Progress and prospects of ROR2 targeted therapy in the field of cancer

1. Biological Characteristics of ROR2 and Its Relevance in Tumors

Receptor tyrosine kinase-like orphan receptor 2 (ROR2) is a crucial receptor in the Wnt signaling pathway and belongs to the ROR family of receptor tyrosine kinases. As a single-pass transmembrane protein, ROR2 plays a vital role in embryonic development, particularly in the formation of the skeletal, cardiovascular, and nervous systems. In adult tissues, ROR2 expression is typically maintained at low levels, but it is significantly overexpressed in various malignancies.

Research has shown that aberrant ROR2 expression is closely associated with cancer progression and poor prognosis. In melanoma, high ROR2 expression correlates with increased tumor invasiveness and metastatic potential. In renal cell carcinoma, ROR2 levels are positively correlated with disease stage, while in osteosarcoma patients, ROR2 positivity often predicts worse clinical outcomes. Additionally, ROR2 overexpression is widely observed in gastrointestinal stromal tumors (GIST), colorectal cancer, pancreatic ductal adenocarcinoma, and non-small cell lung cancer (NSCLC), among other solid tumors.

From a molecular mechanism perspective, ROR2 promotes tumorigenesis and progression through the following pathways:

Activation of canonical and non-canonical Wnt signaling pathways, enhancing tumor cell proliferation

Induction of epithelial-mesenchymal transition (EMT), increasing tumor invasiveness

Modulation of extracellular matrix remodeling to facilitate metastasis

Maintenance of cancer stem cell properties, contributing to therapy resistance

2. Potential and Challenges of ROR2 as a Therapeutic Target

Given its specific expression pattern in multiple malignancies, ROR2 has emerged as a promising novel target in cancer therapy. Compared to traditional targets, ROR2 offers several advantages:

Broad expression across refractory tumors, enabling a wide range of potential indications

Limited expression in normal tissues, potentially reducing off-target toxicity

Involvement in multiple pro-tumorigenic pathways, allowing for multifaceted therapeutic effects

However, developing ROR2-targeted therapies also presents significant challenges. The primary issue is mitigating "on-target, off-tumor" effects—where drugs correctly target ROR2 but may still affect normal ROR2-expressing tissues, leading to adverse reactions. Additionally, heterogeneity in ROR2 expression across tumors, complexity in downstream signaling, and potential resistance mechanisms complicate drug development.

3. Strategies and Advances in ROR2-Targeted Therapy

3.1 Antibody-Drug Conjugate (ADC) Approach

Antibody-drug conjugate (ADC) technology provides a promising strategy for ROR2-targeted therapy. By linking cytotoxic drugs to ROR2-specific monoclonal antibodies, ADCs enable precise tumor cell killing. An ideal ROR2 ADC should possess:

High-affinity, ROR2-specific antibodies

Stable linkers to prevent premature drug release in circulation

Efficient internalization for effective payload delivery

Optimal drug-to-antibody ratio (DAR) to balance efficacy and toxicity

Recent advances in conditionally activated ADCs have brought breakthroughs in ROR2 targeting. These ADCs exploit differences between the tumor microenvironment (e.g., acidic pH, specific proteases) and normal tissues to achieve selective activation at tumor sites, significantly improving the therapeutic window.

3.2 Bispecific Antibody Approach

Bispecific antibodies represent another promising ROR2-targeting strategy. By simultaneously binding ROR2 and immune cell surface molecules (e.g., CD3), these drugs redirect T cells to tumors, eliciting specific immune responses. Compared to ADCs, bispecific antibodies offer:

Independence from cytotoxic payloads, resulting in different toxicity profiles

Potential induction of long-term immune memory

Better adaptability to tumor heterogeneity

3.3 Small-Molecule Inhibitor Approach

Small-molecule inhibitors targeting the ROR2 kinase domain are also under development. These compounds block ROR2-mediated downstream signaling to exert antitumor effects. Despite development challenges, small molecules offer advantages such as oral administration and superior tissue penetration.

4. Advantages of Conditionally Activated ROR2-Targeted Therapies

Conditionally activated targeting strategies represent a major advancement in ROR2 therapy. These approaches utilize various mechanisms for tumor-specific activation:

pH-Dependent Activation: Leveraging the pH difference between the tumor microenvironment (pH 5.3–6.7) and normal tissues (pH 7.4), engineered antibody variants bind ROR2 with high affinity only under acidic conditions. Unlike irreversible enzymatic cleavage, this strategy relies on reversible binding for selective targeting.

Protease-Dependent Activation: Incorporating tumor-specific protease (e.g., MMP, uPA) cleavage sites into antibodies ensures activation only in tumor tissues. The prodrug remains inert in normal tissues until cleaved by tumor-associated proteases.

Redox-Dependent Activation: Utilizing the highly reducing intracellular environment of tumors, specialized linker chemistry enables payload release under reducing conditions.

Key advantages of conditionally activated ROR2 therapies include:

Minimized impact on normal ROR2-expressing tissues

Higher maximum tolerated doses for improved efficacy

Potential to overcome limitations in target expression levels

Expanded therapeutic window and enhanced safety

5. Current Clinical Translation and Future Directions

Several ROR2-targeted therapies have entered clinical trials, with conditionally activated ADCs showing particular promise. Early clinical data indicate encouraging antitumor activity and manageable safety profiles in head and neck squamous cell carcinoma (HNSCC), melanoma, and other indications, with notable disease control rates in HPV-associated malignancies.

Future directions for ROR2-targeted therapy may focus on:

Optimizing conditional activation technologies for improved tumor selectivity

Developing novel payloads to overcome limitations of current cytotoxic drugs

Exploring rational combination strategies (e.g., with immune checkpoint inhibitors)

Establishing reliable biomarkers for precise patient stratification

Expanding to additional ROR2-high refractory tumor types

With deepening biological understanding and technological advancements, ROR2-targeted therapies hold promise as new treatment options for various cancers. The success of conditionally activated strategies may also provide a blueprint for developing therapies against other challenging targets.