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

Cancer Res. 2017 Jan 1;77(1):112-122. doi: 10.1158/0008-5472.CAN-15-2951. Epub 2016 Oct 26.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Blotting, Western
  • Camptothecin / pharmacology*
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Chemoradiotherapy / methods
  • Cyclodextrins / pharmacology*
  • DNA Repair / drug effects*
  • Fluorescent Antibody Technique
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / biosynthesis*
  • Immunohistochemistry
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Nude
  • Nanoconjugates
  • Radiation-Sensitizing Agents / pharmacology*
  • Rectal Neoplasms / pathology*
  • Xenograft Model Antitumor Assays

Substances

  • Cyclodextrins
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • IT-101
  • Nanoconjugates
  • Radiation-Sensitizing Agents
  • Camptothecin

Associated data

  • ClinicalTrials.gov/NCT02010567