May 1, 2023
Reston, VA—A pair of articles published in the May issue of The Journal of Nuclear Medicine illustrate the promise of the novel FAPI radiotracer in diagnosing, staging, and treating multiple types of cancer. Results from the largest study of patients undergoing 68Ga-FAPI PET demonstrate the superiority of 68Ga-FAPI over standard 18F-FDG PET in evaluating multiple types of cancer. In a separate study, a newly designed FAPI-targeted treatment was found to suppress tumor growth in several common cancers in a preclinical setting. These advances have strong potential to provide more precise staging and management for cancer patients.
Cancer-associated fibroblasts are involved with tumor growth, migration and progression. A sub-population of cancer-associated fibroblasts express fibroblast activation protein (FAP). FAP is prominently expressed in solid tumors but virtually absent from healthy tissues, which makes it an attractive diagnostic and therapeutic target for fibroblast activation protein inhibitors (FAPI).
In the first study, 324 patients with 21 different tumor types underwent 68Ga-FAPI PET over a three-year period; 237 of them also received 18F-FDG PET imaging. Researchers compared 68Ga-FAPI PET and 18F-FDG PET in terms of uptake across tumor entities. They also examined whether there was a correlation between 68Ga-FAPI uptake on PET scan and FAP expression on stained tissue samples.
Uptake was significantly higher for 68Ga-FAPI as compared to 18F-FDG in primary lesions of pancreatic cancers and sarcoma and in metastatic lesions of pancreatic cancers. 68Ga-FAPI PET showed superior detection for local and regional disease in sarcoma as well as for distant metastatic disease in sarcoma and cancers of the pancreas, head and neck, bile ducts, lung, and bladder. A positive correlation was also found between radiotracer uptake and FAP expression levels in the tissue samples.
“68Ga-FAPI PET can be used as a tool for diagnosis of tumors, with the potential for more precise staging and management of patients with the aforementioned tumor entities,” said Nader Hirmas, MD, ScD, a PhD candidate at the Department of Nuclear Medicine at Essen University Hospital in Essen, Germany. “It could also be used as a tool to screen patients who would potentially benefit from FAP-directed radioligand therapy.”
|Supplemental Figure 6. A 57-year-old male with stage 1B pancreatic adenocarcinoma (T2N0M0). (A) FAPI maximum-intensity projection (B) fused FAPI PET/CT (C) FAPI PET and (D) accompanying low dose CT along with concomitant (E) FDG maximum-intensity projection (F) fused FDG PET/CT (G) FDG PET and (H) accompanying high dose CT. Arrows point towards primary lesion in the pancreas (FAP SUVmax 25.1, FDG SUVmax 6.2).|
In the second study, researchers developed a new FAP radiopharmaceutical therapy that targets naturally occurring cancer-associated fibroblasts. “In previous tumor models, researchers altered cancer cells to express high levels of FAP as a target for therapy. In this study we sought to create a treatment that would be effective in the natural tumor environment,” said Philip S. Low, PhD, presidential scholar for drug discovery and Ralph C. Corley distinguished professor in the Department of Chemistry at Purdue University in West Lafayette, Indiana.
Researchers used a modern bioanalytical method (single cell RNA-seq) to determine which cells in 34 human breast, ovarian, colorectal and lung tumors expressed FAP. Two radiopharmaceutical conjugates—FAP6-DOTA and FAP6-IP-DOTA (the latter of which contains an albumin-binder to prolong circulation and improve tumor uptake)—were developed and tested on human FAP-expressing cells. Radiopharmaceutical therapies of 177Lu-FAP6-DOTA and 177Lu-FAP6-IP-DOTA were also investigated in a mouse model.
FAP was found to be overexpressed on five percent of human tumor cells; cancer-associated fibroblasts constituted 77 percent of this FAP-subpopulation, while two percent were cancer cells. FAP6-IP-DOTA was shown to exhibit high FAP affinity, prolonged circulation, increased tumor uptake, and minimal retention in healthy tissue. In addition, single doses of 177Lu-FAP6-IP-DOTA suppressed tumor growth by nearly 50 percent in all tested tumor models without causing reproducible toxicities.
“These data suggest that this newly designed FAP-targeted radiotherapy should be capable of treating many more types of human cancers in which the FAP expression is limited to only the cancer-associated fibroblasts,” noted Spencer D. Lindeman, PhD, visiting scholar in the Department of Chemistry at Purdue University. “This could be a powerful and versatile tool for the field of clinical nuclear medicine.”
|Supplemental Figure 7B. Optimization of the specific activities of 111In-FAP6-IP-DOTA in HT29 tumors over time as a function of molar amount of FAP6 conjugate injected while maintaining the dose of radioactivity constant (~10 MBq). Arrows: a = 4T1 tumors; b = liver; c = kidneys.|
The authors of “Fibroblast activation protein positron emission tomography and histopathology in a single-center database of 324 patients and 21 tumor entities” include Nader Hirmas, Miriam Sraieb, Lukas Kessler, Kim M. Pabst, Francesco Barbato, Katharina Luekerath, Michael Nader, Hubertus Hautzel, Ken Herrmann, and Wolfgang P. Fendler, Department of Nuclear Medicine, University of Duisburg-Essen and German Cancer Consortium (DKTK)-University Hospital Essen, Essen, Germany; Rainer Hamacher and Stefan Kasper, Department of Medical Oncology, West German Cancer Center, University of Duisburg-Essen and German Cancer Consortium (DKTK)-University Hospital Essen, Essen, Germany; Marc Ingenwerth, Institute of Pathology, University Hospital Essen, Essen, Germany; Hans-Ulrich Schildhaus, Institute of Pathology, University Hospital Essen, Essen, Germany, and Targos Molecular Pathology, Inc., Kassel, Germany; Claudia Kesch, Boris Hadaschik, and Viktor Grünwald, Department of Urology, University of Duisburg-Essen and German Cancer Consortium (DKTK)-University Hospital Essen, Essen, Germany; Bastian von Tresckow and Christine Hanoun, Department of Hematology and Stem Cell Transplantation, University of Duisburg-Essen and German Cancer Consortium (DKTK)-University Hospital Essen, Essen, Germany; Clemens Aigner, Department of Thoracic Surgery and Thoracic Endoscopy, University of Duisburg-Essen and German Cancer Consortium (DKTK)-University Hospital Essen, Essen, Germany; Martin Glas, Division of Neurooncology, Department of Neurology, University of Duisburg-Essen and German Cancer Consortium (DKTK)-University Hospital Essen, Essen, Germany; Martin Stuschke, Department of Radiation Therapy, University of Duisburg-Essen and German Cancer Consortium (DKTK)-University Hospital Essen, Essen, Germany; Sherko Kümmel, Breast Unit, Essen-Mitte, Germany, Charité- Universitätsmedizin Berlin, Department of Gynecology with Breast Center, Berlin, Germany; Philipp Harter, Department of Gynecology and Gynecology Oncology, Ev. Kliniken Essen-Mitte (KEM), Essen, Germany; Celine Lugnier, Department of Hematology and Oncology with Palliative Care, Ruhr-University Bochum, Bochum, Germany; Waldemar Uhl, Department of General and Visceral Surgery, Ruhr-University Bochum, Bochum, Germany; Marco Niedergethmann, Clinical for General and Visceral Surgery, Alfried Krupp Hospital, Essen, Germany; and Jens T. Siveke, Bridge Institute of Experimental Tumor Therapy, West German Cancer Center, University Hospital Essen, Essen, Germany, and Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK, Partner Site Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany.
The authors of “Fibroblast activation protein targeted radioligand therapy for treatment of solid tumors” include Spencer D. Lindeman, Ramesh Mukkamala, Autumn Horner, Pooja Tudi. Owen C. Booth, Roxanne Huff, Joshua Hinsey, Anders Hovstadius, Peter Martone, Fenghua Zhang, Madduri Srinivasarao, and Philip S. Low, Department of Chemistry and Institute for Drug Discovery, Purdue University; West Lafayette, Indiana; and Abigail Cox, Department of Comparative Pathobiology, Purdue College of Veterinary Medicine; West Lafayette, Indiana.
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