Advances in targeted and immunobased therapies for colorectal cancer in the genomic era

Abstract

Targeted therapies require information on specific defective signaling pathways or mutations. Advances in genomic technologies and cell biology have led to identification of new therapeutic targets associated with signal-transduction pathways. Survival times of patients with colorectal cancer (CRC) can be extended with combinations of conventional cytotoxic agents and targeted therapies. Targeting EGFR- and VEGFR-signaling systems has been the major focus for treatment of metastatic CRC. However, there are still limitations in their clinical application, and new and better drug combinations are needed. This review provides information on EGFR and VEGF inhibitors, new therapeutic agents in the pipeline targeting EGFR and VEGFR pathways, and those targeting other signal-transduction pathways, such as MET, IGF1R, MEK, PI3K, Wnt, Notch, Hedgehog, and death-receptor signaling pathways for treatment of metastatic CRC. Additionally, multitargeted approaches in combination therapies targeting negative-feedback loops, compensatory networks, and cross talk between pathways are highlighted. Then, immunobased strategies to enhance antitumor immunity using specific monoclonal antibodies, such as the immune-checkpoint inhibitors anti-CTLA4 and anti-PD1, as well as the challenges that need to be overcome for increased efficacy of targeted therapies, including drug resistance, predictive markers of response, tumor subtypes, and cancer stem cells, are covered. The review concludes with a brief insight into the applications of next-generation sequencing, expression profiling for tumor subtyping, and the exciting progress made in in silico predictive analysis in the development of a prescription strategy for cancer therapy.

Targeting HER2 in colorectal cancer: The landscape of amplification and short variant mutations in ERBB2 and ERBB3

“…The standard‐of‐care treatment for mCRC using multiagent chemotherapy is effective at slowing the progress of the disease, but long‐term remissions are rare and the treatment side effects are often significant . This has prompted the development of less toxic targeted therapies for the disease, but progress has been slow . Although anti‐EGFR antibody therapeutics have been approved for the treatment of mCRC for several years, the use of these agents has been personalized by determining which patients should not be treated due to predicted resistance rather than identifying individuals significantly likely to benefit from treatment .…”

“…56,57 This has prompted the development of less toxic targeted therapies for the disease, but progress has been slow. [58][59][60][61] Although anti-EGFR antibody therapeutics have been approved for the treatment of mCRC for several years, the use of these agents has been personalized by determining which patients should not be treated due to predicted resistance rather than identifying individuals significantly likely to benefit from treatment. 62 Thus, interest has emerged in finding targeted therapies for which biomarkers can positively predict patient benefit from therapy.…”

Hedgehog signaling pathway in colorectal cancer: function, mechanism, and therapy

“…Since first discovered in Drosophila melanogaster , the Hh signaling pathway has received extensive attention 1–7. Massive research has confirmed its contributions in embryonic generation and postembryonic regulation of the development of various organs and tissues, including the patterning, growth, and differentiation in the gastrointestinal tracts 1–5.…”

“…Hh signaling pathway has been implicated in the pathogenesis of various human cancers; however, the role of the Hh pathway in CRC remains controversial 6. There are two mechanisms of Hh activation: through Hh ligand-dependent activation or through ligand-independent activation, namely, by loss-of-function mutations in Ptc1 or gain-of-function mutations in the proto-oncogene Smo 7. The Hh pathway is viewed as a cancer-related pathway and a potential therapeutic target.…”

Safety and efficacy of fruquintinib in patients with previously treated metastatic colorectal cancer: a phase Ib study and a randomized double-blind phase II study

“…In patients with metastatic colorectal cancer (mCRC), addition of anti-vascular endothelial growth factor (VEGF) and anti-endothelial growth factor receptor (EGFR) biologic agents to chemotherapy regimens, either in the first or second line, improves overall survival (OS), progression-free survival (PFS), and anti-tumor response compared with chemotherapy alone [1–3]. However, patients frequently develop resistance and ultimately experience disease progression, highlighting a demand for more therapeutic strategies after failure of standard chemotherapy [4, 5].…”