Cancer Gene Therapy: Targeted Genomedicines

Given the fact that malignant cells proliferate more rapidly than normal cells, damage to the cancer cells is anticipated to be markedly greater than normal cells. However, cancer cells generate chemoresistance mechanisms within the tumor microenvironment, while undesired toxicity may occur in the normal cells. For example, in colorectal cancer (CRC), there exist well-described sequences of mutational events that evince the shift of normal colon epithelium to premalignant adenoma and malignant adenocarcinoma. These events are 1) loss of the function of the adenomatous polyposis coli (APC) gene (encoding a protein involved in cell adhesion and transcription) in up to 85% of all cases of CRC, 2) mutation of KRAS (a GTP-ase that controls cell proliferation) in 50–60% of all cases of CRC, and 3) downregulated expression of the cell-adhesion transmembrane glycoprotein E-cadherin in almost 50–60% of all cases of CRC. Mutations in the mismatch-repair genes MLH1 and MSH2 contribute to genetic instability. Besides, there exist a number of genes alterations leading cells toward remodeling that include: 1) SMAD4 involved in the transforming growth factor signal transduction suppressing epithelial-cell growth, 2) INK4A involved in the retinoblas‐ toma tumor-suppressor pathway, and 3) TP53 alterations increasing the resistance of cancer cells to apoptosis [1]. Similar molecular/cellular alterations occur in various solid tumors, highlighting the intricacy of biological events leading to initiation and progression of malignancies. Therefore, necessity for development and advancement of more effective modalities targeting such genetic changes is perceptible to achieve successful cancer treatment and cure. After decades of disappointment, targeted therapy of cancer has been advanced by integration of immunotherapy as well as gene and cell therapy. As proof-ofconcept, recent clinical trials (e.g., anti-CTLA4 antibody, ipilimumab) have shown signifi‐