MMSC

Novel therapeutic antibodies for multiple myeloma

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 Obiettivo del progetto (Objective)

'Multiple Myeloma (MM) is an incurable plasma cell neoplasm with a median survival of 3 years. A critical step towards the development of more effective therapies is the identification of dominantly acting oncogenes. We have implemented an integrated oncogenomic approach that utilizes high-resolution gene-specific array-CGH and comprehensive expression profiling to identify the spectrum of genetic alterations in a large panel of MM cell lines (n=46) and annotated primary tumors (n=65). These efforts have uncovered a strikingly high number of novel recurrent focal amplifications and deletions. To select the most critical amplicons, a stringent filtering algorithm that takes in account the amplification level, recurrence and the presence of similar lesions in an extensive array-CGH database of more than 600 tumors and cell lines from different cancer types yielded 13 highly-selected amplicons. Within these, 117 genes demonstrated significant upregulation when compared with normal plasma cells, with 28 genes considered potential targets for Monoclonal Antibodies based on their structural features. This dataset will be prioritized by key parameters including oncogenic validation assays and in vivo testing. The ultimate goal of this proposal is to provide a list of functionally validated antibody targets, which can be enlisted into therapeutic monoclonal antibody development.'

Introduzione (Teaser)

Multiple myeloma (MM) is an incurable cancer affecting white blood cells. European researchers have isolated two genes and their proteins that can be targeted using antibodies for potential therapy.

Descrizione progetto (Article)

The 'Novel therapeutic antibodies for multiple myeloma' (MMSC) project aimed to identify candidate oncogenes, genes that can cause cancer, by screening for activity of their proteins.

Two genes have been isolated using small hairpin (sh) RNA based screening tools. shRNA molecules can be used to silence target genes and thus assess their function. The proteins from the translated genes can be targeted using monoclonal antibodies or small molecules, many of which are already used in chemotherapy.

An attractive candidate, the first gene is part of the Wingless (WNT) pathway, first recognised for its role in carcinogenesis. Mutations of WNT are critical in breast and prostate cancer. This protein is also a receptor tyrosine kinase (RTK). RTKs are often overexpressed in a variety of tumours, leading to enhanced cancer cell survival, and metastasis.

Several RTKs are expressed in MM and there is mounting evidence of their relevance in this disease. RTK-targeting therapeutic antibodies and small molecule inhibitors such as Herceptin, Cetuximab, Gleevec, Tarceva and Iressa have successfully induced death in cancerous cells where RTKs are overexpressed.

The second gene is also a kinase and part of the Hippo pathway. Inhibition of this kinase using shRNAs was able to trigger cell death in a large range of myeloma cells. Downregulation of this gene in an in vivo setting confirmed that it could be used to unravel mechanisms of cancer cell survival.

The results of the MMSC project have provided a firm knowledge platform for the development of targeted drug therapies for MM. Besides advanced research opportunities for pharmaceutical SMEs, MM patients also stand to benefit from improved life quality and outcome.