Scientists at A*STAR’s Institute of Molecular and Cell Biology (IMCB) have made a landmark discovery in the battle against the rapid spread of aggressive cancers associated with PRL-3 oncoprotein . Contrary to the current accepted theory that antibodies can only bind to cancer proteins found on the cancer cell surface, the IMCB team led by Dr Zeng Qi is the first to discover that antibodies can in fact directly target intracellular oncoproteins like PRL-3 that reside within the cancer cells to suppress cancer growth successfully. This breakthrough finding will pave the way for more targeted solutions for cancer treatment and also offers hope for cancer prevention.
Antibody-based therapies have better specificity and thus improved efficacy over standard chemotherapy regimens, which result in extended survival and improved quality of life for cancer patients. Because antibodies are viewed as too large to access intracellular locations, antibody therapy has traditionally targeted extracellular or secreted proteins expressed by cancer cells. However, many oncogenic proteins are found within the cell (such as intracellular phosphatases/kinases and transcription factors) and have therefore not been pursued for antibody therapies. Here, we explored the possibility of antibody therapy or vaccination against intracellular proteins. As proofs of concept, we selected three representative intracellular proteins as immunogens for tumor vaccine studies: PRL-3 (phosphatase of regenerating liver 3), a cancer-associated phosphatase; EGFP (enhanced green fluorescent protein), a general reporter; and mT (polyomavirus middle T), the polyomavirus middle T oncoprotein. A variety of tumors that expressed these intracellular proteins were clearly inhibited by their respective exogenous antibodies or by antigen-induced host antibodies (vaccination). These anticancer activities were reproducibly observed in hundreds of C57BL/6 tumor-bearing mice and MMTV-PymT transgenic breast tumor mice. Our in vivo data suggest that immunotherapies can target not only extracellular but also intracellular oncoproteins.
There is the intriguing possibility that intracellular tumor antigen–specific monoclonal antibodies (mAbs) inhibit tumor growth and metastasis and prolong survival of tumor-bearing mice. Here, I discuss the implications of using intracellular targets in mAb-based immunotherapy as well as the possible underlying mechanisms of action.
This study showed for the first time that it is possible to successfully suppress cancer growth by direct targeting of intracellular oncoproteins, such as PRL-3, with the respective cancer-specific antibodies.” Using mouse models in this study, by directly introducing PRL-3 antibodies into the mice, the scientists observed a 70% to 90% reduction of tumours caused by PRL-3 expressing cancer cells. This significant reduction is also achieved by vaccinating the mice with PRL-3 antigen to produce antibodies that could specifically target PRL-3-expressing cancer cells.
The hope is this research will pave the way for cancer vaccination to become a mainstream cancer treatment that is both effective and affordable for the cancer patients. Especially for individuals who are genetically pre-disposed to specific types of cancer, tailor-made vaccination may one day be able to prevent cancer before it strikes.