The overall goal of this proposal is to develop clinical PET methods to quantitate unoccupied somatostatin receptor (SSTR) fraction during therapy to allow optimization of the dose of somatostatin analogs in the treatment of patients with small bowel carcinoid tumors. Somatostatin analogs, including octreotide LAR, have previously been used only for symptom relief in patients with functionally active carcinoid tumors, but not to prevent disease progression. Recently, a well-controlled multicenter trial in patients with advanced carcinoid tumors demonstrated that treatment with octreotide LAR more than doubled the time to tumor progression. This data has led to a change in both treatment guidelines and clinical practice; somatostatin analogs are now used as an antineoplastic therapy for this disease. However, all patients in the monotherapy study received an arbitrary, non-optimized, fixed once monthly dose of octreotide LAR 30 mg. Whether this dose was optimal for controlling tumor growth is unknown; indeed, there is little data regarding the optimal dose of octreotide and other somatostatin analogs for tumor growth control. Furthermore, known variability between patients' tumors suggests that methods to individually optimize dose could be helpful to improve treatment outcomes. The use of receptor imaging provides a method to directly assess somatostatin receptor occupancy, and therefore could be an ideal technique to optimize the choice and dose of somatostatin analogs in patients. To support this research we have optimized 68Ga-DOTATOC radiosynthesis, developed human-use formulation, automated the synthesis, measured SSTR-mediated cellular uptake and demonstrated quantitative measurement of partial and complete receptor block using dynamic PET imaging, quantitatively evaluated proliferation changes, performed kinetic modeling of radioligand uptake preclinically, and automated total tumor volume determination for human 68Ga-DOTATOC scans. In the proposed work, we will further develop quantitative parametric imaging methods in preclinical murine systems and use these techniques to model free and total SSTR density, based on 68Ga-DOTATOC uptake at peak and trough octreotide LAR conditions. We will expand this to evaluate preclinically the increased prediction provided by evaluating upstream receptor block and downstream proliferation changes. We will translate the validated techniques to a clinical trial enrolling a small bowel carcinoid patient population, and correlate the early calculated imaging parameters with subsequent tumor progression. If successful, our approach will provide data on the correlation between somatostatin receptor occupancy and clinical outcomes, and introduce molecular imaging guidance for individualized chemotherapy dosing in patients with carcinoid tumors. This technique has the further potential to be expanded to other targeted drug therapies used to treat a broad range of cancers.

Public Health Relevance

The overall goal of this proposal is to develop clinical PET methods to quantitate unoccupied somatostatin receptor (SSTR) fraction during therapy to allow optimization of the dose of somatostatin analogs in the treatment of patients with small bowel carcinoid tumors. The methods will be developed and refined in vivo in preclinical model systems, and then tested in a clinical trial that correlates these measured parameters with subsequent tumor growth. The information gained from this research may help guide individualized therapy dosing, and help optimize therapy timing in the future in patients with carcinoid tumors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA166582-03
Application #
8828121
Study Section
Special Emphasis Panel (ZRG1-DTCS-A (81))
Program Officer
Henderson, Lori A
Project Start
2013-04-01
Project End
2018-03-31
Budget Start
2015-04-01
Budget End
2016-03-31
Support Year
3
Fiscal Year
2015
Total Cost
$358,179
Indirect Cost
$135,689
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02114
Larimer, Benjamin M; Wehrenberg-Klee, Eric; Dubois, Frank et al. (2017) Granzyme B PET Imaging as a Predictive Biomarker of Immunotherapy Response. Cancer Res 77:2318-2327
Qian, Zhi Rong; Li, Tingting; Ter-Minassian, Monica et al. (2016) Association Between Somatostatin Receptor Expression and Clinical Outcomes in Neuroendocrine Tumors. Pancreas 45:1386-1393
Heidari, Pedram; Szretter, Alicia; Rushford, Laura E et al. (2016) Design, construction and testing of a low-cost automated (68)Gallium-labeling synthesis unit for clinical use. Am J Nucl Med Mol Imaging 6:176-84
Mahmood, Umar (2015) 2015 SNMMI Highlights Lecture: Oncology, Part I. J Nucl Med 56:9N-16N
Heidari, Pedram; Esfahani, Shadi A; Turker, Nazife S et al. (2015) Imaging of Secreted Extracellular Periostin, an Important Marker of Invasion in the Tumor Microenvironment in Esophageal Cancer. J Nucl Med 56:1246-51
Mahmood, Umar (2014) 2014 SNMMI highlights lecture: Oncology. J Nucl Med 55:9N-24N
Leece, Alicia K; Heidari, Pedram; Yokell, Daniel L et al. (2013) A container closure system that allows for greater recovery of radiolabeled peptide compared to the standard borosilicate glass system. Appl Radiat Isot 80:99-102
Heidari, Pedram; Wehrenberg-Klee, Eric; Habibollahi, Peiman et al. (2013) Free somatostatin receptor fraction predicts the antiproliferative effect of octreotide in a neuroendocrine tumor model: implications for dose optimization. Cancer Res 73:6865-73