HER2 and CD24 Emerge as Promising Radiotheranostic Targets in Endometrial Cancer

Introduction

Endometrial cancer, the most common gynecological cancer in developed countries, has been steadily rising in incidence worldwide. While early-stage disease often responds well to surgery and conventional therapies, advanced and recurrent cases remain challenging to treat. Over the last decade, researchers have been exploring precision oncology strategies—approaches that target specific molecular markers in cancer cells to improve outcomes.

Among these emerging strategies is radiotheranostics, a cutting-edge field that combines diagnostic imaging and targeted radionuclide therapy. The idea is simple yet powerful: use the same molecule to both detect and destroy cancer cells. Recent studies highlight two promising molecular candidates for radiotheranostic development in endometrial cancer—HER2 (human epidermal growth factor receptor 2) and CD24, a cell surface glycoprotein.

In this article, we will explore how HER2 and CD24 are reshaping the treatment landscape for endometrial cancer, the science behind radiotheranostics, and the future implications for patients and clinicians.

Understanding Endometrial Cancer

Endometrial cancer arises from the inner lining of the uterus, known as the endometrium. It is broadly classified into two types:

Type I (endometrioid): Generally hormone-dependent, linked to estrogen exposure, and often diagnosed at an early stage.
Type II (non-endometrioid): Includes serous and clear cell carcinomas, usually more aggressive, with poorer prognosis.

Risk factors include obesity, hormonal imbalances, diabetes, hypertension, and genetic predispositions such as Lynch syndrome. While surgery remains the primary treatment for localized disease, advanced cases often require radiation therapy, chemotherapy, or hormonal therapy. Unfortunately, outcomes for metastatic or recurrent disease remain suboptimal.

This unmet need has driven the search for novel biomarkers that can be leveraged to personalize treatment, improve early detection, and enhance therapeutic precision.

The Promise of Radiotheranostics

Radiotheranostics represents a paradigm shift in oncology. Instead of separating diagnosis and therapy into different agents, radiotheranostics uses one targeting molecule—often an antibody, peptide, or small ligand—labeled with a diagnostic or therapeutic radioisotope.

For imaging: The molecule is tagged with a diagnostic isotope (such as gallium-68 or fluorine-18) to visualize cancer cells through PET/CT or SPECT scans.
For therapy: The same molecule is labeled with a therapeutic isotope (such as lutetium-177 or actinium-225) to deliver lethal radiation directly to cancer cells.

This dual approach ensures high specificity, reduces off-target toxicity, and allows real-time monitoring of treatment response. Radiotheranostics has already demonstrated success in prostate cancer with PSMA-targeted therapies and in neuroendocrine tumors with somatostatin receptor-targeted therapies. The next frontier is gynecological cancers—particularly endometrial cancer.

HER2 in Endometrial Cancer

What is HER2?

HER2 is a member of the EGFR (epidermal growth factor receptor) family of tyrosine kinase receptors. It plays a crucial role in regulating cell growth, differentiation, and survival. HER2 overexpression or amplification is best known in breast and gastric cancers, where it drives aggressive tumor behavior.

HER2 in Gynecologic Malignancies

In endometrial cancer, HER2 overexpression is particularly common in uterine serous carcinoma, a highly aggressive subtype. Studies suggest that up to 30–35% of serous endometrial cancers exhibit HER2 amplification or overexpression, making it a rational therapeutic target.

HER2 as a Radiotheranostic Target

HER2 has already been explored in radiotheranostic settings for breast cancer, with radiolabeled antibodies such as trastuzumab being used for imaging and therapy. The same concept is being applied to endometrial cancer:

Imaging: HER2-targeted PET tracers allow clinicians to visualize HER2-positive lesions and assess disease spread.
Therapy: HER2 antibodies conjugated with beta- or alpha-emitting isotopes can selectively deliver radiation to HER2-expressing cancer cells.

Early preclinical studies have demonstrated that radiolabeled HER2 antibodies can significantly reduce tumor burden in HER2-positive endometrial cancer models, while sparing healthy tissues.

Clinical Implications

The use of HER2 as a radiotheranostic marker could help:

Identify patients most likely to benefit from HER2-targeted therapy.
Monitor therapeutic response in real time.
Combine with existing HER2 therapies (e.g., trastuzumab, trastuzumab-emtansine) for a synergistic effect.

CD24 in Endometrial Cancer

What is CD24?

CD24 is a small glycosylphosphatidylinositol (GPI)-anchored cell surface protein involved in cell adhesion, immune evasion, and metastasis. It is often considered a “don’t eat me” signal, helping tumor cells escape immune destruction.

CD24 Expression in Endometrial Cancer

High CD24 expression has been observed across multiple cancer types, including ovarian, breast, and colorectal cancers. In endometrial cancer, CD24 is associated with:

Aggressive histological subtypes.
Poor prognosis and reduced survival rates.
Increased metastatic potential.

These findings make CD24 not only a prognostic biomarker but also a promising therapeutic target.

CD24 as a Radiotheranostic Target

Radiotheranostic strategies targeting CD24 are still in their infancy, but the concept is gaining traction. The advantages of targeting CD24 include:

Widespread expression in aggressive endometrial cancer subtypes.
Potential synergy with immunotherapies, as CD24 blockade may enhance immune recognition.
Feasibility of radiolabeled antibodies or small molecules that bind specifically to CD24.

Early laboratory studies suggest that CD24-targeted imaging agents could improve tumor detection, especially in cases where HER2 is not overexpressed. This opens the door for dual-targeting approaches (HER2 + CD24) to maximize treatment coverage.

Comparing HER2 and CD24 as Targets

Feature	HER2	CD24
Expression	Overexpressed in 30–35% of uterine serous carcinomas	Frequently overexpressed in aggressive and metastatic subtypes
Prognostic Value	Associated with poor prognosis	Linked to poor survival, metastasis, and chemoresistance
Current Therapeutic Use	Already targeted in breast and gastric cancers; drugs available	Still under early-stage investigation
Radiotheranostic Potential	Strong (imaging + therapy validated in other cancers)	Emerging (conceptual stage, promising in immune modulation)

Both markers hold promise, but HER2 currently has more robust clinical evidence, while CD24 represents an exciting novel frontier.

The Future of Radiotheranostics in Endometrial Cancer

Personalized Medicine

HER2 and CD24 testing could become routine in the diagnostic workup of endometrial cancer, guiding patient selection for radiotheranostic therapies. This ensures that only patients with target expression undergo treatment, maximizing efficacy and minimizing unnecessary toxicity.

Combination Therapies

Radiotheranostics may be combined with:

Immunotherapy: CD24 blockade could make tumors more visible to the immune system.
Chemotherapy: Radiotheranostic therapy may sensitize tumors to chemotherapy.
Targeted therapies: HER2-targeted radiotheranostics could be used alongside HER2 inhibitors for a one-two punch against cancer.

Real-Time Treatment Monitoring

Since radiotheranostic agents can be used for both imaging and therapy, physicians can continuously monitor how tumors are responding and adjust therapy accordingly. This real-time adaptability is a major advantage over conventional treatments.

Challenges Ahead

Despite the excitement, several hurdles remain:

Need for large-scale clinical trials to validate efficacy.
Potential for radiation-related toxicity if not carefully controlled.
Cost and availability of radiopharmaceuticals in resource-limited settings.

Patient Impact and Hope

For patients, the emergence of HER2 and CD24 as radiotheranostic targets offers renewed hope. Many women diagnosed with advanced endometrial cancer currently face limited options and poor outcomes. Personalized radiotheranostic therapy could:

Improve survival rates.
Offer better quality of life by reducing side effects.
Enable more accurate disease monitoring and early detection of relapse.

As more clinical trials move forward, patients may soon have access to therapies tailored not just to their cancer type, but to the unique molecular fingerprint of their tumor.

Conclusion

Endometrial cancer remains a significant health challenge, particularly in advanced and aggressive forms. The discovery of HER2 and CD24 as promising radiotheranostic targets marks a pivotal step toward precision oncology in gynecologic malignancies.

HER2 offers a well-established pathway with immediate translational potential, building on decades of research in breast and gastric cancers.
CD24, while less explored, holds unique promise by combining tumor detection with immune modulation.

Together, they represent a dual opportunity to revolutionize the way endometrial cancer is diagnosed, treated, and monitored. As radiotheranostics continues to expand from prostate and neuroendocrine cancers into gynecologic oncology, patients may soon benefit from therapies that are more targeted, effective, and personalized than ever before.

The future of endometrial cancer treatment is not only about fighting tumors—it’s about precision, personalization, and hope.

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