Endometrial clear cell carcinoma (ECC) represents one of the more uncommon and biologically aggressive forms of endometrial cancer, copyrighted not only by a peculiar histological profile but also by its distinct clinical trajectory. At Protheragen, we are dedicated to accelerating the development of novel diagnostics and therapeutics for challenging diseases like ECC. Our expertise spans the entire preclinical research pipeline, from target identification and validation to the comprehensive characterization of drug candidates.
Overview of Endometrial Clear Cell Carcinoma (ECC)
Endometrial Clear Cell Carcinoma (ECC), while rare, stands out as one of the most aggressive subtypes of endometrial malignancies, representing roughly 2% to 5% of all endometrial tumor diagnoses. Its defining microscopic features—abundant clear cytoplasm coupled with poorly differentiated, high-grade nuclei—coupled with an early tendency to metastasize, contribute to generally unfavorable outcomes. The disease is most often documented in East Asian populations, presenting predominantly in postmenopausal women. Diagnostic confirmation of ECC remains complex; marked variability in interpretation among pathologists necessitates comprehensive histopathological reevaluation, frequently supplemented by targeted immunohistochemical stains, to establish the diagnosis with confidence.
Fig.1 Pathological characteristics of clear cell endometrial cancer. (Bogani G.,
et al., 2022)
Pathogenesis of Endometrial Clear Cell Carcinoma (ECC)
ECC develops through a complex interplay of inherited and acquired molecular changes. A survey of ECC samples has shown that nearly half harbor alterations in the TP53 gene, a sentinel of genomic integrity; parallel analyses reveal mutations in PIK3CA and PPP2R1A in a third of cases, and disruptions of FBXW7 and ARID1A in a quarter to a fifth. These lesions converge on pathways that modulate the cell cycle, DNA repair, and programmed cell death. Additionally, ECCs can be classified into molecular subtypes similar to those described for endometrial endometrioid and serous carcinomas, including POLE ultramutated, MMR-deficient, copy-number low (endometrioid), and copy-number high (serous-like)/p53 abnormal. Understanding these molecular subtypes is crucial for developing targeted therapies.
Diagnostics Development for Endometrial Clear Cell Carcinoma (ECC)
- Morphological and Immunohistochemical Diagnostics
Diagnosis of ECC relies heavily on morphological assessment and immunohistochemical markers. ECC typically exhibits clear cell morphology with abundant eosinophilic or clear cytoplasm and high-grade nuclei. Immunohistochemical analysis often reveals loss of ARID1A expression and abnormal DNA mismatch repair protein expression. For example, loss of ARID1A expression is observed in approximately 22% of ECC cases, while abnormal DNA MMR protein expression is seen in 19% of cases. These markers are essential for distinguishing ECC from other types of endometrial cancer.
- Molecular and Genomic Diagnostics
Molecular diagnostics involve targeted sequencing of cancer-related genes to identify specific genetic alterations. ECCs frequently harbor mutations in TP53, PIK3CA, PPP2R1A, FBXW7, and ARID1A. Additionally, ECCs can be classified into molecular subtypes based on the presence of POLE exonuclease domain mutations, MMR-deficiency, and copy-number alterations. For instance, two ECCs (6%) in a recent study harbored POLE exonuclease domain mutations, characterized by a high mutational burden. These molecular diagnostics provide a deeper understanding of ECC and guide the development of targeted therapies.
Therapeutics Development for Endometrial Clear Cell Carcinoma (ECC)
- Targeted Therapies
Targeted therapies for ECC focus on specific genetic alterations identified through molecular diagnostics. For example, ECCs with PIK3CA mutations may benefit from PI3K/AKT/mTOR pathway inhibitors. Similarly, ECCs harboring ERBB2 amplifications or mutations may respond to anti-HER2 therapies. Targeted therapies aim to exploit the molecular vulnerabilities of ECC, providing more effective and less toxic therapy options.
- Immunotherapies
Immunotherapies, particularly immune checkpoint inhibitors, have shown promise in ECC therapeutics. ECCs with MMR-deficiency or high mutational burden may respond well to immunotherapies such as pembrolizumab. For example, a recent study demonstrated that ECCs with MMR deficiency had a favorable outcome when treated with immune checkpoint inhibitors. Combination therapies, such as pembrolizumab plus lenvatinib, have also shown significant antitumor activity in ECC cases.
Table 1. Ongoing trials on clear cell endometrial carcinoma. (Bogani G., et al., 2022)
| Agents |
Phase |
Mechanism of action |
Participants |
Primary endpoint |
Estimated completion date |
| Target therapy |
| Onapristone, Anastrozole |
II |
Synthetic and steroidal antiprogestin with additional antiglucocorticoid activity, aromatase inhibitor |
77 pts. with advanced or recurrent EC, including also CCEC |
Objective response rate |
Dec-23 |
| AZD6738, + Olaparib |
II |
ATR inhibitor and PARP inhibitor |
40 pts. with Ovarian cancer and EC, including also CCEC |
Objective response rate |
Mar-23 |
| VSV-hIFNbeta-NIS, with/without Ruxolitinib |
I |
Oncolytic vesicular stomatitis virus-human interferon beta-sodium iodide symporter |
77 pts. with advanced or recurrent EC, including also CCEC |
Maximum tolerated dose of VSV-hIFNbeta-NIS |
Jun-21 |
| Nintedanib |
II |
Triple kinase inhibitor blocking VEGFR, PDGFR, and FGFR |
120 pts.: 90 with ovarian clear cell carcinoma and up to 30 with CCEC |
Progression-free survival |
Mar-21 |
| Immunotherapy |
| Atezolizumab + Bevacizumab + Rucaparib |
I |
Anti-PD1, Anti-VEGF, PARP inhibitor |
30 pts. with advanced or recurrent EC, including also CCEC |
Objective response rate |
Jun-26 |
| Tislelizumab |
I |
Anti PD1 |
20 pts. with advanced or recurrent EC with MSI high or evidence of LS, including also CCEC |
T-cell receptor (TCR) profiles, clonality, and diversity |
Dec-24 |
| Pembrolizumab + Lenvatinib |
III |
Anti PD1, TKI |
875 pts. with advanced or recurrent EC, including also CCEC |
Progression-free and overall survivals |
Sep-24 |
| Atezolizumab + platinum-based chemotherapy |
III |
Anti PD1 |
550 pts. with advanced or recurrent EC, including also CCEC |
Progression-free and overall survivals |
Dec-23 |
| Pembrolizumab (MK-3475) + platinum-based chemotherapy |
III |
Anti PD1 |
810 pts. with advanced or recurrent EC, including also CCEC |
Progression-free survival |
Jun-23 |
| Atezolizumab + Bevacizumab |
II |
Anti PD1, Anti-VEGF |
20 pts. with advanced or recurrent EC, including also CCEC |
Objective response rate |
May-23 |
| Nivolumab + RMS-986205 |
II |
Anti PD1, Anti-IDO |
50 pts. with advanced or recurrent EC, including also CCEC |
Objective response rate |
Sep-22 |
| Nivolumab + Cabozantinib |
II |
Anti PD1, TKI |
50 pts. with advanced or recurrent EC, including also CCEC |
Progression-free survival |
Jan-22 |
| Pembrolizumab + Doxorubicin |
II |
Anti PD1, Chemotherapy |
51 pts. with advanced or recurrent EC, including also CCEC |
Progression-free survival |
Jun-21 |
| Nivolumab + Ipilimumab |
II |
Anti PD1, Anti-CTLA4 |
60 pts. with advanced or recurrent EC, including also CCEC |
Objective response rate |
Dec-20 |
Abbreviations: EC, endometrial cancer; CCEC, Clear cell endometrial carcinoma; pts, patients; PD-1, Programmed cell death protein 1; TKI, Tyrosine Kinase Inhibitors; PARP, Poly (ADP-ribose) polymerase; MSI, microsatellite instability; LS, Lynch syndrome.
Disclaimer: Protheragen focuses on providing preclinical research services. This table is for information exchange purposes only. This table is not a treatment plan recommendation. For guidance on treatment options, please visit a regular hospital.
Our Services
Protheragen's diagnostics and therapeutics development services are designed to support every stage of your project. We offer a full suite of services, including custom synthesis of analytical reference standards and the development of novel drug delivery systems. Our therapeutic development services include high-throughput screening for potential drug candidates, target-specific assay development, and mechanism-of-action studies.
Protheragen also provides customized services to meet the unique needs of each client. Whether you require a specific chemical synthesis, a specialized bioassay, or a tailored preclinical study design, our team of seasoned experts can craft a solution. Our services are flexible and collaborative, ensuring we work closely with you to meet your project goals with precision and reliability. If you are interested in our services, please feel free to contact us.
References
- Bogani, Giorgio, et al. "Clear cell carcinoma of the endometrium." Gynecologic oncology 164.3 (2022): 658-666.
- DeLair, Deborah F., et al. "The genetic landscape of endometrial clear cell carcinomas." The Journal of pathology 243.2 (2017): 230-241.
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