EpCAM-Targeted Therapy for Human Hepatocellular Carcinoma

Ogawa, Kousuke; Tanaka, Shinji; Matsumura, Satoshi; Murakata, Ayano; Ban, Daisuke; Ochiai, Takanori; Irie, Tetsumi; Kudo, Atsushi; Nakamura, Noriaki; Tanabe, Minoru; Arii, Shigeki

doi:10.1245/s10434-013-3430-7

Cited by 46 publications

(30 citation statements)

References 32 publications

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“…Previous studies reported that VB4-845, an immunotox in targeting EpCAM, showed potent cytotoxicity and was significantly effective in combination with 5-FU in hepatocellular carcinoma cells [20]. Treatment with an anti-EpCAM monoclonal antibody (MAb17-1A) combined with alpha-interferon; 5-FU and granulocyte-macrophage colony-stimulating factor could improve the therapeutic effect in patients with metastatic colorectal carcinoma [21].…”

Section: Discussionmentioning

confidence: 99%

Knockdown of EpCAM Enhances the Chemosensitivity of Breast Cancer Cells to 5-fluorouracil by Downregulating the Antiapoptotic Factor Bcl-2

et al. 2014

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Resistance to fluoropyrimidine-based chemotherapy is the main reason for the failure of cancer treatment, and drug resistance is associated with an inability of tumor cells to undergo apoptosis in response to treatment. Alterations in the expression of epithelial cell adhesion molecule (EpCAM) affect the sensitivity or resistance of tumor cells to anticancer treatment and the activity of intracellular signaling pathways. However, the role of EpCAM in the induction of apoptosis in breast cancer cells remains unclear. Here, we investigated the effect of EpCAM gene knockdown on chemosensitivity to 5-fluorouracil (5-FU) in MCF-7 cells and explored the underlying mechanisms. Our results showed that knockdown of EpCAM promoted apoptosis, inhibited cell proliferation and caused cell-cycle arrest. EpCAM knockdown enhanced the cytotoxic effect of 5-FU, promoting apoptosis by downregulating the expression of the anti-apoptotic protein Bcl-2 and upregulating the expression of the pro-apoptotic proteins Bax, and caspase3 via the ERK1/2 and JNK MAPK signaling pathways in MCF-7 cells. These results indicate that knockdown of EpCAM may have a tumor suppressor effect and suggest EpCAM as a potential target for the treatment of breast cancer.

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Section: Discussionmentioning

confidence: 99%

Knockdown of EpCAM Enhances the Chemosensitivity of Breast Cancer Cells to 5-fluorouracil by Downregulating the Antiapoptotic Factor Bcl-2

et al. 2014

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“…Another approach for eliminating CSCs has been suggested to be monoclonal antibodies targeting CSC-speciic antigens [46], such as CD13, EpCAM, and CD133 antibodies, against hepatic CSCs [47][48][49]. However, these markers express in not only CSCs but also normal liver cells and tissue SCs.…”

Section: Therapy For Hccmentioning

confidence: 99%

Cancer Stem Cells and Aldehyde Dehydrogenase 1 in Liver Cancers

Tomita¹,

Kanayama²,

Niwa³

et al. 2017

Updates in Liver Cancer

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The cancer stem cell (CSC) theory posits that a small population of cells with stem celllike features is responsible for tumor growth, resistance, and recurrence in many malignancies. This theory could be a useful paradigm for designing innovative targeted drug therapies. Liver cancer is the ifth most common cancer worldwide, with hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) as the predominant forms. Hepatic stem/progenitor cells are believed to be the origin of HCCs and CCAs; however, this remains a controversial topic. Aldehyde dehydrogenase (ALDH) is the main enzymatic system responsible for the clearance of acetaldehyde from the hepatocytes in the liver tissue. Therefore, ALDH1 has been suggested to be a potential, biological and CSC marker in liver cancers. We here provide an overview of the current state of knowledge of CSCs in liver and the role of ALDH1 in the development and progression of liver cancers and discuss its potential value as a prognostic and diagnostic biomarker.

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“…Other targets in HCC include: glypican-3 (GC33), c-Met (onartuzumab), epidermal growth factor receptor (cetuximab), insulin-like growth factor-1 receptor (cixutumumab), insulin-like growth factor I and II (MEDI-573), platelet-derived growth factor receptor A (MEDI-575), activin receptor-like kinase 1 (PF-03446962), endoglin (TRC105), and TROP-2 (sacituzumab) [69,70,71,72,73,74,75]. Additional targets like EpCAM and CD133 are being evaluated in preclinical studies as potential markers for HCC [45,76,77,78]. As HCC is better understood, the list of potential targets will continue to grow.…”

Section: Anti-gpc3 Recombinant Immunotoxinsmentioning

confidence: 99%

“…Immunotoxins have been used to treat intracranial tumors in rodent models by targeting the EGF receptor expressed in glioblastomas [42]. Similarly, anti-c-Met and anti-epithelial cell adhesion molecule (EpCAM) have been evaluated for their ability to target gastric cancer and a wide range of solid tumors including breast, colon, and liver cancers, respectively [43,44,45]. Instead of substituting the antibody portion to make new immunotoxins, it is also possible to substitute the toxin fragment.…”

Section: Introductionmentioning

confidence: 99%

Glypican-3 Targeting Immunotoxins for the Treatment of Liver Cancer

Fleming

2016

Toxins

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Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer, yet no effective therapeutics exist. This review provides an overview of the recent development of recombinant immunotoxins for the treatment of glypican-3 (GPC3) expressing HCC. GPC3 is a cell surface heparan sulfate proteoglycan that is overexpressed in HCC, but is absent from normal adult human tissues. Treatment of HCC with anti-GPC3 immunotoxins represents a new therapeutic option. Using phage display and hybridoma technologies, three high affinity antibodies (HN3, HS20 and YP7) have been generated against GPC3. Two of these antibodies (HN3 and HS20) have demonstrated the ability to inhibit Wnt/Yap signaling, leading to a reduction in liver cancer cell proliferation. By combining the HN3 antibody capable of inhibiting Wnt/Yap signaling with the protein synthesis inhibitory domain of the Pseudomonas exotoxin, a recombinant immunotoxin that exhibits a dual inhibitory mechanism was generated. This immunotoxin was found to be highly effective in the treatment of human HCCs in mouse xenograft models. Engineering of the toxin fragment to reduce the level of immunogenicity is currently being explored. The development of immunotoxins provides opportunities for novel liver cancer therapies.

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EpCAM-Targeted Therapy for Human Hepatocellular Carcinoma

Abstract: Our preclinical investigation suggests that EpCAM-targeted therapy may offer a promising and novel approach for the treatment of HCC with a poorer prognosis.

Cited by 46 publications

References 32 publications

Knockdown of EpCAM Enhances the Chemosensitivity of Breast Cancer Cells to 5-fluorouracil by Downregulating the Antiapoptotic Factor Bcl-2

Knockdown of EpCAM Enhances the Chemosensitivity of Breast Cancer Cells to 5-fluorouracil by Downregulating the Antiapoptotic Factor Bcl-2

Cancer Stem Cells and Aldehyde Dehydrogenase 1 in Liver Cancers

Glypican-3 Targeting Immunotoxins for the Treatment of Liver Cancer

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