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

Peng Wang, Ravshan Burikhanov, Rani Jayswal, Heidi L. Weiss, Susanne M. Arnold, John L. Villano, Vivek M. Rangnekar

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

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.

Original languageEnglish
Pages (from-to)190-197
Number of pages8
JournalGenes and Cancer
Volume9
Issue number5-6
DOIs
StatePublished - May 2018

Bibliographical note

Funding Information:
This research was funded by developmental funds from P30CA177558 to B. Mark Evers, Markey Cancer Center. RB and VMR were supported by NIH/NCI R01 CA187273.

Funding Information:
This research was supported by developmental funds (P30CA177558), and the Cancer Research informatics and Biospecimen Procurement and Translational Pathology Shared Resource Facilities from the University of Kentucky Markey Cancer Center, as well as the MCC Clinical Research Office and the MCC Research Communications Office. RB and VMR were supported by NIH/NCI R01 CA187273 (to VMR). We thank Ms. Dana Napier for conducting IHC and TUNEL assays. FINANCIAL SUPPORT This research was funded by developmental funds from P30CA177558 to B. Mark Evers, Markey Cancer Center. RB and VMR were supported by NIH/NCI R01 CA187273.

Funding Information:
This research was supported by developmental funds (P30CA177558), and the Cancer Research informatics and Biospecimen Procurement and Translational Pathology Shared Resource Facilities from the University of Kentucky Markey Cancer Center, as well as the MCC Clinical Research Office and the MCC Research Communications Office. RB and VMR were supported by NIH/NCI R01 CA187273 (to VMR). We thank Ms. Dana Napier for conducting IHC and TUNEL assays.

Publisher Copyright:
© Wang et al.

Keywords

  • Clinical trial
  • Hydroxychloroquine
  • Par-4
  • Tumor apoptosis

ASJC Scopus subject areas

  • Genetics
  • Cancer Research

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