MRA awarded four young investigators whose work has the potential to transform melanoma diagnosis and treatment.
Counteracting metastatic spread and outgrowth by MCSP-targeted therapy
SkinCeuticals - MRA Young Investigator Award
Edwin Bremer, Ph.D., University Medical Center Groningen
Life expectancy of melanoma patients diagnosed with metastases is very limited, because metastasized melanoma is largely resistant to current treatment regimens. Therefore, new approaches that block the spread and outgrowth of metastasizing melanoma cells are urgently needed. Here, we aim to develop such novel approaches using two proteins normally involved in the fight against cancer in the human body. These proteins are called TRAIL and Galectin-9. TRAIL specifically induces cell death in melanoma cells, but not in normal cells, whereas Galectin-9 specifically blocks the ability of melanoma cells to metastasize. Unfortunately, these potentially promising proteins are not ideally equipped to hunt down melanoma cells by themselves. To overcome this hurdle, we fused TRAIL and Galectin-9 to a so-called antibody fragment that is uniquely suited to hunt down melanoma cells. This antibody fragment recognizes and strongly binds to a protein called MCSP, which is highly expressed on melanoma cells. Of note, MCSP also promotes metastasis formation, but this pro-metastatic activity is inhibited by the antibody fragment. Therefore the two fusion proteins we designed will: 1. selectively hunt down and bind to melanoma cells; 2. inhibit pro-metastatic signaling by MCSP; and 3. simultaneously attack tumor cells by TRAIL or Galectin-9. The current project aims to preclinically evaluate the approach outlined above and is expected to yield a candidate drug that will be particularly suited for the prevention/inhibition of melanoma metastases.
Publications:
Identifying therapeutic targets for melanoma brain metastases
Michael Davies, M.D., Ph.D.,
University of Texas M.D. Anderson Cancer Center
One of the most common and devastating complications of advanced melanoma is the development of brain metastases. Unfortunately, there are no effective treatments for this complication, and patients with brain metastases survival less than 4 months on average. In preliminary studies, we have demonstrated that melanoma brain metastases have significant molecular differences when compared to metastases from other sites in the body. We propose to study a set of patients for whom we have tissue samples from both their brain metastases and metastases from other sites to determine what factors and pathways contribute to the aggressive nature of these tumors. These studies should improve our understanding of brain metastases, and set the stage for rational clinical trials for these patients.
Epigenomic analysis of melanoma metastatic behavior
Remco van Doorn, M.D., Ph.D.,
Leiden University Medical Centre
Most patients currently diagnosed with melanoma present at an early stage of the disease, when the prognosis after surgical removal of the primary tumor is favorable. However, a subset of patients with early melanoma lesions will develop metastatic disease. Metastasis, the spread of tumor cells from a primary tumor to distant sites, currently poses the biggest problem to melanoma treatment and is the main cause of death. Our means of identifying those patients at increased risk of metastasis, who might benefit from additional treatment are limited. This is partly due the fact that it is not well known what actually drives melanoma tumor cells to invade and spread to foreign tissues. Recent findings suggest that the capacity to metastasize is engrained and detectable in tumor cells of the primary melanoma. This study is aimed at identifying alterations in DNA methylation, a chemical modification of the molecules that carry genetic information, in metastatic melanoma. Tumor cells often harbor many DNA methylation alterations, which deregulate gene activity. We will examine whether the pattern of DNA methylation in melanomas that metastasize is different from the pattern observed in melanomas that do not metastasize. We expect to find specific molecular markers that can predict whether a primary melanoma will show metastatic spread. In addition, we will examine if and how these DNA alterations promote the metastatic behavior of melanoma tumor cells. In doing so, we hope to find new approaches to treatment by specifically targeting molecules that contribute to metastatic behavior of melanoma cells.
miRNA down-regulation in melanoma– Diagnostic and therapeutic implications
Stewart Rahr - MRA Young Investigator Award
Raya Leibowitz-Amit, M.D., Ph.D.,
Sheba Medical Center
Metastatic melanoma is a devastating disease with currently limited treatment options. miRNAs are small RNA species within cells that regulate gene expression. Aberrant expression of miRNAs leads to cancerous transformation, but their role in melanoma is still unknown. We have observed that many miRNAs are not expressed in malignant melanocytes in comparison to normal melanocyets. Interestingly, many of the genes encoding these miRNAs are found in very close proximity in a chromosomal region known to be implicated in differentiation and development. Indeed, some of these miRNAs were shown to suppress the growth of several cancer types but not of melanoma so far. Our preliminary results demonstrate that in some melanoma cell lines, these miRNAs are silenced because of a chromosomal deletion. Conversely, in other cell lines these miRNAs are most likely silenced by a mechanism that merely alters the chromosomal material without deleting it (termed ‘epigenetic modification’), because treatment of the cells with epigenetic modifiers restores their expression.
We plan to further investigate the mechanism and timing of miRNA silencing during melanocyte transformation. We also plan to molecularly characterize the sub-group of melanoma patients with the potential to undergo tumor suppression in response to epigenetic modifiers. Eventually, we plan to design a clinical trial evaluating the use of such agents (already approved for hematological malignancies) in this specific patient sub-group. Our translational research will hopefully yield a new treatment approach along with a novel molecular assay that predicts response, thus enlarging our therapeutic arsenal in this yet incurable disease.