Hyperpolarized MRI Visualizes Warburg Effects and Predicts Treatment Response to mTOR Inhibitors in Patient-Derived ccRCC Xenograft Models

Cancer Res. 2019 Jan 1;79(1):242-250. doi: 10.1158/0008-5472.CAN-18-2231. Epub 2018 Nov 20.

Abstract

The ever-changing tumor microenvironment constantly challenges individual cancer cells to balance supply and demand, presenting tumor vulnerabilities and therapeutic opportunities. Everolimus and temsirolimus are inhibitors of mTOR (mTORi) approved for treating metastatic renal cell carcinoma (mRCC). However, treatment outcome varies greatly among patients. Accordingly, administration of mTORi in mRCC is diminishing, which could potentially result in missing timely delivery of effective treatment for select patients. Here, we implemented a clinically applicable, integrated platform encompassing a single dose of [1-13C] pyruvate to visualize the in vivo effect of mTORi on the conversion of pyruvate to lactate using hyperpolarized MRI. A striking difference that predicts treatment benefit was demonstrated using two preclinical models derived from patients with clear cell RCC (ccRCC) who exhibited primary resistance to VEGFRi and quickly succumbed to their diseases within 6 months after the diagnosis of metastasis without receiving mTORi. Our findings suggest that hyperpolarized MRI could be further developed to personalize kidney cancer treatment. SIGNIFICANCE: These findings demonstrate hyperpolarized [1-13C]pyruvate MRI as a tool for accurately assessing the clinical success of mTOR inhibition in patients with ccRCC.

Publication types

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

MeSH terms

  • Animals
  • Antibiotics, Antineoplastic / pharmacology
  • Carcinoma, Renal Cell / drug therapy
  • Carcinoma, Renal Cell / metabolism
  • Carcinoma, Renal Cell / secondary*
  • Humans
  • Image Processing, Computer-Assisted
  • Kidney Neoplasms / drug therapy
  • Kidney Neoplasms / metabolism
  • Kidney Neoplasms / pathology*
  • Magnetic Resonance Imaging / methods*
  • Mice
  • Pyruvic Acid / metabolism*
  • Sirolimus / pharmacology*
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • Antibiotics, Antineoplastic
  • Pyruvic Acid
  • TOR Serine-Threonine Kinases
  • Sirolimus

Supplementary concepts

  • Clear-cell metastatic renal cell carcinoma