Dr. Alan Rapraeger, professor of human oncology at the University of Wisconsin School of Medicine and Public Health, has been awarded a five-year, $1.9 million R01 grant from the National Cancer Institute to investigate signaling mechanisms that drive myeloma cell proliferation, survival and invasion.
Multiple myeloma is a cancer of plasma cells. Patients with this disease experience fatigue, intractable bone pain, renal failure and recurrent infections. Current treatments dramatically slow disease progression and improve survival rates, but patients ultimately relapse.
Rapraeger and his collaborator, Dr. Fotis Asimakopoulos, a UWSMPH associate professor of hematology/oncology who specializes in myeloma, aim to uncover the molecular underpinnings of myeloma signaling and test potential new therapeutics in mouse models.
Rapraeger and members of his laboratory have discovered that syndecans, a family of four cell-matrix adhesion receptors, serve to organize cell surface signaling complexes composed of integrins (matrix receptors) and receptor tyrosine kinases—two types of signaling receptors that are thought to be essential for tumor cells to proliferate, survive and invade.
Rapraeger has studied these mechanisms in a variety of cancers. He recently discovered that syndecan-1, which is highly expressed in myeloma cells, governs key interactions within bone marrow that are critical for myeloma cell growth, survival, drug resistance, invasion, angiogenesis and suppression of immune response.
In this project, Rapraeger will use synstatins—peptides that mimic docking sites on the syndecan—to compete with the syndecan for capture of its integrin and receptor tyrosine kinase partners, thus preventing the receptors from being activated on the tumor cells.
“We are attempting identify receptors on tumor cells that depend on a syndecan and to understand the mechanism,” Rapraeger says. “If we can make a synstatin peptide that specifically prevents the activation of a particular group of receptors, we can use it as a tool to identify the signaling mechanisms have been disrupted. At the same time, we enter it into the pipeline for development as a potential cancer therapeutic. That’s a win-win for us and hopefully for future cancer patients.”
Specifically, this project will investigate three mechanisms that drive myeloma and three potential inhibitors of these mechanisms. One mechanism involves the type 1 insulin-like growth factor receptor (IGF-1R), which is critical for the survival of myeloma cells. Another involves VLA-4, an integrin that enables myeloma cells to adhere to the matrix, grow, survive and develop drug resistance. The third involves vascular endothelial growth factor receptor-2 (VEGFR2), which acts on VLA-4 when the two are coupled to the syndecan to drive myeloma cell invasion and may also suppress recruitment of natural killer cells and cytotoxic T-cells to the tumor.
Rapraeger and his team will use a different synstatin to disrupt each of these mechanisms to study how each affects signaling in myeloma cells. They also will use rigorous mouse models to test these synstatins as potential new therapeutics. “We’re still some time away from clinical trials, but our work will hopefully increase the chances that the synstatins do enter clinical trials and can provide successful treatments for cancer patients,” Rapraeger says.