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Fibroblast Activation Protein (FAP): A Crucial Modulator of the Microenvironment in Metastatic Melanoma Case
Address for correspondence: Dr. Leila Hassanzadeh, Leila Hassanzadeh, Iran University of Medical Sciences, Shahid Hemmat Highway, Tehran 14496-14535, Iran. E-mail: hassanzadeh.l@iums.ac.ir
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Received: ,
Accepted: ,
This article was originally published by Wolters Kluwer - Medknow and was migrated to Scientific Scholar after the change of Publisher.
Abstract
A 55-year-old male with advanced malignant melanoma received surgery, radiotherapy, and chemotherapy. Despite these treatments, [18F]FDG PET/CT showed significant disease progression. Targeted imaging with gallium-68 radiotracers for CXCR4, SSTR2, and FAP identified biomarkers for personalized therapy. This led to the choice of [177Lu]Lu-FAPI-2286. After the first cycle, the patient reported pain relief, but subsequent imaging revealed rapid brain metastasis. This case highlights the importance of personalized medicine and molecular imaging in treating advanced melanoma.
Keywords
177Lu-FAPI-2286
melanoma
personalized medicine
Introduction
The selection of appropriate treatment for advanced malignancies is a significant challenge in oncology. Gallium-68 (Ga-68) labeled radiotracers have emerged as a valuable tool in positron emission tomography/computed tomography (PET/CT) imaging for identifying the most effective treatment strategies. By targeting CXCR4, somatostatin receptor subtype 2 (SSTR2), and fibroblast activation protein (FAP) receptors, these radiotracers enable the visualization of cancerous lesions and guide treatment decisions, ensuring that patients receive the most effective therapy without missing opportunities for treatment.
Case Report
A 55-year-old male patient was diagnosed with malignant melanoma in his left leg and underwent a comprehensive treatment regimen consisting of surgical excision, radiotherapy, and chemotherapy. To monitor treatment response, the patient underwent (18F) fluorodeoxyglucose (FDG) PET/CT imaging 6½ months after the previous scan. The comparison of preradiotherapy and chemotherapy (18F) FDG PET/CT images revealed a rapid and significant progression of the disease [Figure 1]. Given the patient’s lack of response to previous treatments and rapid disease progression, the treatment team opted for targeted imaging using radiotracers that bind to CXCR4, SSTR2, and FAP receptors [Figure 2]. This approach aimed to identify biomarkers for personalized therapy and enhance treatment outcomes. PET/CT imaging revealed mild (68Ga) Ga-Pentixafor uptake in the malignancy and metastases. In addition, the study showed mildly FAPI-avid skin lesions on the left leg and associated metastases, as well as non-to-faint uptake of Ga-68 DOTATATE in the malignancy and metastases. Based on these imaging findings, the therapeutic radiotracer (177 Lu) Lu-FAPI-2286, a FAP inhibitor and beta-emitting agent, was chosen for the patient’s treatment due to its high expression of FAP receptors. The therapeutic intervention was conducted in accordance with the ethical code IR.IUMS.FMD.REC.1401.248 and following the acquisition of informed consent from the patient, ensuring the preservation of their autonomy and self-determination.
![(a) Non/faintly DOTATATE-avid malignant/metastases in pulmonary nodules, left inguinal lymph nodes, left lower extremity lymph nodes, and a skin lesion in the anterior aspect of the left leg (5.4 mCi injected dose). (b) Mildly Pentixafor-avid malignancy/metastases in bilateral pulmonary nodules (maximum standardized uptake value [SUVmax] =2.5–5.9), left inguinal lymph nodes (SUVmax = 3.3), left lower extremity lymph nodes (SUVmax = 2.8–4.9), and a skin lesion in the anterior aspect of the left leg (SUVmax = 3.2) (7.3 mCi injected dose). (c) Mildly FAPI-avid metastases in bilateral pulmonary nodules (SUVmax = 2.6–3.3), left external iliac lymph node (SUVmax = 4.7), left inguinal lymph nodes (SUVmax = 4.7), a skin lesion in the anterior aspect of the left leg (SUVmax = 5.4), and left lower extremity lymph nodes (SUVmax = 2.4-7.6) (5 mCi injected dose) (the fragmented image is due to the necessity to stop during the imaging process)](/content/210/2025/40/1/img/IJNM-40-28-g002.png)
Discussion
Melanoma is an aggressive form of skin cancer that originates from melanocytes. Once melanoma has metastasized, it rapidly becomes life-threatening.[12] The CXCR4 chemokine receptor is highly expressed in melanoma cells and plays a crucial role in the invasion and metastasis of melanoma, independently predicting poor prognosis in primary melanoma.[34] In addition, malignant melanoma has been found to overexpress the SSTR2, which can be detected by Octreoscan[56] and is considered for targeted therapy. The FAP is typically low or undetectable in most normal adult tissues but is highly upregulated in various cancers, including carcinomas.[78] Peptide receptor radionuclide therapy (PRRT) is a highly targeted and effective form of radiopharmaceutical therapy with minimal side effects. PRRT and other molecular therapies offer more personalized cancer treatment by selectively reaching and damaging tumor cells while limiting radiation exposure to healthy tissue, making it generally well-tolerated.[9] In the reported case, a comparison of (18F) FDG PET/CT images obtained before and after treatment showed that medical therapy was unsuccessful in controlling the disease, and the new image indicated disease progression [Figure 1]. The available 177 Lu-labeled peptides, (177 Lu)-Pentixafor, (177 Lu)-DOTATATE, and (177 Lu)-FAPI-2286, target CXCR4, SSTR2, and FAP, respectively. Surprisingly, the imaging studies revealed low expression of SSTR2 receptors in the malignant lesions [Figure 2]. This finding underscores the significance of personalized medicine, which relies on the ability to make treatment decisions based on the in vivo visualization of biochemical and biological processes using molecular imaging modalities.[10] Based on the imaging results, which showed a distinct pattern of activity uptake in the Ga-68 Pentixafor and Ga-68 FAPI-46 studies and lower accumulation of radioligand in nontarget organs in the Ga-68 FAPI-46 images, the treatment team chose (177 Lu)-FAPI-2286 to minimize the dose received by nontarget organs, particularly bone marrow, compared to (177 Lu)-Pentixafor treatment. On the day of treatment, the patient’s pain intensity was assessed at the highest possible level, a score of 10 out of 10, on a standard 0–10-point pain rating scale. To manage this excruciating pain, the patient required the administration of analgesic medications. In the 1st week after the first cycle of (177 Lu)-FAPI-2286 radiolabeled therapy, the patient expressed that there was a significant reduction in pain in the area affected by melanoma in the left leg. During this period, the patient did not require any additional pain medication. Planar imaging studies performed on days 3 and 10 after administration of the (177 Lu)-FAPI-2286 radiolabeled agent demonstrated the continued presence of the radiotracer within the tumor lesions, suggesting the radiolabeled agent maintains stability in vivo over this time [Figure 3]. Unfortunately, the patient was in the final stages of melanoma, and despite the initial pain relief, experienced speech difficulties after 2 weeks of (177 Lu)-FAPI-2286 administration. A CT scan confirmed the presence of brain metastasis, which had not been evident in any of the previous imaging studies. This rapid development of brain metastasis underscores the high rate of metastasis associated with melanoma cancer.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that his name and initials will not be published and due efforts will be made to conceal his identity, but anonymity cannot be guaranteed.
Conflicts of interest
There are no conflicts of interest.
Nil.
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