Brian C. Grieb, MD, PhD, instructor, clinical medicine, clinical fellow, Division of Hematology/ Oncology, Department of Medicine, Vanderbilt University Medical Center, discusses remaining unmet needs in the treatment of patients with colorectal cancer (CRC), highlighting the identification of novel pan-CRC biomarkers for drug development.

There has been a multitude of recent advances in the use of targeted therapy in CRC, including both the refinement of newly developed agents and the development of additional tools for patients with specific molecular targets.

For example, the phase 3 SUNLIGHT trial (NCT04737187) investigated the combination of trifluridine/tipiracil (TAS-102; Lonsurf) with bevacizumab (Avastin) in patients with heavily pretreated, refractory metastatic CRC. Previously reported data from the trial showed that the combination improved median overall survival (OS) and progression-free survival (PFS) vs TAS-102 alone.

Additionally, use of the VEGF-targeted agent fruniquinib (HMPL-013) alongside best supportive care (BSC) produced superior OS and PFS benefit vs placebo and BSC in the phase 3 FRESCO-2 trial (NCT04322539). Improved survival outcomes were seen regardless of the number of prior lines of therapy or the specific agent administered. Based on these findings, a new drug application for fruquintinib was granted priority review by the FDA in May of 2023.

Notably, the most recent advances within the treatment space have involved the development of agents targeting well-established biomarkers. Moreover, many of these mutations are only present in smaller patient subsets, signaling a substantial need for research on new actionable biomarkers that are present in many patients with CRC.

Research efforts focused on identifying unconventional targets in CRC, such as the ongoing, open-label, phase 1/2 MYCure trial (NCT04808362), are attempting to address this unmet need. The trial aims to indirectly target WD repeat-containing protein 5 (WDR5), a cofactor for the oncogenic transcription factor MYC, by using the novel small molecule inhibitor Omomyc (OMO-103).

Regardless of whether the findings from MYCure are positive, the identification of more widely applicable biomarkers in CRC is vital to improving outcomes in the overall population, Grieb says.

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Brian C. Grieb, MD, PhD, discusses unmet needs for patients with colorectal cancer, including the identification of novel pan-CRC biomarkers for drug development.

Dr Grieb on the Need for Novel Biomarkers in CRC

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.

Brian C. Grieb, MD, PhD, emphasizes the importance of investigating agents that target the MYC oncogene, as well as supportive cofactors, in colorectal cancer and other tumor types.

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, discusses historical barriers to targeting the MYC oncogene in patients with colorectal cancer (CRC) and the rationale for an ongoing phase 1/2 clinical trial that may demonstrate an effective way to target MYC in CRC and other solid tumors. 

Dr Grieb on the Future of Targeting MYC in CRC

MYC is an oncogenic transcription factor that regulates gene expression, Grieb says. Although most other transcription factors regulate a few select genes that they can turn on manyfold, MYC controls many genes and turns them on 2- or 3-fold, Grieb notes.MYC also programs cells for proliferation that, when uncontrolled, can induce tumor formation and cancer survival, Grieb explains.

Although MYC was the second oncogene ever discovered, effective small molecule inhibitors of MYC have yet to be developed, Grieb emphasizes. Current research is focused on understanding the necessary proteins for MYC to function as a transcription factor and learn how those proteins interact with MYC to determine whether they can be used in a therapeutic setting, Grieb says.

The protein Omomyc (OMO-103) represents a potential avenue for inhibiting MYC, Grieb explains. Omomyc research has moved from the lab to the ongoing, open-label, 2-part, phase 1/2 MYCure trial (NCT04808362), which is investigating the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of the protein in patients with advanced solid tumors, including non–small cell lung cancer, triple-negative breast cancer, and CRC. The dose-escalation part of this trial evaluated Omomyc at 5 dose levels to determine the recommended phase 2 dose (RP2D). The dose-expansion part treated patients at the RP2D to further evaluate the safety and antitumor activity of this protein.

Although the findings from this trial are not yet available, they will be important for understanding the efficacy of Omomyc and the mechanism of action of this protein, Grieb concludes.

Brian C. Grieb, MD, PhD, discusses historical barriers to targeting the MYC oncogene in patients with colorectal cancer and the rationale for an ongoing phase 1/2 clinical trial that may demonstrate an effective way to target MYC in CRC and other solid tumors. 

Brian C. Grieb, MD, PhD

Articles

Dr Grieb on the Need for Novel Biomarkers in CRC

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

Dr Grieb on MYC in CRC