Theranostic imaging and treatment of chemotherapy resistant muscle invasive bladder cancer by targeting FAP and CXCR4: The Bladder BRIDGister experience.
Authors: Wirtz Ralph M. , Kastner Lucas , Voss Paula Carolin , Friedersdorff Frank , Schlomm Thorsten , Barski Dimitri , Otto Thomas , Waldner Michael , Graff Johannes , Veltrup Elke , Hake Roland , Eidt Sebastian , Roggisch Jenny , Rieger Constantin , Koch Stefan , Klatte Tobias , Ecke Thorsten H. , Heidenreich Axel , Greifenstein Lukas , Baum Richard P. 
Published: January 2024

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Background: Patients with muscle invasive urothelial carcinoma achieving pathological complete response (pCR) upon neoadjuvant chemotherapy (NACT) have improved prognosis. Previously we did show that luminal tumors respond better to NACT (Ecke et al 2022), while the radioligand targets CXCR4 and FAP are found in chemoresistant, stroma-associated tumors. The objective of this study was to exploit the expression of CXCR4 & FAP for theranostic imaging & treatment in selected patients by radioligand instillation into the bladder to justify subsequent adopted clinical trials within the Bladder BRIDGister framework. Methods: FFPE tumor tissues from 511 TURB samples were prospectively collected as part of the Bladder BRIDGister. RNA was extracted by commercial kits, relative gene expression of subtyping markers and radioligand target genes were analyzed by RT-qPCR. Hierarchical clustering, Kruskal-Wallis and contingency tests were done by JMP 9.0.0 (SAS software). PET/CT Imaging by CXCR4 and/or FAP instillation was performed in selected patients followed by systemic radioligand application after completion of cisplatinum based NACT to enable improved staging. Results: The prospective molecular registry cohort consisted of 511 bladder cancer patients included into the Bladder BRIDGister (median age: 75, male 74% vs. female 26%) with 5% Tis, 54% Ta, 16% T1 and 15% T2 stage and concomitant CIS being in 7%. CXCR4 expression was negatively associated with ERBB2 & FGFR3 mRNA (r=-0,3021 and r=-0,3326, p<0,0001). Inverse relation of FAP expression with ERBB2 & FGFR3 was even more pronounced (r=-0,4883 and r=-0,5177, p<0,0001). Clustering validated that CXCR4 and FAP are elevated in non-luminal tumors not responding to NACT. Exemplarily one stromal rich pT2 G3 MIBC patient with elevated FAP expression, who was predicted to be unresponsive to NACT, was selected for FDG and FAP PET/CT imaging after two cycles of NACT. Indeed metastatic lesion were detected in the liver and pancreatic tissue. FAP imaging revealed to be more sensitive than conventional FDG imaging. In a next step 68Ga-CXCR4 was instilled into the bladder of a patient with NACT-resistant MIBC rejecting cystectomy to establish a non-systemic approach for radioligand therapy. Theranostic instillation imaging revealed strong uptake into the invading MIBC and subsequent instillation therapy with 177Lu-FAP led to partial remission and increased immune cell infiltration indicating initial effectivity. Conclusions: Expression of the radioligand targets CXCR4 and FAP are associated with aggressive stromal and basal like tumors being resistant to NACT. This could be validated by selecting patients for FAP & CXCR4 PET/CT imaging. Instillation of radioligands into the bladder revealed to be safe with first signs of effectivity justifying clinical approaches as part of phase 1 / 2 clinical trials.