Dr Grieb on the Importance of Targeting the MYC Oncogene in CRC and Solid Tumors

Brian C. Grieb, MD, PhD, instructor, clinical medicine, clinical fellow, Division of Hematology/ Oncology, Department of Medicine, Vanderbilt University Medical Center, emphasizes the importance of investigating agents that target the MYC oncogene, as well as supportive cofactors, in colorectal cancer (CRC) and other tumor types.

The oncogenic transcription factor MYC is a key regulator of gene expression, Grieb begins. Alterations or mutations in MYC can lead to overexpression of genes controlling cell proliferation, metabolic reprogramming, and apoptosis. Accordingly, MYC is a key driver of tumor growth in the majority of cancers, including CRC, Grieb states. Despite its prominence, efforts to effectively target this oncogene have been largely unsuccessful. However, continued research is vital to determine unconventional avenues for targeting MYC, develop effective small molecule inhibitors of MYC, and investigate their clinical utility, Grieb emphasizes.

Many research programs focused on MYC inhibition aim to target MYC directly, Grieb continues. However, some efforts in this space are also focused on targeting key cofactors for MYC activity, such as the WD repeat-containing protein 5 (WDR5), Grieb notes. This includes research of the first MYC-targeted therapy Omomyc (OMO-103), which inhibits the binding of WDR5 and KMT2A to MYC. This agent is being investigated in the ongoing, open-label, phase 1/2 MYCure trial (NCT04808362). Identifying and pharmacologically targeting these proteins can indirectly inhibit MYC by preventing its recruitment.

Although this cofactor is only involved in a small portion of MYC activity, disrupting the MYC–WDR5 connection could still promote tumor regression without producing significant toxicity, he states. Preclinical mouse and animal models have already shown that agents targeting MYC cofactors have been well tolerated, Grieb adds. Additionally, few toxicities have been seen with these agents at the dose required to produce an antineoplastic effect, Grieb concludes.