New research identifies potential hepatoblastoma treatment target
Washington, US: Hepatoblastoma is the most prevalent juvenile liver cancer. However, it is rare compared to adult liver tumours and its incidences have been rising.
Researchers looking at a mouse model of hepatoblastoma describe in an original study that the protein heat shock transcription factor 1 (HSF1) is required for aggressive tumour growth and may be a promising pharmacologic target for hepatoblastoma treatment.
"This study grew out of my long-standing interest in fetal and perinatal fetal liver development," explained lead investigator Edward H. Hurley, MD, Department of Pediatrics and the Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. "Premature and growth-restricted babies are at increased risk for hepatoblastoma for reasons currently unknown.
"The fact that liver transplantation with its associated lifelong immunotherapy and risk for secondary malignancies is considered a viable option for severe hepatoblastoma speaks to the critical clinical need for more effective therapeutic options for hepatoblastoma-specific therapies that are more effective but with fewer side effects," said Dr Hurley.
"However, the effort to develop more targeted hepatoblastoma-specific therapies has been stymied by the lack of fundamental knowledge about hepatoblastoma biology."
HSF1 is a transcription factor that is a canonical inducer of heat shock proteins (HSPs), which act as chaperone proteins to prevent or undo protein misfolding. Over the last 20 years, there has been a growing appreciation for the role of HSF1 in cancer pathophysiology. Recent work has shown a role for HSF1 in cancer beyond the canonical heat shock response. However, its role in hepatoblastoma remained elusive.
Researchers working at the laboratory of Dr Satdarshan P. Monga at the University of Pittsburgh School of Medicine developed a mouse model of hepatoblastoma based on transfecting mice with constitutively active beta-catenin and yes-associated protein 1 (YAP1) using hydrodynamic tail vein injection. They found increased HSF1 signalling in hepatoblastoma versus normal liver. Also, less differentiated, more embryonic tumours had higher levels of HSF1 than more differentiated, more fetal-appearing tumours.
The research group used the mouse model to test how inhibiting HSF1 early in tumour development would impact cancer growth. They found fewer and smaller tumours when HSF1 was inhibited suggesting HSF1 is needed for aggressive tumour growth. Moreover, increased apoptosis (cell death) in tumour foci was noted when HSF1 is inhibited. This work provides evidence that HSF1 may be a novel biomarker and pharmacologic target for hepatoblastoma.
"We were not surprised by the association of HSF1 signalling and hepatoblastoma given its role in multiple other cancers," commented Dr. Hurley. "We were intrigued to find that less differentiated and more embryonic tumours had higher HSV1 expression levels than fetal-like, more differentiated tumours. However, we were surprised to find an association between HSF1 expression levels and mortality. In in vivo experiments, we anticipated that HSF1 inhibition would slow tumour formation and growth, but we were surprised by the near total prevention of tumour development.
"This work has established the importance of HSF1 in hepatoblastoma development and suggests HSF1 may be a viable pharmacologic target for hepatoblastoma treatment. Currently, HSF1 inhibitors are being developed for other cancers. We can foresee the potential of testing these agents in hepatoblastoma," he concluded.
Hepatoblastoma treatment was developed decades ago for the treatment of adult cancers and currently includes surgical resection with or without chemotherapy, but in severe cases, children require liver transplantation if the tumour cannot be successfully resected.
Every treatment has negative side effects that can affect growth and hearing. The 10-year survival rate for patients with resectable tumours has historically been 86 per cent compared to 39 per cent for non-resectable tumours. The number of individuals undergoing liver transplants climbed from 8 per cent to about 20 per cent between the late 1990s and late 2010.
