CRLX101, a Nanoparticle-Drug Conjugate Containing Camptothecin, Improves Rectal Cancer Chemoradiotherapy by Inhibiting DNA Repair and HIF1α

Xi Tian; Minh Nguyen; Henry P Foote; Joseph M Caster; Kyle C Roche; Christian G Peters; Pauline Wu; Lata Jayaraman; Edward G Garmey; Joel E Tepper; Scott Eliasof; Andrew Z Wang

doi:10.1158/0008-5472.CAN-15-2951

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CRLX101, a Nanoparticle-Drug Conjugate Containing Camptothecin, Improves Rectal Cancer Chemoradiotherapy by Inhibiting DNA Repair and HIF1α

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CRLX101, a Nanoparticle-Drug Conjugate Containing Camptothecin, Improves Rectal Cancer Chemoradiotherapy by Inhibiting DNA Repair and HIF1α

Xi Tian, Minh Nguyen, Henry P Foote, Joseph M Caster, Kyle C Roche, Christian G Peters, Pauline Wu, Lata Jayaraman, Edward G Garmey, Joel E Tepper, …

Cancer research (Chicago, Ill.), Vol.77(1), pp.112-122

01/01/2017

DOI: 10.1158/0008-5472.CAN-15-2951

PMCID: PMC5214961

PMID: 27784746

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Abstract

Novel agents are needed to improve chemoradiotherapy for locally advanced rectal cancer. In this study, we assessed the ability of CRLX101, an investigational nanoparticle-drug conjugate containing the payload camptothecin (CPT), to improve therapeutic responses as compared with standard chemotherapy. CRLX101 was evaluated as a radiosensitizer in colorectal cancer cell lines and murine xenograft models. CRLX101 was as potent as CPT in vitro in its ability to radiosensitize cancer cells. Evaluations in vivo demonstrated that the addition of CRLX101 to standard chemoradiotherapy significantly increased therapeutic efficacy by inhibiting DNA repair and HIF1α pathway activation in tumor cells. Notably, CRLX101 was more effective than oxaliplatin at enhancing the efficacy of chemoradiotherapy, with CRLX101 and 5-fluorouracil producing the highest therapeutic efficacy. Gastrointestinal toxicity was also significantly lower for CRLX101 compared with CPT when combined with radiotherapy. Our results offer a preclinical proof of concept for CRLX101 as a modality to improve the outcome of neoadjuvant chemoradiotherapy for rectal cancer treatment, in support of ongoing clinical evaluation of this agent (LCC1315 NCT02010567). Cancer Res; 77(1); 112-22. ©2016 AACR.

Immunohistochemistry

Cell Survival - drug effects

Chemoradiotherapy - methods

DNA Repair - drug effects

Humans

Mice, Inbred C57BL

Radiation-Sensitizing Agents - pharmacology

Male

Blotting, Western

Nanoconjugates

Xenograft Model Antitumor Assays

Animals

Mice, Nude

Fluorescent Antibody Technique

Cell Line, Tumor

Hypoxia-Inducible Factor 1, alpha Subunit - biosynthesis

Mice

Rectal Neoplasms - pathology

Camptothecin - pharmacology

Cyclodextrins - pharmacology

Details

Title: Subtitle: CRLX101, a Nanoparticle-Drug Conjugate Containing Camptothecin, Improves Rectal Cancer Chemoradiotherapy by Inhibiting DNA Repair and HIF1α
Creators: Xi Tian - Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, Carolina Center for Cancer Nanotechnology Excellence, Carolina Institute of Nanomedicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
Minh Nguyen - Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, Carolina Center for Cancer Nanotechnology Excellence, Carolina Institute of Nanomedicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
Henry P Foote - Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, Carolina Center for Cancer Nanotechnology Excellence, Carolina Institute of Nanomedicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
Joseph M Caster - Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, Carolina Center for Cancer Nanotechnology Excellence, Carolina Institute of Nanomedicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
Kyle C Roche - Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, Carolina Center for Cancer Nanotechnology Excellence, Carolina Institute of Nanomedicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
Christian G Peters - Cerulean Pharma Inc., Waltham, Massachusetts
Pauline Wu - Cerulean Pharma Inc., Waltham, Massachusetts
Lata Jayaraman - Cerulean Pharma Inc., Waltham, Massachusetts
Edward G Garmey - Cerulean Pharma Inc., Waltham, Massachusetts
Joel E Tepper - Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, Carolina Center for Cancer Nanotechnology Excellence, Carolina Institute of Nanomedicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
Scott Eliasof - Cerulean Pharma Inc., Waltham, Massachusetts
Andrew Z Wang - Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, Carolina Center for Cancer Nanotechnology Excellence, Carolina Institute of Nanomedicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. zawang@med.unc.edu
Resource Type: Journal article
Publication Details: Cancer research (Chicago, Ill.), Vol.77(1), pp.112-122
DOI: 10.1158/0008-5472.CAN-15-2951
PMID: 27784746
PMCID: PMC5214961
NLM abbreviation: Cancer Res
ISSN: 0008-5472
eISSN: 1538-7445
Publisher: United States
Grant note: U54 CA198999 / NCI NIH HHS U54 CA151652 / NCI NIH HHS P30 CA016086 / NCI NIH HHS R01 CA178748 / NCI NIH HHS
Language: English
Date published: 01/01/2017
Academic Unit: Radiation Oncology
Record Identifier: 9984047730602771

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