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

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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 HIF1a 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).

LanguageEnglish (US)
Pages112-122
Number of pages11
JournalCancer Research
Volume77
Issue number1
DOIs
StatePublished - Jan 1 2017

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Camptothecin
Chemoradiotherapy
Rectal Neoplasms
DNA Repair
Nanoparticles
Pharmaceutical Preparations
oxaliplatin
Investigational Drugs
IT-101
Therapeutics
Heterografts
Fluorouracil
Colorectal Neoplasms
Neoplasms
Radiotherapy
Drug Therapy
Cell Line

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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CRLX101, a nanoparticle-drug conjugate containing camptothecin, improves rectal cancer chemoradiotherapy by inhibiting DNA repair and HIF1α. / Tian, Xi; Nguyen, Minh; Foote, Henry P.; Caster, Joseph M.; Roche, Kyle C.; Peters, Christian G.; Wu, Pauline; Jayaraman, Lata; Garmey, Edward G.; Tepper, Joel E.; Eliasof, Scott; Wang, Andrew Z.

In: Cancer Research, Vol. 77, No. 1, 01.01.2017, p. 112-122.

Research output: Contribution to journalArticle

Tian, X, Nguyen, M, Foote, HP, Caster, JM, Roche, KC, Peters, CG, Wu, P, Jayaraman, L, Garmey, EG, Tepper, JE, Eliasof, S & Wang, AZ 2017, 'CRLX101, a nanoparticle-drug conjugate containing camptothecin, improves rectal cancer chemoradiotherapy by inhibiting DNA repair and HIF1α' Cancer Research, vol. 77, no. 1, pp. 112-122. https://doi.org/10.1158/0008-5472.CAN-15-2951
Tian, Xi ; Nguyen, Minh ; Foote, Henry P. ; Caster, Joseph M. ; Roche, Kyle C. ; Peters, Christian G. ; Wu, Pauline ; Jayaraman, Lata ; Garmey, Edward G. ; Tepper, Joel E. ; Eliasof, Scott ; Wang, Andrew Z. / CRLX101, a nanoparticle-drug conjugate containing camptothecin, improves rectal cancer chemoradiotherapy by inhibiting DNA repair and HIF1α. In: Cancer Research. 2017 ; Vol. 77, No. 1. pp. 112-122.
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