Project title ： Combine targeted therapy with chemotherapy for liver cancer treatment
Principal investigator ： Dr S.T. Cheung, Assistant Professor, Department of Surgery, The Hong Kong University of Hong Kong
    Prof S.T. Fan, Department of Surgery, The Hong Kong University of Hong Kong


First Progress Report
Background
 
Liver cancer is the second major cause of cancer death in China. Surgical resection is the mainstay of curative treatment. However, liver cancer is usually diagnosed at an advanced stage and so precludes curative treatment. Chemotherapy remains the principal approach in treating unresectable HCC. However, both single-agent chemotherapy and combination chemotherapy have shown marginal efficacy. A new treatment strategy is essential to sensitize the cancer cells to chemotherapeutic agents.

We have demonstrated the overexpression of granulin-epithelin precursor (GEP, also called progranulin, acrogranin, or PC-derived growth factor) in primary liver cancer, and that GEP is a therapeutic target for liver cancer treatment. We hypothesize that GEP-targeted therapy will enhance the sensitivity of hepatoma cells to chemotoxic agents. In a pilot study, we demonstrated that GEP-targeted therapy in combination with cisplatin could further enhance treatment efficacy. We propose further pre-clinical studies to examine the optimal regimen for cancer treatment. Specific Aim 1: To examine the functional effect of anti-GEP mAb in combination with chemotoxic agents. Specific Aim 2: To evaluate the treatment efficacy of anti-GEP mAb treatment in combination with chemotoxic agents in mouse model. The study will improve the treatment strategies for liver cancer.
 
Research Progress
 
  1. Neutralization of GEP by anti-GEP mAb further enhanced the anti-proliferative effect induced by conventional chemotherapeutic agents
 
Different classes of drug compounds were examined, including doxorubicin (anti-neoplastic antibiotic), cisplatin (alkylating agent) and 5-Fluorouracil (5-FU) (anti-metabolite). Low dose of chemotherapeutic agents inhibited the proliferation of Hep3B cells by MTT assay (Figure 1). Importantly, combination of low-dose chemo drugs and anti-GEP mAb further enhanced the anti-proliferative effect compared to single-agent treatment.
 
  1. Neutralization of GEP by anti-GEP mAb further enhanced the apoptotic effect induced by chemotherapeutic agents
 
Tumor growth is an imbalanceof cell proliferation and cell death. Thus, the role of anti-GEP mAb in cell apoptosis would need to be elucidated. Anti-GEP mAb treatment alone at 100ug/ml for 24 hours demonstrated no effect on cell apoptosis compared to control treatment (saline control or non-specific mouse IgG control) as examined by flow cytometry. The in vitro observation was consistent with our earlier in vivo study that anti-GEP mAb treatment on Hep3B xenograft in mouse model revealed only decreased proliferation but not significant change in apoptosis by TUNEL staining [Ref 1]. Nonetheless, combination of anti-GEP mAb at 100ug/ml and cisplatin at 4ug/ml demonstrated synergistic effect on induction of apoptosis (28.4%) compared to single-agent treatment (6.7% and 15.8%, respectively) (Figure 2). We will continue the pre-clinical studies to examine the optimal regimen for liver cancer treatment.
 
Research output
 
Invited Lecture. Cheung ST (presenting author) and Fan ST. From Gene Expression Profile to Identification of Molecular Target Granulin-Epithelin Precursor for Liver Cancer. The Ehrlich II – 2nd World Conference on Magic Bullets. Oct 3-5, 2008. Nuremberg, Germany.