Exploring the FAP-Targeted Therapeutics for Adrenocortical Carcinoma Choosing the Right Track
Sejal Chopra, MSc,* Rama Walia, MD, ¡ Komalpreet Kaur, MSc,* Frank Roesch, PhD,¿
Euy Sung Moon, PhD,¿ Bhagwant Rai Mittal, MD, DNB,* and Jaya Shukla, PhD*
Abstract: Metastatic or recurrent adrenocortical carcinoma is a potentially
lethal malignancy, presenting significant challenges in disease management
owing to absence of effective systemic treatments. Significantly diminished
survival rates necessitate rapid identification of specific molecules for the
development of targeted therapeutics. Fibroblast activation protein (FAP)-
expressing cancer-associated fibroblasts have been a major breakthrough
causing a paradigm shift in targeted theranostics focusing on the tumor mi-
croenvironment. The effectiveness of various FAP inhibitors (FAPis) and
FAP targeting peptide has been extensively documented in diverse clinical
investigations. We have evaluated 3 molecules, that is, DOTA.SA.FAPi
(SA.FAPi), FAPi46, and FAP2286, as potential theranostic probes for
adrenocortical carcinoma.
Received for publication June 27, 2024; revision accepted July 28, 2024.
From the *Department of Nuclear Medicine, Postgraduate Institute of Medical
Education and Research, Chandigarh, India; ¡ Department of Endocrinology,
Postgraduate Institute of Medical Education and Research, Chandigarh,
India; and įDepartment of Chemistry, Johannes Gutenberg University,
Mainz, Germany.
Conflicts of interest and sources of funding: none declared.
Financial disclosure: The authors would like to acknowledge Postgraduate
Institute of Medical Education and Research, Chandigarh (Project ID:
9719-126) for providing financial support to conduct the study.
Ethical approval: The study was approved by the Institutional Ethics Committee
(INT/IEC/2021/SPL-500).
Correspondence to: Jaya Shukla, PhD, Department of Nuclear Medicine, Postgraduate
Institute of Medical Education and Research, Sector-12, Chandigarh, 160012,
India. E-mail: shuklajaya@gmail.com.
Copyright C 2024 Wolters Kluwer Health, Inc. All rights reserved.
ISSN: 1536-0229/25/5003-e160
DOI: 10.1097/RLU.0000000000005483
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FIGURE 1. A 50-year-old woman underwent right adrenalectomy for histopathology-proven adrenocortical carcinoma (ACC) followed by 4 cycles of EDP-M chemotherapy. Subsequently, 68Ga-SA.FAPi (118.4 MBq) PET was planned for treatment response evaluation. The fused PET/CT images identified multiple lung lesions, ill-defined hypodense lesion in right lobe of liver (segment IV), subcapsular liver deposit, heterogeneously enhancing soft tissue mass in the postoperative bed with multiple serosal (A; SULpeak 8.5, SULavg 6.3, total lesion FAP [TLF] expression 90.9 calculated as the product of SULavg and SA.FAPi-avid tumor volume), subcutaneous and peritoneal deposits. In view of 68Ga-SA.FAPi lesion avidity, the patient was given a diagnostic dose (740 MBq) of 177Lu-SA.FAPi for dosimetry study (IEC no: INT/IEC/2021/SPL-500). This was followed by regional SPECT/CT (B) and a static whole-body (WB) image (C), which demonstrated prompt tracer localization within the all lesions with peak uptake in 10-15 minutes postinjection. Serial WB static images were acquired for studying the tracer pharmacokinetics. Approximately, 1.4% of the injected dose (ID) was localized in the lesion, 3.8% in the liver, and 3.3% in the pancreas at 4 hours posttherapy (D). 1.2% of the ID was retained in the lesion at 24 hours posttherapy (E). Maximum washout of the radiotracer from the lesion and other body organs was observed at 48 hours with 0.6% of the ID retained in the lesion, 0.8% in the liver, and 0.6% in the pancreas (F).
A
B
C
D
E
F
Anterior
Anterior
Anterior
Anterior
Pre-therapy
68Ga-SA.FAPi
PET
Immediate
SPECT-CT
Immediate
4 hours
24 hours
48 hours
Low-dose 177Lu-SA.FAPi post-therapy serial images
FIGURE 2. A 40-year-old woman diagnosed with histopathology-proven ACC underwent right adrenalectomy followed by 6 cycles of EDP-M chemotherapy. The 68Ga-SA.FAPi (111 MBq) PET done for response assessment was suggestive of metastatic disease with tracer-avid soft tissue lesions in bilateral lung fields (A; largest in RUL; SULpeak 11.3, SULavg 8.4, TLF 78.0) and aortocaval lymph nodal metastases. Given the 68Ga-SA.FAPi lesion avidity, the patient was given a diagnostic dose (740 MBq) of 177Lu-FAPi46 for dosimetry study. This was followed by regional SPECT/CT (B) and a static WB image (C), which demonstrated rapid tracer localization within all lesions. Serial WB static images acquired for studying the tracer pharmacokinetics revealed approximately, 1.0% of the ID localization in the lesion at 4 hours posttherapy (D). Maximum washout of the radiotracer from the lesion was observed at 24 hours with 0.8% of the ID retained in the lesion (E). 0.7% of the ID was retained in the lesion at 48 hours posttherapy (F).
A
B
C
D
E
F
1
-
Posterior
Posterior
Posterior
Posterior
Pre-therapy
68Ga-SA.FAPi
PET
Immediate
SPECT-CT
Immediate
4 hours
24 hours
48 hours
Low-dose 177Lu-FAPI46 post-therapy serial images
FIGURE 3. A 47-year-man diagnosed with histopathology-proven ACC underwent right adrenalectomy followed by radiotherapy and 6 cycles of EDP-M chemotherapy. The FDG PET revealed a residual soft tissue lesion in paracaval region, lung nodules, and liver metastases for which he underwent TACE. The 68Ga-FAPi46 (104 MBq) PET done for response assessment was suggestive of metastatic disease (A) with tracer-avid lung nodules (LLL; SULpeak 4.0, SULavg 3.6, TLF 3.7), solid-cystic lesions in right lobe of liver (B; largest in segment VI, SULpeak 16.3, SULavg 10.1, TLF 836.2), and residual paracaval/right suprarenal soft tissue mass (C; SULpeak 24.5, SULavg 14.6, TLF 549). In view of the intense 68Ga-FAPi46 lesion avidity, the patient was given a diagnostic dose (740 MBq) of 177Lu-FAP2286 for dosimetry study. Following slow IV infusion of 177Lu-FAP2286 over 10 minutes, regional SPECT/CT (D) and a static WB image (E) revealed prompt tracer localization with 11.5% of the ID in the lesions. The WB static (F) and SPECT/CT (G) images acquired for studying the tracer pharmacokinetics and dosimetry profile revealed approximately 11.5% of the ID retention in the lesion at 24 hours posttherapy. Serial WB images (H-J) and SPECT/CT (K) demonstrated prolonged tracer retention with 7.8% of the ID within the lesion up to 10 days posttherapy. The dosimetry study conducted using the Dosimetry Toolkit (Xeleris; GE Healthcare, Milwaukee, WI) and OLINDA/EXM V2.0 software revealed effective absorbed doses of 1.97 mGy/MBq to the suprarenal/paracaval lesion, 2.29 mGy/MBq to the liver lesion, 0.001 mGy/ MBq to the healthy kidneys, and 0.003 mGy/MBq to the lungs. Given the prompt localization, prolonged retention, and favorable dosimetry profile, the patient received therapy with 100 mCi (3700 MBq) of 177Lu-FAP2286. The 24-hour posttherapy images (L-N) showed good localization and prolonged retention of the radiotracer, highlighting its potential as a promising theranostic probe.
A
B
D
E
F
G
C
Anterior
Anterior
Immediate
SPECT-CT
Immediate
WB
24 hours
WB
24 hours WB
SPECT-CT
Pre-therapy 68Ga-FAPI46 PET
Low-dose 177Lu-FAP2286 post-therapy serial images
H
I
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L
M
N
X
Anterior
Anterior
Posterior
Anterior
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Day 5
WB
Day 10
WB
Day 10
WB
Day 10
SPECT-CT
100 mCi 177Lu-FAP2286 24 hours post-therapy
WB and SPECT-CT
Low-dose 177Lu-FAP2286 post-therapy serial images
FIGURE 4. The graphical representation of the % ID in the lesion as a function of time elapsed posttherapy is depicted in the figure. 177Lu-FAP2286 shows higher % ID lesion localization of 11.5% with prolonged retention up to 10 days in comparison to the other 2 FAPI derivatives. ACC is a rare and aggressive malignancy with poor prognosis. Surgery is preferred for localized ACC, but over 70% patients present with advanced disease, reducing survival rates.1,2 The toxicity of the current treatment for metastatic ACC, involving mitotane with or without chemotherapy, highlights the urgent need for identification of molecular probes to advance precision oncology for this potentially lethal cancer.2 Cancer-associated fibroblasts characterized by high FAP expression are promising stromal targets, and 2 FAPi derivatives DOTA.SA.FAPi and FAPi46 have demonstrated excellent diagnostic efficacy in diverse malignancies.3-6 In this case series, all the 3 FAP targeting molecules were able to identify and accumulate within the lesions; however, 177Lu-SA.FAPi and 177Lu-FAPi46 demonstrated a faster washout and lower retention time (<48 hours) within the lesion. On contrary, 177Lu-FAP2286 demonstrated favorable pharmacokinetics with good localization and higher lesion retention time (>10 days), making it an ideal molecular probe for targeted therapy.7-11 Moreover, within the realm of FAPi-directed theranostics, 177Lu-FAP2286 therapy may open new avenues in the disease management for metastatic or recurrent ACC. Additionally, integrating the volumetric parameter TLF with conventional clinicopathological parameters may offer a novel approach for prognostic stratification, enabling more refined treatment planning and response assessment.