ABSTRACT
Rationale for Targeted Investigation The rationale for the development of drugs which target extracellular and intracellular pathways has been predicated on the observation that there are a variety of overexpressed and underglycosylated molecules on the cell surface to which ligands bind or somehow interact causing a cascade of events that lead to intracellular signaling modulation and/or interference with cell growth (Tables 1 and 2). However, while some extracellular molecules can serve as potential targets for drug development, one of the major concerns is that they may not always be in contact with intracellular pathways to affect cellular function; their expression on the cell surface may also be variable because of a wide variety of host factors. Despite targeting receptor-like molecules such as the epidermal growth factor receptor (EGFR), human epidermal growth factor receptor-2 (HER-2)/neu, and BCL-2 pathways which can stimulate intracellular signaling pathways, the cell can develop ‘‘collateral’’ signaling and survival pathways. Although target activation can be blocked using ‘‘small’’ molecules or monoclonal antibodies, the cell can still overcome blockade via multiple mechanisms rendering treatment markedly inadequate. There are multiple cell surface molecules which can serve as targets for immunologic approaches including those on the cell surface such as mucins [MUC-1 (1-3), MUC-2 (3-5), and MUC-18 (6)], glycolipids [Globo H (7-9) and GM2 (10)], and glycoproteins [prostate-specific antigen (PSA) (11,12), prostate-specific membrane antigen (PSMA) (Figs. 1 and 2) (13,14), and prostate stem-cell antigen (PSCA) (15)], in addition to the androgen receptor (16,17), EGFR (18-20), insulin growth factor receptor (21), laminin receptor (22), granulocytemacrophage colony-stimulating factor (GM-CSF) receptor (23), Platelet-derived growth factor receptor (PDGFR) (24) and checkpoint molecules such as cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) (25-27). Agents which target-specific intracellular sites have included calcitriol (28,29) for the vitamin D receptor; Hsp90 via the ansamycins, e.g., 17-AAG (30,31); the proteasome via PS-341, i.e., VelcadeTM
(32-34), histone deacetylase (HDACs) via suberoylanilide hydroxamic acid (35-37), as well as the relationship of all of these molecules to stroma and neovasculature. The interactions between the binding of cell surface molecules to their respective ligands leading to a cascade of intracellular events have become extraordinarily complex with multiple interactions occurring synchronously. The article will highlight some of the many extracellular surface molecules to which novel drugs can be
targeted with the idea that there remains a stunning diversity of other mechanisms by which cell growth can be modulated.
