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

doi:10.18632/genesandcancer.181

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 journal › Article › peer-review

24 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 language	English
Pages (from-to)	190-197
Number of pages	8
Journal	Genes and Cancer
Volume	9
Issue number	5-6
DOIs	https://doi.org/10.18632/genesandcancer.181
State	Published - May 2018

Bibliographical note

Publisher Copyright:
© Wang et al.

Funding

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. 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. 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.

Funders	Funder number
MCC Clinical Research Office
NCI/NIH
National Institutes of Health (NIH)
National Childhood Cancer Registry – National Cancer Institute	R01 CA187273
University of Kentucky
University of Kentucky Markey Cancer Center

Keywords

Clinical trial
Hydroxychloroquine
Par-4
Tumor apoptosis

ASJC Scopus subject areas

Genetics
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.18632/genesandcancer.181

Cite this

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

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{\textquoteright} tumors.",

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author = "Peng Wang and Ravshan Burikhanov and Rani Jayswal and Weiss, {Heidi L.} and Arnold, {Susanne M.} and Villano, {John L.} and Rangnekar, {Vivek M.}",

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volume = "9",

pages = "190--197",

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AU - Jayswal, Rani

AU - Weiss, Heidi L.

AU - Arnold, Susanne M.

AU - Villano, John L.

AU - Rangnekar, Vivek M.

N1 - Publisher Copyright: © Wang et al.

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N2 - 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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Neoadjuvant administration of hydroxychloroquine in a phase 1 clinical trial induced plasma par-4 levels and apoptosis in diverse tumors

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

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