Genes & Cancer

Neoadjuvant administration of hydroxychloroquine in a phase 1 clinical trial induced plasma Par-4 levels and apoptosis in diverse tumors

Peng Wang1,2, Ravshan Burikhanov3, Rani Jayswal2, Heidi L. Weiss1,2, Susanne M. Arnold1,2, John L. Villano1,2 and Vivek M. Rangnekar2,3

1 Department of Internal Medicine, University of Kentucky, Lexington, Kentucky, USA

2 Markey Cancer Center, University of Kentucky, Lexington, Kentucky, USA

3 Department of Radiation Medicine, University of Kentucky, Lexington, Kentucky, USA

Correspondence:

Peng Wang, email:

Keywords: clinical trial; Par-4; tumor apoptosis; hydroxychloroquine

Received: September 13, 2018 Accepted: October 20, 2018 Published: November 03, 2018

Abstract

Chloroquine and hydroxychloroquine (HCQ) are robust inducers of the tumor suppressor Par-4 secretion from normal cells. Secreted Par-4 causes paracrine apoptosis of tumor cells and inhibits metastasis in mice. We report the clinical results with pharmacodynamic analyses of our Phase I trial using neoadjuvant administration of HCQ in patients with surgically removable early stage solid tumors. This was a single-institution trial of oral HCQ (200 or 400 mg twice daily) given for 14 days prior to planned surgery. Dose escalation was based on isotonic regression to model safety and biological effect based on plasma Par-4 analysis. Eight of the nine patients treated with HCQ showed elevation in plasma Par-4 levels over basal levels. No toxicities were observed with these dose regimens. The resected tumors from the eight HCQ-treated patients with elevated plasma Par-4 levels, but not the resected tumor from the patient who failed to induce plasma Par-4 levels, exhibited TUNEL-positivity indicative of apoptosis. Resected tumors from all nine HCQ-treated patients showed p62/sequestosome-1 induction indicative of autophagy-inhibition by HCQ. Our findings indicate that both dose levels of HCQ were well-tolerated and that Par-4 secretion but not induction of the autophagy-inhibition marker p62 correlated with apoptosis induction in patients’ tumors.


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