New Prognosis Marker for Uterine Cancer Identified

A research team from the Leuven Cancer Institute in Belgium has identified a protein marker of prognosis for leiomyosarcoma, a difficult to treat uterine sarcoma. Initial studies have shown that patients who have the protein P-S6S240 respond well to PI3K/mTOR inhibitors. The study that was published in The American Association for Cancer Research’s Journal of Clinical Cancer Research was led by Dr. Frédéric Amant who is a professor at the Leuven Cancer Institute (Belgium) and at the Netherlands Cancer Institute (Amsterdam)

Identifying the Protein Marker

The research team identified 5 proteins from 288 uterine sarcoma samples analyzed, which included

• 157 leiomyosarcomas
• 52 benign uterine stromal tumors
• Endometrial sarcomas
• Adenosarcomas
• Certain other undifferentiated types of cancer
• 41 normal uterine tissues

The study aided in finding that the presence of the activated S6 ribosomal protein P-S6S240 was 32% higher in high-grade tumors when compared to 9% in low-grade tumors. The P-S6S240 protein present in patients with leiomyosarcoma was also indicative of

• Shorter span of progression-free survival
• Disease-specific survival

The newly identified protein marker P-S6S240 is involved in the PI3K/mTOR cell-signaling pathway, which is associated with stimulation of cancer growth.

Validation Studies

Human tumor fragments were implanted into mice by the research team to get five leiomyosarcoma patient-derived xenograft (PDX) models. These mice were then treated with PI3K/mTOR inhibitors and it was found that

• The tumor shrunk in two xenograft mice models
• The tumor remained stable in the third model
• There was reduced growth of tumor in the fourth model

The xenograft model that did not respond to the treatment with PI3K/mTOR inhibitor did not contain the activated S6 protein, as evidenced by the negative result in the test. All other xenograft models of mice responded positively to the S6 protein. The scientists who were involved in the study, thus stated that the protein could be used as a therapy marker by attacking them with PI3K/mTOR inhibitors. This protein can further be used as a prognosis marker as uterine leiomyosarcoma patients who had activated S6 protein relapsed faster.

New Generation mTOR Inhibitors

Previous versions of mTOR inhibitors that were used in the treatment of uterine leiomyosarcoma targeted only certain active mTOR complexes with minimal response and were associated with increased toxicity. The Food and Drug Administration (FDA), therefore, did not approve these drugs. The scientists involved in the study used new-generation dual PI3K/mTOR inhibitors [BEZ235; dactolisib], which were found to have better efficacies when compared to the earlier ones. Dr. Amant added that the strong response obtained on using PI3K/mTOR inhibitors was rare for leiomyosarcomas. Research into development of drugs that had an acceptable level of toxicity was important to ensure safety.

There are very few studies that are conducted on uterine sarcomas, as the disease is very rare. However, the disease grows rapidly and is difficult to treat, which makes it imperative to identify a method of treatment. Leiomyosarcomas occur less significantly, but the findings from the current study warrant further research into the use of PI3K/mTOR inhibitors against this disease.

The xenograft mice that were used in the study did not have a good immune system; therefore, immune responses to the treatment and toxicities could not be ascertained as a part of the study.

Advertisement

The identification of a protein biomarker that serves as a method of determining treatment choice as well as a prognostic marker for patients with leiomyosarcomas will aid in better treatment and care for such patients.

Uterine Carcinomas

About 95% of the cancers that occur in the uterus originate in the endometrium, called endometrial cancer. Uterine sarcomas constitute 2 to 5 % of all uterine carcinomas and originate from other tissues, like the muscles and tissues of the uterus that begin to grow at an abnormal rate. Other forms of uterine carcinomas include clear cell carcinoma, uterine papillary serous carcinoma and carcinosarcoma.

• In the U.S, uterine cancer is the fourth most common cancer for women.
• Around 60,050 women in the United States are diagnosed with uterine cancer every year.
• An estimated 10,470 women die due to the disease every year.
• Uterine cancer is the sixth most common cause of cancer related death among women.
• The 5 year survival rate for uterine cancer is 82%.
• Leiomyosarcomas constitute 30% of all uterine sarcomas (National Cancer Institute).
• The 5 year survival rate for women with leiomyosarcomas is 50%.

Dr. Amant stated that the research team wanted to identify new protein targets for the various types of uterine cancer to improve treatment options and disease identification. The team further analyzed if the new targets identified could be used as biomarkers for determining the prognosis of the condition. The need to identify biomarkers is important as newer therapies for cancer are very expensive; also, particular treatment methods could be validated based on these biomarkers.

Advertisement

References:

1. Uterine Sarcoma Facts - (https://www.seattlecca.org/diseases/uterine-sarcoma/uterine-sarcoma-facts)

Source-Medindia