Peptidic heterodimer-based radiotracer targeting fibroblast activation protein and integrin αvß3.

PURPOSE: Several studies have demonstrated the advantages of heterodimers over their corresponding monomers due to the multivalency effect. This effect leads to an increased number of effective targeted receptors and, consequently, improved tumor uptake. Fibroblast activation protein (FAP) and integrin αvß3 are found to be overexpressed in different components of the tumor microenvironment. In our pursuit of enhancing tumor uptake and retention, we designed and developed a novel peptidic heterodimer that synergistically targets both FAP and integrin αvß3. METHODS: FAP-RGD was synthesized from FAP-2286 and c(RGDfK) through a multi-step organic synthesis. The dual receptor binding property of 68Ga-FAP-RGD was investigated by cell uptake and competitive binding assays. Preclinical pharmacokinetics were determined in HT1080-FAP and U87MG tumor models using micro-positron emission tomography/computed tomography (micro-PET/CT) and biodistribution studies. The antitumor efficacy of 177Lu-FAP-RGD was assessed in U87MG tumor models. The radiation exposure and clinical diagnostic performance of 68 Ga-FAP-RGD were evaluated in healthy volunteers and cancer patients. RESULTS: Bi-specific radiotracer 68Ga-FAP-RGD exhibited high binding affinity for both FAP and integrin αvß3. In comparison to 68Ga-FAP-2286 and 68Ga-RGDfK, 68Ga-FAP-RGD displayed enhanced tumor uptake and longer tumor retention time in preclinical models. 177Lu-FAP-RGD could efficiently suppress the growth of U87MG tumor in vivo when applied at an activity of 18.5 and 29.6 MBq. The effective dose of 68Ga-FAP-RGD was 1.06 × 10-2 mSv/MBq. 68Ga-FAP-RGD demonstrated low background activity and stable accumulation in most neoplastic lesions up to 3 h. CONCLUSION: Taking the advantages of multivalency effect, the bi-specific radiotracer 68Ga-FAP-RGD showed superior tumor uptake and retention compared to its corresponding monomers. Preclinical studies with 68Ga- or 177Lu-labeled FAP-RGD showed favorable image contrast and effective antitumor responses. Despite the excellent performance of 68Ga-FAP-RGD in clinical diagnosis, experimental efforts are currently underway to optimize the structure of FAP-RGD to increase its potential for clinical application in endoradiotherapy.

Clinical translation of a novel FAPI dimer [68Ga]Ga-LNC1013.

Fibroblast activation protein (FAP) has emerged as a highly promising target for cancer diagnostic imaging and targeted radionuclide therapy. To exploit the therapeutic potential of suitably radiolabeled FAP inhibitors (FAPIs), this study presents the design and synthesis of a series of FAPI dimers to increase tumor uptake and retention. Preclinical evaluation and a pilot clinical PET imaging study were conducted to screen the lead compound with the potential for radionuclide therapy. METHODS: Three new FAPI dimers were synthesized by linking two quinoline-based FAPIs with different spacers. The in vitro binding affinity and preclinical small animal PET imaging of the compounds were compared with their monomeric counterparts, FAPI-04 and FAPI-46. The lead compound, [68Ga]Ga -LNC1013, was then evaluated in a pilot clinical PET imaging study involving seven patients with gastrointestinal cancer. RESULTS: The three newly synthesized FAPI homodimers had high binding affinity and specificity in vitro and in vivo. Small animal PET imaging and biodistribution studies showed that [68Ga]Ga-LNC1013 had persistent tumor retention for at least 4 h, also higher uptake than the other two dimers and the monomer counterparts, making it the lead compound to enter clinical investigation. In the pilot clinical PET imaging study, seven patients were enrolled. The effective dose of [68Ga]Ga-LNC1013 was 8.24E-03 mSv/MBq. The human biodistribution of [68Ga]Ga-LNC1013 demonstrated prominent tumor uptake and good tumor-to-background contrast. [68Ga]Ga-LNC1013 PET imaging showed potential in capturing primary and metastatic lesions and outperforming 18F-FDG PET in detecting pancreatic and esophageal cancers. The SUVmax for lesions with [68Ga]Ga-FAPI-46 decreased over time, whereas [68Ga]Ga-LNC1013 exhibited persistently high tumor uptake from 1 to 4 h post-injection. CONCLUSION: Dimerization is an effective strategy to produce FAPI derivatives with favorable tumor uptake, long tumor retention, and imaging contrast over its monomeric counterpart. We demonstrated that [68Ga]Ga-LNC1013, the lead compound without any piperazine moiety, had superior diagnostic potential over [68Ga]Ga-FAPI-46 and 18F-FDG, suggesting the future potential of LNC1013 for radioligand therapy of FAP-positive cancers.

The predictive value of 18F-FDG PET/CT combined with inflammatory index for major pathological reactions in resectable NSCLC receiving neoadjuvant immunochemotherapy.

OBJECTIVES: To investigate whether the combination of inflammatory biomarkers and metabolic parameters of 18F-FDG PET/CT could predict the major pathological reactions (MPR) in resectable NSCLC patients after neoadjuvant immunochemotherapy more accurately and screen out patients who may benefit from the neoadjuvant therapy. MATERIALS AND METHODS: 114 resectable NSCLC patients who underwent neoadjuvant immunochemotherapy and radical surgery were retrospectively enrolled. Detailed clinical characteristics, B-R and 18F-FDG PET/CT images were collected for analyzing their correlation with MPR. A metabolic-inflammation comprehensive prognostic index (MICPI) combined 18F-FDG PET/CT metabolic parameters and inflammatory index was proposed to predict MPR. RESULTS: 66.7 % patients achieved MPR. Smoking history, gender and ILO were influencing factors for MPR acquisition in NSCLC patients. High absolute neutrophils count (PreN ≥ 3.65), metabolic parameters (PreSUVmax ≥ 11.73) before treatment and ΔSUVmean (≥54.18) were significantly associated with MPR (P＜0.01, P＜0.05 and P＜0.001 respectively). MICPI-B based on PreN and PreSUVmax categorized NSCLC patients into three groups and among the groups of high, intermediate and low MICPI-B score, MPR accounted for 80.00 %, 51.72 % and 28.57 % respectively (P < 0.01). In high, intermediate and low MICPI-P groups which based on PreN and ΔSUVmean, MPR accounted for 92.31 %, 53.57 % and 11.11 %, respectively (P < 0.001). CONCLUSION: PreN and metabolic parameter of 18F-FDG PET/CT may be an accurate alternative biomarker for predicting MPR in NSCLC patients after neoadjuvant immunochemotherapy. Moreover, MICPI can stratify patients into different groups based on their likelihood of obtaining MPR, allowing clinicians to identify patients who may most likely benefit from neoadjuvant immunochemotherapy.

Protein arginine N-methyltransferase 2 reverses tamoxifen resistance in breast cancer cells through suppression of ER-α36.

Breast cancer is one of the most common malignancies in females, and 17ß-estradiol (E2)/estrogen receptor α (ERα) signaling plays an important role in the initiation and progression of breast cancer. The role of the ER-α subtype and its co-regulator in the initiation of breast cancer and the occurrence of tamoxifen resistance remains to be further elucidated. In our previous studies, protein arginine N-methyltransferase 2 (PRMT2), a co-regulator of estrogen receptor-α (ER-α), was confirmed to interact with ER-α66 and has the ability to inhibit cell proliferation in breast cancer cells. In the present study, we found that tamoxifen treatment induced a decrease in PRMT2 and an increase in ER-α36 as well as ER-α36-mediated non-genomic effect in MDA-MB-231 cells, which were relatively resistant to tamoxifen by contrast to MCF-7 cells. Moreover, PRMT2 was able to interact with ER-α36 directly, suppress ER-α36 and downstream PI3K/Akt and MAPK/ERK signaling, reversing the tamoxifen resistance of breast cancer cells. The present study may be meaningful for understanding the role of PRMT2 in breast cancer progression and for developing a new endocrine therapeutic strategy for breast cancer patients with tamoxifen resistance.