Small molecule drugs with immunomodulatory effects in cancer

Abstract

Immunotherapy shows promise for positively changing the landscape of the management of many advanced solid tumors, including gastrointestinal (GI) malignancies. Many of these developments have been focused on vaccine-based, monoclonal antibody therapies and more recently, checkpoint inhibitors, although many small molecule inhibitors can function as immunomodulators. Small molecule compounds have several advantages over conventional immunotherapeutic agents including: ease of production and the potential for oral administration. There is a potential niche for small molecule immunomodulators to enhance the efficacy of existing immunotherapeutic and cytotoxic agents. This article focuses on two categories of small molecule compounds with immunomodulatory effects: IDO and MEK inhibitors. Indoleamine -2, 3- dioxygenase (IDO) is known for its effects in tumor immunity. IDO inhibitors are generally well-tolerated and have the potential to enhance anti-tumor responses when combined with checkpoint inhibitors. MEK inhibitors affect signal transduction of the RAS-RAF-MEK pathway and numerous MEK inhibitors are currently being investigated in solid tumors. Small molecule immunomodulators are currently being investigated for their potential role in augmenting the effects of conventional immunotherapeutic agents although further research is required to identify those patients most likely to respond to combination therapy.

Keywords:

• gastrointestinal malignancies
• immunotherapy
• IDO inhibitors
• MEK inhibitors
• small molecule

Funding

This work was supported in part by the NIH K23 CA148964-01 (L.Z.), NIH 1 R01 CA197296-01 (L.Z.), Viragh Foundation and the Skip Viragh Pancreatic Cancer Center at Johns Hopkins (L.Z.), the NCI SPORE in Gastrointestinal Cancers P50 CA062924 (L.Z.).