Recently, 2021 American Society of Clinical Oncology (ASCO) Annual Meeting announced the abstract of a fourth generation of GPC3 CAR-T (4G-CAR-GPC3 T) cells therapy. The abstract suggested that 4G-CAR-GPC3 T cells treatment in hepatocellular carcinoma contributed to a 50% disease control rate. Besides, 4G-CAR-GPC3 T cells treated alone or in combination with TKIs showed a manageable safety profile. In early 2020, a Chinese team firstly conducted a clinical trial of GPC3 CAR-T therapy in advanced HCC. The patients showed excellent tolerance and clinical benefit [1]. To date, increasing studies identified that GPC3 was closely related to the prognosis of hepatocellular carcinoma. GPC3 has emerged as one of the most promising targets for hepatocellular carcinoma treatment. So, what is GPC3? How's the potential of GPC3 in cancer immunotherapy? Let's learn more about it.
1. What Is the Structure of GPC3 and Its Functions?
2. What Signal Transduction Pathways Are Associated with GPC3?
3. How's the Role of GPC3 in Cancer?
Glypican-3 (GPC3), also known as MXR7, OCI-5, GTR2-2, is a member of the heparan sulfate proteoglycan (HSPG) family [2]. The GPC3 gene is located on human chromosome Xq26.10. It is an HSPG glycoprotein anchored to the cell membrane by glycosylphosphatidylinositol (GPI). As shown in Figure 1, GPC3 encodes 580 amino acids with a core protein relative molecular mass of approximately 70 kDa [3, 4]. The internal cleavage site generates an ∼40-kDa N-terminal subunit, as well as an ∼30-kDa C-terminal subunit that carries two acetyl heparan sulfate (HS) chains, which is involved in regulating the relevant signaling pathways [5-7].
Figure 1. GPC3 structure
*The figure was derived from European journal of cancer publications [4]
GPC3 is highly expressed in normal embryonic tissues, including liver and placenta, while absent in normal adult tissues [8]. GPC3 interacts with various ligands and receptors, such as extracellular matrix components, cell adhesion molecules, growth factors, enzymes and enzyme inhibitors. Numerous studies have found that highly expressed GPC3 is closely related to the prognosis of hepatocellular carcinoma [9]. In addition, expression of GPC3 in other tumors has also been identified, such as melanoma and ovarian clear cell carcinoma [10, 11]. Studies suggest that GPC3 may be involved in multiple signaling pathways and play important roles in tumor cells growth.
Currently, a large number of studies have focused on the specific expression of GPC3 in HCC cells, but its mechanism hasn't been clarified clearly. As shown in Figure 2, there are three theories: 1) Hedgehog (Hh) signaling pathway, GPC3 can bind to Hh, resulting in the loss of binding ability of Hh to its receptor Ptc. Ptc inhibits Smo protein activity, thereby inhibiting the downstream pathways; 2) Wnt signaling pathway, overexpressed GPC3 can upregulate the c-Myc expression, which is a key protein in Wnt signaling pathway. c-Myc can also increase GPC3 expression at the transcriptional level. It has been shown that mutated GPC3 can block the Wnt signaling pathway and inhibit Wnt-dependent tumor growth; 3) FGF2 signaling pathway, it has been found that GPC3 can bind to FGF2, which could restrain the activity of FGF2 and BMP-7, thus inhibiting the growth of HCC cells [12, 13].
Figure 2. GPC3-related signal transduction pathways
*The figure was derived from Medicinal research reviews [12]
In addition, as mentioned earlier, the C-terminus of GPC3 contains two HS chains. Although the HS chains of GPC3 does not play its roles in the interaction of GPC3 with Wnt and Hh pathway, it has been suggested that the HS chains can interact with the growth factor FGF2 and then regulate cell growth [14]. Additionally, researches also showed that GPC3 protein can bind to insulin-like growth factor 2 (IGF2) and insulin-like growth factor type I receptor (IGFIR) to induce HCC cells growth [15]. Currently, GPC3 as a diagnostic biomarker for HCC, it values should not be underestimated.
GPC3, a new tumor marker for HCC, has been widely reported for its specific high expression in HCC tissues. More studies have found that GPC3 is also associated with a variety of cancers and is differentially expressed in tumor tissues. It is highly expressed in non-small cell lung cancer, melanoma, ovarian yolk sac tumor, ovarian clear cell carcinoma, and colon cancer. The low expression of GPC3 was observed in ovarian cancer, and bile duct cancer [16, 17], but GPC3 has been reported to be upregulated or downregulated in gastric cancer [18]. Currently, the diagnostic significance of GPC3 in human tumors other than HCC needs to be further investigated.
In HCC, extensive data have shown that GPC3-positive patients have a lower 5-year survival rate than GPC3-negative patients [19-20]. In addition, GPC3 is a potential and reliable biomarker for predicting tumor recurrence and overall survival after radical resection in HCC patients. Patients with low GPC3 expression generally have a good prognosis, while upregulated GPC3 expression is used as a key indicator for cancer recurrence. Although targeting GPC3 has become a hot topic in the treatment of hepatocellular carcinoma, the role of GPC3 in other tumors is largely unknown. Therefore, more in-depth study would be necessary to find a more way for tumor immunotherapy.
So far, there are no targeted drugs for GPC3 available worldwide. Targeted therapies against GPC3 protein mainly include antibodies, antibody-drug couples (ADCs), immunotoxins, tumor vaccines, targeted peptides, chimeric antigen receptors, gene therapy, etc. In recent years, researchers have conducted a large number of drug development and cell therapy studies targeting GPC3, some of which have entered clinical trials, such as the GPC3 humanized monoclonal antibody GC33, GPC3-peptide vaccine, and chimeric antigen receptor modified T cells (CAR-T) targeting GPC3. Here, a summary of clinical drugs of targeting GPC3 was shown in the table.
Name | Research Phase | Company | Indications | Last update date |
---|---|---|---|---|
ECT-204 | Phase II | / | Liver cancer; Hepatocellular carcinoma; |
2021-05-06 |
Anti-GPC3 chimeric antigen receptor T cell therapy (Shanghai Genechem) | Phase II | Shanghai GeneMed Technology Co; | Liver cancer; Hepatocellular carcinoma; |
2020-12-18 |
Anti-CD3/MUC1-armed cytokine-induced killer cells | Phase II | Bencom Biopharmaceutical (Shenzhen) Co; | Lung cancer; Liver cancer; Colorectal cancer; Breast cancer; Renal cell carcinoma; Stomach cancer; Pancreatic cancer; |
2020-12-18 |
Codrituzumab/GC33 | Phase II | Chugai Pharmaceutical Co; Roche; |
Hepatocellular carcinoma; | 2020-08-28 |
GPC-3298306 | Phase II | National Cancer Center Of Japan; | Hepatocellular carcinoma; Ovarian cancer; |
2020-08-28 |
ERY-974 | Phase I | Chugai Pharmaceutical Co; | Solid tumors; | 2020-08-28 |
GPC3-CAR-T cell therapy (Beijing Tsinghua Chang Gung Hospital) | Phase I | Beijing Tsinghua Changgeng Hospital; | Hepatocellular carcinoma; | 2020-12-18 |
MDX-1414 | Phase I | Bristol-Myers Squibb; | Tumors; | 2020-08-28 |
Anti-GPC3 chimeric antigen receptor T cell therapy (Hunan Yongren Medical Innovation/Guangdong Zhaotai InVivo Biomedicine) | Phase I | Hunan Zhaotai Medical Group Co; | Lung cancer; Liver cancer; |
2020-12-18 |
GPC3-CAR-T cell therapy (targeting phosphatidylinositol proteoglycan-3 chimeric antigen receptor-modified autologous T cells) | Phase I | Keji Biomedical (Shanghai) Co; | Solid tumors; Hepatocellular carcinoma; Squamous cell carcinoma; |
2020-08-28 |
Anti-GPC3 CAR T-cell therapy (Nanjing University) | Phase I | Nanjing University; | Hepatocellular carcinoma; | 2020-12-18 |
GLYCAR T cell therapy (Baylor College of Medicine) | Phase I | Baylor College of Medicine; | Hepatocellular carcinoma; | 2020-08-28 |
GPC3-T2 CAR-T cell therapy (The Second Affiliated Hospital of Guangzhou Medical University) | Phase I | The Second Hospital of Guangzhou Medical University; | Hepatocellular carcinoma; Squamous cell carcinoma; |
2020-12-18 |
B010-A | Clinical stage unknown | Shanghai Pharmaceutical Group Co; | Hepatocellular carcinoma; | 2021-03-15 |
GPC3 CAR-T (HuaDao CAR-Tcell) | Preclinical | Huadao (Shanghai) Biopharmaceutical Co; | Hepatocellular carcinoma; | 2020-08-28 |
GPC3-CART(Shanghai Unicar-Therapy Bio-Medicine Technology) | Preclinical | Shanghai Ucadi Bio-medical Technology Co; | Liver cancer; | 2020-12-18 |
HLX-63 | Preclinical | Shanghai Fohong Hanlin Bio-pharmaceutical Co; | Solid tumors; | 2021-01-04 |
LQ-102 | Preclinical | / | Hepatocellular carcinoma; | 2021-02-04 |
*This data was derived from pharmacodia
GC33 (Codrituzumab) is the first antibody targeting GPC3, but data from clinical trials show that GC33 does not completely eliminate HCC cells. In addition, GPC-3298306, a tumor vaccine based on GPC3 for the treatment of HCC, has entered the phase II clinical trial. The results of the clinical trials are not available currently. In CAR-T cell immunotherapy targeting GPC3, clinical results have shown that targeting GPC3 can inhibit the cells growth of HCC and is considered as a promising target in cancer immunotherapy.
A growing body of evidence suggests that GPC3 is an attractive target option for cancer drug development and a promising molecular target for improving prognosis of tumor patients. Although the molecular signaling pathway of GPC3 in HCC cells growth has not been fully elucidated, the value of GPC3 as a biomarker in early diagnosis, prognosis determination, and immunotherapy of HCC has gradually emerged. Deeper exploration on GPC3, combined with immunotherapy such as antibodies, vaccines, and CAR-T, is expected to provide new directions for effective cancer treatment.
Recombinant HumanGPC3 (G537R), partial (Active) (CSB-MP009705HU(M))
References
[1] Shi, Donghua, et al. "Chimeric antigen receptor-glypican-3 T-cell therapy for advanced hepatocellular carcinoma: Results of phase I Trials." Clinical Cancer Research 26.15 (2020): 3979-3989.
[2] Feng, Mingqian, et al. "Recombinant soluble glypican 3 protein inhibits the growth of hepatocellular carcinoma in vitro." International journal of cancer. journal international du cancer 128.9 (2011): 2246.
[3] Zong, Jingjing, Zhe Fan, and Yewei Zhang. "Serum Tumor Markers for Early Diagnosis of Primary Hepatocellular Carcinoma. "Journal of Hepatocellular Carcinoma 7 (2020): 413.
[4] Ho, Mitchell, and Heungnam Kim. "Glypican-3: a new target for cancer immunotherapy. "European journal of cancer 47.3 (2011): 333- 338.
[5] Nishida, Takahiro, and Hiroaki Kataoka. "Glypican 3-targeted therapy in hepatocellular carcinoma. "Cancers 11.9 (2019): 1339.
[6] Montalbano, Mauro, et al. "Role of Glypican-3 in the growth, migration and invasion of primary hepatocytes isolated from patients with hepatocellular carcinoma." Cellular Oncology 41.2 (2018): 169-184.
[7] Filmus, Jorge, and Mariana Capurro. "Glypican-3: a marker and a therapeutic target in hepatocellular carcinoma. "The FEBS journal 280.10 (2013): 2471-2476.
[8] Ou-Yang, Robin J., et al. "Expression of glypican 3 in placental site trophoblastic tumor." Diagnostic pathology 5.1 (2010): 1-6.
[9] Pan, Zhijian, et al. "Overexpression of GPC3 inhibits hepatocellular carcinoma cell proliferation and invasion through induction Molecular medicine reports 7.3 (2013): 969-974.
[10] Maeda, Daichi, et al. "Glypican-3 expression in clear cell adenocarcinoma of the ovary." modern pathology 22.6 (2009): 824-832.
[11] Nakatsura, Tetsuya, et al. "Identification of glypican-3 as a novel tumor marker for melanoma." clinical cancer research 10.19 ( 2004): 6612-6621.
[12] Zhou, Fubo, et al. "Glypican-3: A promising biomarker for hepatocellular carcinoma diagnosis and treatment." medicinal research reviews 38.2 (2018): 741-767.
[13] Midorikawa, Yutaka, et al. "Glypican-3, overexpressed in hepatocellular carcinoma, modulates FGF2 and BMP-7 signaling. " International journal of cancer 103.4 (2003): 455-465.
[14] Nakano, Kiyotaka, et al. "Anti-glypican 3 antibodies cause ADCC against human hepatocellular carcinoma cells. "Biochemical and biophysical research communications 378.2 (2009): 279-284.
[15] Sung, Young Kwan, et al. "Glypican-3 is overexpressed in human hepatocellular carcinoma." cancer science 94.3 (2003): 259-262.
[16] Murthy, Siva S., et al. "Expression of GPC3, an X-linked recessive overgrowth gene, is silenced in malignant mesothelioma." Oncogene 19.3 (2000): 410-416.
[17] Peters, M. G., et al. "Inhibition of invasion and metastasis by glypican-3 in a syngeneic breast cancer model." Breast cancer research and treatment 80.2 (2003): 221-232.
[18] Lin, Qiang, et al. "Expression of GPC3 protein and its significance in lung squamous cell carcinoma." medical oncology 29.2 (2012) : 663-669.
[19] Li, B., et al. "Diagnostic value of glypican-3 in alpha fetoprotein negative hepatocellular carcinoma patients. "African health sciences 13.3 (2013): 703-709.
[20] Ning, Su, et al. "Glypican-3, a novel prognostic marker of hepatocellular cancer, is related with postoperative metastasis and recurrence in hepatocellular cancer patients." Molecular biology reports 39.1 (2012): 351-357.
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