Fibroblast activation protein targeted therapy using [177Lu]FAPI-46 compared with [225Ac]FAPI-46 in a pancreatic cancer model

Abstract Purpose Fibroblast activation protein (FAP), which has high expression in cancer-associated fibroblasts of epithelial cancers, can be used as a theranostic target. Our previous study used 64Cu and 225Ac-labelled FAP inhibitors (FAPI-04) for a FAP-expressing pancreatic cancer xenograft imaging and therapy. However, the optimal therapeutic radionuclide for FAPI needs to be investigated further. In this study, we evaluated the therapeutic effects of beta-emitter (177Lu)-labelled FAPI-46 and alpha-emitter (225Ac)-labelled FAPI-46 in pancreatic cancer models. Methods PET scans (1 h post injection) were acquired in PANC-1 xenograft mice (n = 9) after the administration of [18F]FAPI-74 (12.4 ± 1.7 MBq) for the companion imaging. The biodistribution of [177Lu]FAPI-46 and [225Ac]FAPI-46 were evaluated in the xenograft model (total n = 12). For the determination of treatment effects, [177Lu]FAPI-46 and [225Ac]FAPI-46 were injected into PANC-1 xenograft mice at different doses: 3 MBq (n = 6), 10 MBq (n = 6), 30 MBq (n = 6), control (n = 4) for [177Lu]FAPI-46, and 3 kBq (n = 3), 10 kBq (n = 2), 30 kBq (n = 6), control (n = 7) for [225Ac]FAPI-46. Tumour sizes and body weights were followed. Results [18F]FAPI-74 showed rapid clearance by the kidneys and high accumulation in the tumour and intestine 1 h after administration. [177Lu]FAPI-46 and [225Ac]FAPI-46 also showed rapid clearance by the kidneys and relatively high accumulation in the tumour at 3 h. Both [177Lu]FAPI-46 and [225Ac]FAPI-46 showed tumour-suppressive effects, with a mild decrease in body weight. The treatment effects of [177Lu]FAPI-46 were relatively slow but lasted longer than those of [225Ac]FAPI-46. Conclusion This study suggested the possible application of FAPI radioligand therapy in FAP-expressing pancreatic cancer. Further evaluation is necessary to find the best radionuclide with shorter half-life, as well as the combination with therapies targeting tumour cells directly.

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Fibroblast Activation Protein Targeted Therapy Using [177Lu]FAPI-46 Compared with [225Ac]FAPI-46 in a Pancreatic Cancer Model

10.21203/rs.3.rs-602564/v1 ◽

2021 ◽

Author(s):

Yuwei Liu ◽

Tadashi Watabe ◽

Kazuko Kaneda-Nakashima ◽

Yoshifumi Shirakami ◽

Sadahiro Naka ◽

...

Keyword(s):

Pancreatic Cancer ◽

Body Weight ◽

Treatment Effects ◽

Fibroblast Activation Protein ◽

Dependent Manner ◽

High Accumulation ◽

Fibroblast Activation ◽

Rapid Clearance ◽

Xenograft Mice ◽

Dose Dependent

Abstract Purpose Fibroblast activation protein (FAP), which has high expression in cancer-associated fibroblasts of epithelial cancers, can be used as a theranostic target. Our previous study used 64Cu and 225Ac-labelled FAP inhibitors (FAPI-04) for a FAP-expressing pancreatic cancer xenograft imaging and therapy. However, the optimal therapeutic radionuclide for FAPI still needs to be further investigated. In this study, we evaluated the therapeutic effects of beta-emitter(177Lu)-labelled FAPI-46 and alpha-emitter(225Ac)-labelled FAPI-46 in pancreatic cancer models. Methods PET scans (1 h post injection) were acquired in PANC-1 xenograft mice (n = 9) after the administration of [18F]FAPI-74 (12.4 ± 1.7 MBq) for the companion imaging. The biodistribution of [177Lu]FAPI-46 was evaluated in the same tumour model (n = 6). For the determination of treatment effects, [177Lu]FAPI-46 and [225Ac]FAPI-46 were injected into PANC-1 xenograft mice with different doses: 3 MBq (n = 6), 10 MBq (n = 6), 30 MBq (n = 6), control (n = 4) for [177Lu]FAPI-46, and 3 kBq (n = 3), 10 kBq (n = 2), 30 kBq (n = 5), control (n = 7) for [225Ac]FAPI-46. Tumour size and body weight were followed. Results [18F]FAPI-74 showed rapid clearance via kidneys and high accumulation in the tumour and intestine 1h after administration. [177Lu]FAPI-46 also showed rapid clearance through kidneys and relatively high accumulation in the tumour and large intestine at 24h. Both [177Lu]FAPI-46 and [225Ac]FAPI-46 showed tumour-suppressive effects in a dose-dependent manner, with a mild decrease in body weight. The treatment effects of [177Lu]FAPI-46 were relatively slow but lasted longer than those of [225Ac]FAPI-46. Conclusion The dose-dependent tumour-suppressive effect of [177Lu]FAPI-46 and [225Ac]FAPI-46 suggested promising application in FAP-expressing pancreatic cancer.

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Therapeutic Effects of Microbubbles Added to Combined High-Intensity Focused Ultrasound and Chemotherapy in a Pancreatic Cancer Xenograft Model

Korean Journal of Radiology ◽

10.3348/kjr.2016.17.5.779 ◽

2016 ◽

Vol 17 (5) ◽

pp. 779 ◽

Cited By ~ 9

Author(s):

Mi Hye Yu ◽

Jae Young Lee ◽

Hae Ri Kim ◽

Bo Ram Kim ◽

Eun-Joo Park ◽

...

Keyword(s):

Pancreatic Cancer ◽

High Intensity ◽

Focused Ultrasound ◽

Xenograft Model ◽

High Intensity Focused Ultrasound ◽

Therapeutic Effects

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Inhibition of pyruvate dehydrogenase kinase influence microbiota and metabolomic profile in pancreatic cancer xenograft mice

10.21203/rs.3.rs-43561/v1 ◽

2020 ◽

Author(s):

Kaarel Adamberg ◽

Raivo Vilu ◽

Valerio Pazienza

Keyword(s):

Pancreatic Cancer ◽

Treatment Options ◽

Xenograft Model ◽

Treated Group ◽

Pyruvate Dehydrogenase Kinase ◽

Control Group ◽

Metabolomic Profile ◽

Mouse Xenograft Model ◽

Xenograft Mice

Abstract Objective Despite recent advances in treatment options, pancreatic cancer remains the most deadly major cancer. Targeting metabolism represents an emerging anti-cancer strategy. Results Metagenomic 16S analysis was employed to explore the effect of Dichloroacetate (DCA) on the composition of the fecal microbiota and metabolomic profile was assessed on in vivo pancreatic cancer mouse xenograft model. Pancreatic cancer xenograft mice displayed a shift of microbiota’ profile as compared to control mice without DCA treatment and a significant decrease of the purine bases inosine xanthine together with their metabolically-related compound hypoxanthine were observed in the DCA treated group as compared to the control group. Two aminoacids methionine and aspartic acid resulted decreased and increased respectively. DCA affects tumor environment and studies are needed in order to understand whether DCA supplementation could be supportive as synergistic approach to enhance the efficacy of existing cancer treatments in pancreatic cancer patients.

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Abstract 152: Nicotine inhibits the therapeutic effects of gemcitabine in pancreatic cancer cellsin vitroand in a mouse xenograft model

10.1158/1538-7445.am2012-152 ◽

2012 ◽

Author(s):

Jheelam Banerjee ◽

Hussein A.N. Al-Wadei ◽

Hildegard M. Schuller

Keyword(s):

Pancreatic Cancer ◽

Xenograft Model ◽

Therapeutic Effects ◽

Mouse Xenograft ◽

Mouse Xenograft Model

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Schedule-dependent Therapeutic Effects of Gemcitabine Combined with Uracil-Tegafur in a Human Pancreatic Cancer Xenograft Model

Pancreas ◽

10.1097/01.mpa.0000226882.48204.26 ◽

2006 ◽

Vol 33 (2) ◽

pp. 142-147 ◽

Cited By ~ 9

Author(s):

Masanori Tsujie ◽

Shoji Nakamori ◽

Shin Nakahira ◽

Setsuo Takeda ◽

Yuji Takahashi ◽

...

Keyword(s):

Pancreatic Cancer ◽

Xenograft Model ◽

Human Pancreatic Cancer ◽

Therapeutic Effects

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Targeting fibroblast activation protein (FAP): Next generation PET radiotracers using squaramide coupled bifunctional DOTA and DATA5m chelators

10.21203/rs.3.rs-24915/v1 ◽

2020 ◽

Cited By ~ 1

Author(s):

Euy Sung Moon ◽

Filipe Elvas ◽

Gwendolyn Vliegen ◽

Stef De Lombaerde ◽

Christel Vangestel ◽

...

Keyword(s):

Animal Studies ◽

Ex Vivo ◽

Tumor Stroma ◽

Fibroblast Activation Protein ◽

Squaric Acid ◽

High Accumulation ◽

Fibroblast Activation ◽

Pet Radiotracers

Abstract Background Fibroblast activation protein (FAP) is a proline selective serine protease that is overexpressed in tumor stroma and in lesions of many other diseases that are characterized by tissue remodeling. In 2014, a most potent FAP-inhibitor (referred to as UAMC1110) with low nanomolar FAP-affinity and high selectivity toward related enzymes such as prolyl oligopeptidase (PREP) and the dipeptidyl-peptidases (DPPs): DPP4, DPP8/9 and DPP2 were developed. This inhibitor has been adopted recently by other groups to create radiopharmaceuticals by coupling bifunctional chelator-linker systems. Here, we report squaric acid containing bifunctional DATA5m and DOTA chelators relied on UAMC1110. Results The radiopharmaceuticals DOTA.SA.FAPi and DATA5m.SA.FAPi were synthesized, labeled with gallium-68 and further characterized for in vitro stability, inhibitory efficiency, in vivo targeting properties and ex vivo biodistribution. [68Ga]Ga-DOTA.SA.FAPi and [68Ga]Ga-DATA5m.SA.FAPi showed high complexation after already 10 minutes and high stability over a period of 2 h. Affinity to FAP of DOTA.SA.FAPi and its natGa and natLu-labeled derivatives were in low nanomolar range. Comparable results were obtained for DATA5m.SA.FAPi and its natGa analogue. Additionally, all five compounds showed low affinity for the related protease PREP (high µM range). First proof-of-principle in vivo PET-imaging animal studies of the [68Ga]Ga-DOTA.SA.FAPi precursor in a HT-29 human colorectal cancer xenograft mouse model indicated promising results with high accumulation in tumor and low background signal. Ex vivo biodistribution showed high tumor uptake at 60 min post injection with overall low uptake in healthy tissues. Conclusion In this work, novel PET radiotracers targeting fibroblast activation protein (FAP) were synthesized and biochemically investigated. Critical substructures of the novel compounds are a squaramide linker unit derived from the basic motif of squaric acid, DOTA and DATA5m bifunctional chelators and a FAP-targeting moiety. In conclusion, these new FAP-ligands appear promising, both for further research and development as well as for first human application.

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