Why Is Wnt/β-Catenin Not Yet Targeted in Routine Cancer Care?

Abstract

Despite significant progress in cancer prevention, screening, and treatment, the still limited number of therapeutic options is an obstacle towards increasing the cancer cure rate. In recent years, many efforts were put forth to develop therapeutics that selectively target different components of the oncogenic Wnt/β-catenin signaling pathway. These include small molecule inhibitors, antibodies, and more recently, gene-based approaches. Although some of them showed promising outcomes in clinical trials, the Wnt/β-catenin pathway is still not targeted in routine clinical practice for cancer management. As for most anticancer treatments, a critical limitation to the use of Wnt/β-catenin inhibitors is their therapeutic index, i.e., the difficulty of combining effective anticancer activity with acceptable toxicity. Protecting healthy tissues from the effects of Wnt/β-catenin inhibitors is a major issue due to the vital role of the Wnt/β-catenin signaling pathway in adult tissue homeostasis and regeneration. In this review, we provide an up-to-date summary of clinical trials on Wnt/β-catenin pathway inhibitors, examine their anti-tumor activity and associated adverse events, and explore strategies under development to improve the benefit/risk profile of this therapeutic approach.

Keywords: ADC; Wnt/β-catenin; cancer therapy; clinical trials; drug combination; drug design; drug profiling; nanovectorization; precision medicine; small molecule inhibitors.

Scheme 1

Clinical trials (https://clinicaltrials.gov/) using antibodies as Wnt-dependent inhibitors (WDi). API: active pharmaceutical ingredient; SD: stable disease; PR: partial response; CR: complete response [91,92,93,97,98,99,100,101,104,108,109,112,119].

Scheme 2

Clinical trials (https://clinicaltrials.gov/) using small molecules inhibitors (SMi) as Wnt-dependent inhibitors (WDi). API: active pharmaceutical ingredient; SD: stable disease; PR: partial response; CR: complete response [135,136,137,138,140,147,148,151,152,153,154,155,156,157,158,159,160].

Scheme 3

Clinical trials (https://clinicaltrials.gov/) using small molecules inhibitors (SMi) as Wnt-independent inhibitors (WIi) preventing β-catenin stabilization. API: active pharmaceutical ingredient; SD: stable disease; PR: partial response; CR: complete response [166,169,175,178,184,193,195,196,197,198,199,200,201,202,203,204,205,206,207,208,209,210,211,220,221].

Scheme 3

Clinical trials (https://clinicaltrials.gov/) using small molecules inhibitors (SMi) as Wnt-independent inhibitors (WIi) preventing β-catenin stabilization. API: active pharmaceutical ingredient; SD: stable disease; PR: partial response; CR: complete response [166,169,175,178,184,193,195,196,197,198,199,200,201,202,203,204,205,206,207,208,209,210,211,220,221].

Scheme 4

Clinical trials (https://clinicaltrials.gov/) using small molecules inhibitors (SMi) as Wnt-independent inhibitors (WIi) preventing β-catenin transcriptional activity. API: active pharmaceutical ingredient; SD: stable disease; PR: partial response; CR: complete response [231,232,233,234,235,238,239,246].

Scheme 5

Antibody-drug conjugates (ADC) and peptide-drug conjugates (PDC) targeting the Wnt/β-catenin signaling. MMAE: Monomethyl Auristatin E; Aur0101: Auristatin Microtubule Inhibitor; PNU159682: DNA damaging topoisomerase-inhibiting anthracycline; (ABD)-PA: (Albumin Binding Domain)- Pseudomonas endotoxin A; ABD; DMSA: Streptomyces Duocarmycin [276,277,278,281,283,284,285,286].

Figure 1

Mutation rates in key players of the canonical Wnt/B-catenin pathway in different cancer types (NIH GDC Data Portal release 40.0-March 2024): green (<20%), orange/red (>20%).

Figure 2

Flowchart for using Wnt/β-catenin inhibitors as anti-cancer treatments on the basis of the data presented in Figure 1 and Scheme 1, Scheme 2, Scheme 3 and Scheme 4.