2. Academic Validation
  3. Combination inhibition of PI3K and mTORC1 yields durable remissions in mice bearing orthotopic patient-derived xenografts of HER2-positive breast cancer brain metastases

Combination inhibition of PI3K and mTORC1 yields durable remissions in mice bearing orthotopic patient-derived xenografts of HER2-positive breast cancer brain metastases

  • Nat Med. 2016 Jul;22(7):723-6. doi: 10.1038/nm.4120.
Jing Ni 1 2,  Shakti H Ramkissoon 3 4,  Shaozhen Xie 1 2,  Shom Goel 1 3,  Daniel G Stover 3,  Hanbing Guo 1 2,  Victor Luu 1 2,  Eugenio Marco 5,  Lori A Ramkissoon 3,  Yun Jee Kang 3,  Marika Hayashi 3,  Quang-De Nguyen 6,  Azra H Ligon 4,  Rose Du 7,  Elizabeth B Claus 7 8,  Brian M Alexander 9 10,  Guo-Cheng Yuan 5,  Zhigang C Wang 1 3,  J Dirk Iglehart 1 3,  Ian E Krop 3,  Thomas M Roberts 1 2,  Eric P Winer 3,  Nancy U Lin 3,  Keith L Ligon 3 4,  Jean J Zhao 1 2
Affiliations

Affiliations

  • 1 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
  • 2 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.
  • 3 Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
  • 4 Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
  • 5 Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
  • 6 Lurie Family Imaging Center, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
  • 7 Department of Neurosurgery, Brigham and Women's Hospital, Boston, Massachusetts, USA.
  • 8 School of Public Health, Yale University, New Haven, Connecticut, USA.
  • 9 Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
  • 10 Department of Radiation Oncology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
PMID: 27270588 DOI: 10.1038/nm.4120
Abstract

Brain metastases represent the greatest clinical challenge in treating HER2-positive breast Cancer. We report the development of orthotopic patient-derived xenografts (PDXs) of HER2-expressing breast Cancer brain metastases (BCBM), and their use for the identification of targeted combination therapies. Combined inhibition of PI3K and mTOR resulted in durable tumor regressions in three of five PDXs, and therapeutic response was correlated with a reduction in the phosphorylation of 4EBP1, an mTORC1 effector. The two nonresponding PDXs showed hypermutated genomes with enrichment of mutations in DNA-repair genes, which suggests an association of genomic instability with therapeutic resistance. These findings suggest that a biomarker-driven clinical trial of PI3K Inhibitor in combination with an mTOR Inhibitor should be conducted for patients with HER2-positive BCBM.

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