Can Endoplasmic Reticulum Stress Responses Predict the Development of CIPN in Patients Receiving Paclitaxel-based Therapy?
Michael Limia1, Miriam Fonseca1, Oriana Gelblung1, David Shalowitz1, Samuel Lentz1, Michael Kelly1, Fang-Chi Hsu1, Cristina Furdui1, Juan Cubillos-Ruiz2, Edgar Alfonso Romero-Sandoval1, Roy Strowd1
1Wake Forest University School of Medicine, 2Weil Cornell Graduate School of Medical Sciences
Objective:
To determine if XBP1s correlates with the onset and severity of chemotherapy-induced peripheral neuropathy (CIPN) in patients receiving paclitaxel (PTX) therapy for their cancer.
Background:
Neuroinflammation is one proposed mechanism for the development of CIPN. X-box binding protein 1 (XBP1s), a prominent molecule in the IRE1α–XBP1 signaling pathway (which regulates the production of enzymes that mediate inflammation-induced pain), shows promise as a potential biomarker to predict the onset of CIPN.
Design/Methods:
Patients newly diagnosed with gynecologic malignancy receiving PTX-based first-line therapy were recruited before treatment initiation. Once consented, blood samples were drawn before treatment and at each scheduled PTX infusion. Determination of serum PTX levels using mass spectrometry and Xpb1s mRNA levels in peripheral blood mononuclear cells (PBMCs) by qPCR were performed. In addition, at every infusion time point, each patient’s level of peripheral neuropathy was graded by a physician or advanced provider based on CTCAE (Common Terminology Criteria for Adverse Events) grading criteria (scored 0-5, with 0 being asymptomatic and higher numbers indicating worse neuropathy). Cellular XBP1s, serum PTX, and neuropathy CTCAE scores were statistically associated.
Results:
The study cohort consisted of 8 patients; all female; mean age 55±17 years. All 8 received PTX/carboplatin. Of these, 7 developed symptomatic CIPN (physician assessment). Median peak neuropathy CTCAE grade was 1 (range 0-2). Mean XBP1s peak value was 0.049±0.032; mean baseline XBP1s value was 0.027±0.015. There was a significant association between rise of XBP1s from baseline to peak and neuropathy CTCAE grade (r=0.830, R2=0.725, p=0.018). Patients with higher serum PTX also had higher PBMC XBP1s expression relative to baseline (p=0.022). Patients with longer days to peak of XBP1s also had longer days to onset of CIPN (r=0.757, R2=0.573, p=0.049).
Conclusions:
A greater rise from baseline in XBP1s, a marker of ER stress, correlated with the timing and severity of PTX-induced CIPN.