Massey scientists awarded $2.6M to develop novel therapies for liver cancer
Scientists at VCU Massey Cancer Center and VCU Institute of Molecular Medicine (VIMM) were awarded $2.6 million to develop targeted therapies to treat the most common and deadliest form of liver cancer.
Devanand Sarkar, MBBS, Ph.D., the associate director for education and training who holds the Harrison Foundation Distinguished Professorship in Cancer Research at Massey and associate director at VIMM, and Paul B. Fisher, M.Ph., Ph.D., FNAI, the Thelma Newmeyer Corman Endowed Chair in Oncology Research and member of the Cancer Molecular Genetics research program at Massey and director at VIMM, received a five-year R01 grant from the National Cancer Institute to study novel combination therapies to improve outcomes for patients with hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is the fifth most prevalent cancer overall and is the second leading cause of cancer deaths worldwide.
“HCC is an extremely aggressive and invariably fatal cancer with no currently effective treatment for advanced disease,” said Sarkar, also a member of the Cancer Molecular Genetics research program at Massey and a professor in the Department of Human and Molecular Genetics at the VCU School of Medicine.
This grant will support the investigation of two interacting genes, AEG-1 and MDA-9, and define their roles in the growth and development of HCC.
Over the last decade, Sarkar has repeatedly demonstrated that AEG-1 functions as a major player in the development of HCC, and he developed a methodology for targeting AEG-1 using a novel drug known as PAMAM-AEG-1si, which has shown significant success in mice.
Recent findings indicate that another gene, MDA-9/Syntenin-1, is overexpressed in human HCC patients and cooperates with AEG-1 in the cell membrane to promote tumor growth. Fisher has developed a novel small molecule inhibitor of MDA-9 named PDZ1i, which holds standalone effect against the invasion of cancer cells and demonstrably inhibits HCC in combination with sorafenib, an FDA-approved drug for unresectable HCC.
“Sorafenib is routinely used for HCC treatment. The combination of sorafenib and PDZ1i, if proven successful in our proposed animal models, has the potential to be fast-tracked for evaluation in Phase 1 and 2 clinical trials,” said Fisher, also the chair of the Department of Human and Molecular Genetics at the VCU School of Medicine.
PDZ1i is also shown to have an increased effect on the growth of HCC cells when AEG-1 is inhibited.
The immediate objective of this research is to evaluate the therapeutic benefits of combinations of both PDZ1i and sorafenib and PDZ1i and PAMAM-AEG-1si in models of HCC and understand the molecular mechanisms by which AEG-1 and MDA-9 cooperate to promote cancer growth. The long-term goal of this research is to develop drugs that provide substantial survival benefit to HCC patients.
“Successful completion of our research holds promise for establishing an effective therapeutic protocol for advanced HCC that will help significantly prolong the lives of scores of cancer patients,” Sarkar and Fisher said.
The research team includes Aliasger Salem, Ph.D., from The University of Iowa.
Sarkar has received an additional $5.4 million through separate grants to investigate alternative targeted treatments for liver cancer. Fisher is a co-founder of InVaMet Therapeutics, a company designed to develop inhibitors of MDA-9 for multiple cancer indications.