Emerging drug targets for colon cancer: A preclinical assessment

ABSTRACT

Introduction

Colorectal cancer (CRC) is the second leading cause of cancer-related death in the United States. There have been improvements in screening, and therefore overall survival, but patients continue to present at late stages when minimal treatment options are available to them. While some targeted therapies have been introduced, their application is limited by patient-specific tumor characteristics. Additional targets for CRC in patients who present at a late stage, or who experience tumor relapse, need to be identified to continue to improve patient outcomes.

Areas Covered

This review focuses on emerging pathways and drug targets for the treatment of colorectal cancer. The shift to the cancer stem cell model and potential targets involving Wnt, NF-κB, phosphodiesterases, RAS, and guanylyl cyclase C, are discussed. The current utility of checkpoint inhibitors and evolving immunological options are examined.

Expert Opinion

Surgery and current systemic cytotoxic therapies are inadequate to appropriately treat the full spectrum of CRC, especially in those patients who present with metastatic or treatment-refractory disease. In addition to the identification of new, more generalizable targets, additional focus is being placed on novel administrations. Immuno-oncologic options and stem cell-targeting therapies for mCRC will become available to patients and may increase survival.

KEYWORDS:

• Colorectal cancer
• Wnt
• RAS
• cancer stem cells
• phosphodiesterase
• cancer immunology

Article highlights

• The treatment of colorectal cancer (CRC) requires targeted therapies in addition to anti-EGFR, anti-VEGF, and checkpoint inhibitors.

• Hyper-activation of Wnt signaling is associated with APC inactivation in the majority of colon cancers.

• Multiple potential targets along the Wnt pathway exist. Given the high incidence of APC mutations driving CRC, continued focus on targeting this pathway should improve the management of CRC.

• While targeting the wild-type KRAS protein is extremely toxic, mutant-specific KRAS inhibitors appear to be safe and effective.

• Cancer stem cells have emerged as one key focus of resistance to traditional cytotoxic therapies and the source of residual disease persistence and progression in CRC. A cure of CRCs may not be possible without elimination of this resistant tumor cell type.

• Immune checkpoint inhibitors are effective in high microsatellite instability (MSI^Hi) mismatch repair-deficient tumors but have limited utility in patients with microsatellite stable (MSS) mismatch repair-proficient colorectal cancer.

• Adoptive cell therapies, like chimeric antigen receptor (CAR)-T cells, offer a novel strategy to treat CRCs. Additional work could identify safe and effect CAR-T cell targets in CRC as well as improved delivery.

Declaration of interests

SAW is the Chair of the Scientific Advisory Board and member of the Board of Directors of, and AES is a consultant for, Targeted Diagnostics and Therapeutics, Inc. which provided research funding that, in part, supported this work and has a license to commercialize inventions related to this work. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants, or patents received or pending, or royalties.

Declaration of Interest

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

This work was supported by the National Institutes of Health (R01 CA204881, R01 CA206026, and P30 CA56036), the Department of Defense Congressionally Directed Medical Research Program W81XWH-17-PRCRP-TTSA, and Targeted Diagnostic & Therapeutics, Inc. to SAW. AES was supported by the Department of Defense Congressionally Directed Medical Research Programs (W81XWH-19-1-0263) and West Pharmaceutical Services, Inc. SAW and AES also were supported by a grant from The Courtney Ann Diacont Memorial Foundation and Lorraine and David Swoyer. MC was supported by NIH institutional award T32 GM008562 for Postdoctoral Training in Clinical Pharmacology. SAW is the Samuel M.V. Hamilton Professor of Thomas Jefferson University.