosyl-phosphatidylinositol (GPI) anchor and shows consistent membrane immunostaining pattern, making it a viable target for immunotherapeutic approaches. Targeting GPC3 for therapeutic intervention is a promising approach for the clinical management of HCC and selected other tumors that express the marker.
| S-EPMC3843004 | biostudies-literature