Abstract
Pediatric hepatoblastoma (HB) is commonly treated by neoadjuvant chemotherapy and surgical tumor resection according to international multicenter trial protocols. Complete tumor resection is essential and survival rates up to 95% have now been achieved in those tumors classified as standard-risk HB. Drug resistance and occurrence of metastases remain the major challenges in the treatment of HB, especially in high-risk tumors. These conditions urgently require the development of alternative therapeutic strategies. One of those alternatives is the modulation of apoptosis in HB cells. HBs regularly overexpress anti-apoptotic proteins of the Bcl-family in comparison to healthy liver tissue. This fact may contribute to the development of chemoresistance of HB cells. Synthetic small inhibitory molecules with BH3-mimetic effects, such as ABT-737 and obatoclax, enhance the susceptibility of tumor cells to different cytotoxic drugs and thereby affect initiator proteins of the apoptosis cascade via the intrinsic pathway. Besides additive effects on HB cell viability when used in combination with cytotoxic drugs, BH3-mimetics also play a role in preventing metastasation by reducing adhesion and inhibiting cell migration abilities. Presumably, including additive BH3-mimetic drugs into existing therapeutic regimens in HB patients might allow dose reduction of established cytotoxic drugs and thereby associated immanent side effects, while maintaining the antitumor activity. Furthermore, reduction of tumor growth and inhibition of tumor cell dissemination may facilitate complete surgical tumor resection, which is mandatory in this tumor type resulting in improved survival rates in high-risk HB. Currently, there are phase I and phase II clinical trials in several cancer entities using this potential target. This paper reviews the available literature regarding the use of BH3-mimetic drugs as single agents or in combination with chemotherapy in various malignancies and focuses on results in HB cells.
Highlights
Hepatoblastoma (HB) is the most common primary malignant pediatric liver tumor in children with an incidence of 1.2 per million and an overall median age at diagnosis of 18 months [1].Histologically, the tumors are divided into epithelial and mixed epithelial/mesenchymal subtypes.Tumor cells may appear with a wide variety of characteristics ranging from almost liver-cell-like to undifferentiated blastomal cells
In a pilot study (SIOPEL-2HR) and the following SIOPEL-3HR trial, carboplatin was added to the PLADO backbone and led to improved survival in patients with PRETEXT-IV tumors (3-year event-free survival (EFS) 68%) or metastases (56%) [15]
This effect was moderate with ABT-737, but may be the result of the Mcl-1 expression in HB cells, which can be targeted more effectively using obatoclax
Summary
Hepatoblastoma (HB) is the most common primary malignant pediatric liver tumor in children with an incidence of 1.2 per million and an overall median age at diagnosis of 18 months [1]. The tumors are divided into epithelial and mixed epithelial/mesenchymal subtypes. Tumor cells may appear with a wide variety of characteristics ranging from almost liver-cell-like to undifferentiated blastomal cells. The majority of HB is epithelial, consisting of embryonal and fetal cells. About 5% of the tumors belong to the small-cell undifferentiated subtype, which is associated with a worse prognosis [2]. HB usually expresses α-fetoprotein (AFP), which is elevated in the serum of 90% of children with this tumor. AFP serves as a tumor marker, as an indicator for treatment response, and as a follow up marker to detect early relapses. The HB cell lines HepT1 (derived from a multifocal embryonal HB [3]) and HuH6 (derived from a mixed HB with focal chondroosteogenic tissue and a squamous cell morphology [4]) were eligible
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