Every year in the United States alone, nearly six hundred thousand people die of cancer. This devastating disease comes in many different forms. Almost eighty thousand people in the US are diagnosed with melanoma (skin cancer) every year and this particular form of cancer takes ten thousand lives annually. The research highlighted here aims at developing new molecular therapies for melanoma.
The term S100 was first used in 1965 to denote a mixture of the two founding protein family members, S100A1 and S100B. This term alludes to the solubility of these approximately 10,000 Da proteins in 100% saturated ammonium sulphate. Although S100 family members exhibit a high degree of sequence and structural similarity, they are not functionally interchangeable and they participate in a wide range of biological processes such as proliferation, migration and/or invasion, inflammation and differentiation.
The primary focus of our research efforts is on the role that S100 proteins play in cancer. S100s typically function in a cell-specific manner, as signaling proteins, which bind and regulate a number of protein targets in a Ca2+-dependent manner. In addition to being biomarkers, they often contribute to cancer progression when overproduced. One such S100B target is the tumor suppressor protein, p53. In this case, up-regulation of S100B abrogates p53 transcription activation and UV-dependent apoptosis in cancers containing wild-type p53, such as gliomas and malignant melanoma.
We have discovered that elevated levels found in malignant melanoma result from a well-described mutation in BRAF. We have also demonstrated that inhibiting S100B production in malignant melanoma restores wild-type p53 protein levels and its transcriptional activation/apoptosis activities as found in normal melanocytes. This makes the S100B/p53 interaction an attractive target for drug design. Using structure based drug design approaches and high throughput chemical screening (in collaboration with NCATS), we have engineered novel S100B inhibitors (SBiX). Some of these SBiXs developed over the past several years advanced to in vivo studies (mice, canines) including, in one case, a human phase 2 clinical trial. This work continues as we engineer next generation SBiXs with increased potency and fewer off-target effects including those involving other S100s (i.e. S100A1).