Imaging and Treatment of Intestinal Cancer: Peutz-Jeghers Syndrome

Inventors: David B. Shackelford, Debbie S. Vasquez and Reuben J. Shaw
Potential Uses: Drug Discovery, Oncology

Gastrointestinal Disease or Disorder Imaging and Treatment

A Lkb1+/- mouse before and after treatment with rapamycin.

Peutz-Jeghers syndrome (PJS) is a familial cancer disorder due to inherited loss of function mutations in the LKB1/ STK11 serine/ threonine kinase. PJS patients develop gastrointestinal hamartomas with 100% penetrance often in the second decade of life, and demonstrate an increased predisposition toward the development of a number of additional malignancies.

Our technology has shown that tumors derived from LKB1-deficient mice as well as polyps from human Peutz- Jeghers patients have dramatic up-regulation of the HIF-1 alpha transcription factor and its downstream transcriptional targets hexokinase II and Glut1 in an rapamycin-suppressible manner. Using FDG-PET, we have demonstrated that LKB1/mice show increased glucose utilization in focal regions of their GI tract corresponding to these gastrointestinal hamartomas. Furthermore, like HIF-1 alpha and its target genes, the fluoro-deoxyglucose Positron Emission Tomography (FDG-PET) signal in the GI tract of these mice is abolished by rapamycin treatment (see below). This technology suggests a number of therapeutic modalities for the treatment and detection of hamartomas in PJS patients. Additionally, this technology also can be useful for the screening and treatment of the 30% of sporadic human lung cancers bearing LKB1 mutations.