Many cancer receptors are dynamically altered in response to chemotherapy and targeted agents, and these alterations can be rapidly predictive of therapeutic response or resistance. Dynamic and non-invasive assessment with specific PET imaging agents allows for rapid response assessment and tailored modification for optimization of therapy.

  

Somatostatin Receptor (SSTR) Imaging – SSTR is expressed in high copy number on multiple neuroendocrine tumors, and also represents the main therapeutic target for treatment.  We have conducted studies into SSTR imaging with 68-Ga-DOTATOC to guide octroetide dose optimization, used SSTR as a reporter gene, as well as clinical studies of 68-Ga-DOTATOC.  Dr. Mahmood holds the IND for  68-Ga-DOTATOC imaging.

DOTATOC

  • Imaging of AR42J tumors using static 68Ga-DOTATOC (A-D), 18F-FLT (E-H) and staining for Ki-67 in tumors samples (I-L) in 4 groups of mice treated with vehicle, 1.25, 2.5, or 10 mg/kg. There is high 68Ga-DOTATOC and 18F-FLT uptake as well as 25% cells stained for Ki-67 in tumors in the control group; there is a graded decrease across all the biomarkers with increased dose of octreotide treatment. The 10 mg/kg octreotide dose shows near background levels of 68Ga-DOTATOC and 18F-FLT uptake and 5% staining for Ki-67.

 

Receptor Tyrosine Kinase Imaging – Targeted inhibitors of RTKs such as cetuximab and trastuzumab as well as inhibitors of downstream growth-signaling pathways are important aspects of cancer therapy. However, resistance is often mediated by dynamic upregulation of alternate receptors through feedback loops that allow for persistent growth pathway signaling. Through dynamic PET imaging of the receptor HER3 in multiple cancers and with multiple therapies, we show that HER3 imaging can be used to predict therapeutic resistance and guide subsequent therapeutic choices.

Slide05

  • PI3K/AKT/mTOR signaling is regulated by intrinsic feedback. These feedback patterns are influenced by the signaling node inhibited, as well as multiple cellular factors and are thought to differ meaningfully across patient tumors, such that degree of change in expression cannot be known a priori.

 

Slide06

  • Imaging with HER3 PET probe versus EGFR PET probe demonstrates differential RTK expression in response to treatment with AKT inhibitor. MDAMB468 xenografts imaged with HER3 PET probe after treatment with vehicle (A) or GDC-0068 (B) demonstrate 108% increase in SUVmean (E),*P , 0.05. MDAMB468 xenografts imaged with the EGFR PET probe after treatment with vehicle (C) or GDC-0068 (D) demonstrates no significant change in SUVmean, n 5 4 for all groups.

 

Slide07

  • 68Ga-NOTA-HER3-1 PET Imaging and Tumor HER3 Expression Correlation A) Sagittal and axial maximum intensity projections of the radiolabeled peptide in high HER3 expressing 22RV1 and low HER3 expressing HCC-1954 tumors.

 

Estrogen Receptor Imaging – The estrogen receptor (ER) is a key target in treatment of ER+ breast cancer. Through ER imaging with 18F-estradiol (FES) we can optimize the dosing of ER inhibitors and related therapeutics to improve outcomes in this widely prevalent cancer.  We have conducted these imaging studies in mouse models as well as humans

Slide09

  • Posterior 3D volume rendering of fused PET/CT scans of mice bearing breast tumors in the upper right flank and treated with fulvestrant. Top, 18F-FES PET representative images. 18F-FES uptake decreases in xenografts with increased dose of fulvestrant. The gallbladder and bowel show high uptake consistent with hepatobiliary excretion of 18F-FES. Bottom, 18F-FDG PET representative images. There is no difference among groups in 18F-FDG uptake. Green arrows indicate tumor.