Transforming growth factor beta isoforms (TGF-β1, -β2, -β3) regulate the adaptive immune system and coordinate wound healing, functions that are essential for the long-term survival of humans and other vertebrates. They also play prominent roles in human disease, especially cancer, where they function as tumor suppressors in normal and early neoplastic cells, but as promoters of tumor growth and metastasis in established cancers. TGF-bs also coordinately upregulate the expression of many matrix proteins, such as collagen and fibronection, as well as tissue inhibitors of matrix mettaloproteinases (TIMPs), and have been shown to play a causative role in the progression of many fibrotic disorders, including kidney and pulmonary fibrosis. TGF-β’s disease-promoting activities have made it an important molecular target for treatment of cancer and fibrosis, yet no inhibitors have been FDA-approved.
The Hinck laboratory, together with the laboratory of the cancer cell biologist, Dr. LuZhe Sun is working to develop novel TGF-β receptor trap proteins as alternatives to neutralizing antibodies since the efficacy of the neutralizing antibodies in clinical trials for cancer and fibrosis have been modest. The Hinck laboratory is taking the alternative approach of artificially fusing together the binding domains of the TGF-β receptors (TβRI, TβRII, and betaglycan) to form hetero-dimeric, -trimeric, and –tetrameric sequestering receptor trap proteins with high intrinsic specificity and affinity for the TGF-β isoforms. The first generation heterodimeric inhibitor that the Hinck and Sun lab developed, BGERII, has been shown to be a highly potent in vitro and highly effective in inhibiting metastasis in breast and prostate cancer models. Through a collaborative effort between the Hinck and Sun labs, we have generated additional trimeric receptor traps, which are even more potent. Our labs together successfully competed for NCI RO1 to support to further develop the receptor fusions and recently our labs demonstrated high efficacy for one of them in vitro and a transgenic model of prostate cancer. Our ongoing studies are aimed at further characterizing both the efficacy, mechanism of action, and safety of the receptor trap proteins, with the long-term objective of transitioning these into human clinical trials.