Abstract
Introduction: A potential limiting feature for radiotherapy (RT) in the treatment of cancer is the toxicity that arises due to damage to normal tissues as a result of the radiation. This risk of toxicity is a particular concern in men with localized prostate cancer. Radiation-induced proctitis (RIP) is a common adverse effect of RT in treatment for prostate cancer. RIP limits radiation dose and treatment volumes, interrupts treatment, and lowers patients’ quality of life. Exosomes are 30- to 150-nm-wide nanovesicles originating from the endosomal network and are found in most body fluids. Exosomes are a fundamental driver of intercellular communication by transferring proteins, lipids, and miRNA. Exosomes miRNA signatures may serve as noninvasive prediction biomarkers of late toxicities such as RIP.
Methods: Twelve prostate cancer patients (pts) treated with curative intent with different grades of post-irradiation toxicity were enrolled on an IRB-approved study. Pts were evaluated prospectively weekly during RT and at prescribed intervals following completion of RT for the development of toxicity using a standardized instrument of physician-reported toxicity (CTCAE v4). Blood samples were collected one day before and one year after RT. The 101Bio kit was used to isolate exosomes from plasma of pts. For the miRNAs expression profiling we used ExiLENT SYBR® Green Maser Mix (Exiqon). The expression of 179 miRNA commonly found in human serum/plasma were analyzed by Serum/plasma PCR Panel (QIAGEN) for each sample.
Results: Exosomes miRNAs were analyzed from the plasma of prostate pts divided into two groups: (i) low toxicity grade 0-1 (6 pts) and (ii) high toxicity grades 2-4 (6 pts). Out of the 179 miRNAs analyzed, three miRNAs exhibited differential expression at post-RT compared to pre-RT for low toxicity pts (LTP): miR-132-5p (upregulated, p=0.001), miR-23a-3p (downregulated, p=0.020) and miR-1-3p (upregulated, p=0.047). Four miRNAs exhibited differential expression at post-RT compared to pre-RT for high toxicity pts (HTP): miR-132-5p (downregulated, p=0.003), miR-197-3p (upregulated, p=0.017), miR-151a-5p (upregulated, p=0.031), miR-18b-5p (upregulated, p=0.020). The most interesting results were observed with miR-132-5p. Before RT it showed significantly higher expression in HTP compared to the LTP. However, after RT miR-132-5p expression showed 10.76-fold increase in LTP and 7.87-fold decrease in the HTP. As a result of these dynamic changes, expression of miR-132-5p after RT became significantly higher in LTP compared to the HTP.
Conclusions: Our investigation has revealed miR-132-5p as a potential marker for risk of significant rectal injury following RT for prostate cancer, and changes in the expression of miR-1-3p, miR-18b-5p, miR-23a-3p, miR-151a-5p, and miR-197-3p may reflect the ongoing inflammatory process responsible for radiation-induced rectal injury.
Citation Format: Pratip Rana, Preetam Ghosh, Mitchell S. Anscher, Ross B. Mikkelsen, Vasily A. Yakovlev. Exosomal miRNA as a noninvasive prediction marker of normal tissue toxicity after radiotherapy for prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr A64.
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