Functionally-associated target antigens in cancer. Defined by human antibodies and small interfering RNAs

Abstract: Cancer is the collective name for diseases that have one thing in common ? uncontrolled cell growth. The increase in cancer cell proliferation eventually results in tumor formation and, in the worst case, metastatic spread to other organs. Common treatment modalities of cancer include chemotherapy and radiation therapy. However, these methods are associated with severe side effects as well as induced drug resistance. Accordingly, to improve cancer prognoses, the introduction of innovative therapies, based on novel cancer targets, is needed. This thesis is based upon four original papers, in which we address this issue and seek for new targets for cancer intervention. Specifically, in Paper I, we used phage display to isolate a set of antibodies that bound to breast and pancreatic carcinoma cells, and upon binding to the surface receptors, induced internalization into the cells. In Paper II, we employed the technology described in Paper I to isolate an internalizing antibody, denoted INCA-X, toward pancreatic carcinoma cells. The corresponding antigen was identified as the Ku70/80 heterodimer, a nuclear protein that could also be localized on the cell surface of tumor cells, where it has previously been suggested to function in adhesion, migration and invasion processes. The anti-Ku70/80 antibody (INCA-X) was shown to be a good delivery vehicle for cytotoxic drugs into several different cancer cell lines (pancreatic, breast, prostate, colorectal cancer). In Paper III, we identified three receptors that upon antibody crosslinking could induce apoptosis in B cell lymphoma cell lines. These antigens were HLA-DR/DP, IgM, and ICAM-1. Finally, in paper IV, we used DNA microarray technology to generate a list of 46 genes that are overexpressed in mantle cell lymphoma compared to normal B cells. From this list, three target genes were identified, based on loss-of-function screening after silencing of the corresponding transcripts by siRNA. In conclusion, by employing differential proteomic and genomic approaches, several functionally-associated targets were identified. By interfering with these antigens (via antibodies or siRNAs), changes in cancer cell physiology were induced, thus pointing toward a potential for tumor intervention.