Synergistische Therapiekombinationen für die Behandlung PSMA exprimierender Tumore
Nuklearmedizin, Strahlentherapie, Strahlenbiologie
Zusammenfassung der Projektergebnisse
Metastatic castration-resistant (mCR) prostate cancer (PC) remains a highly lethal disease. 177Lu-PSMA, a new radio-labeled ligand that binds to the prostate specific membrane antigen (PSMA), has been recently introduced as a therapeutic alternative for patients with mCRPC. 177Lu-PSMA radioligand therapy (RLT) is effective in patients, but relapses occur uniformly. Thus, there is an urgent unmet need to identify mechanisms that determine the efficacy of, and resistance to, RLT and use this information to design new, more effective and safe combination therapies for mCRPC patients. At UCLA, I developed new models and methods relevant to the field of preclinical nuclear medicine. Project 1 generated a PC mouse model for PSMA-RLT. In project 2, this model helped determine the previously unexplored relationship between a nuclear medicine imaging signal for PSMA via PET and the actual presence of PSMA on the tumor. The model was then used to investigating how tumor PSMA levels affect the effectiveness of RLT (project 3). I found that the higher the tumor cell PSMA expression, the greater the effect of PSMA-RLT on tumor growth. This finding can be explained by the correlation of PSMA levels with 177Lu-PSMA uptake into tumor cells and the resulting extend of DNA damage. Likewise, the ratio of tumor cells that express and those that do not express PSMA impact PSMA-RLT efficacy. However, in a PC model with ~10x higher PSMA levels, pharmacological upregulation of PSMA expression did not improve the therapeutic outcome of 177Lu-PSMA which might be due to insufficient (pharmacologically induced) increases in PSMA expression (project 4). In parallel, I worked on mouse models of metastatic disease as clinically more relevant experimental models (project 8). Preliminary data indicate that systemic PC in mice can successfully be targeted with RLT. The main focus of my research at UCLA was on tumor cell mechanisms that render tumors resistant to RLT and on the ways in which these adaptive responses can be exploited therapeutically. In project 5., to evaluate RLT induced tumor cell stress response pathways, we profiled the (phospho)proteomic alterations in tumors following RLT in a mouse model of PC. Activity of the kinases ATR and ATM - which coordinate the cell’s response to DNA damage - was highly increased. When mice with PC tumors were treated with a combination of 177Lu-PSMA and an inhibitor of ATR (ATRi), tumor growth was inhibited synergistically. However, tumors were not eradicated suggesting that some PC cells can evade the effects of ATRi/RLT. I hypothesized that adding either an ATMi or a PARPi (another critical DNA damage response effector) to the tested double combination may result in improved tumor control. Following promising in vitro data, ongoing studies evaluate the efficacy of triple combination regimens (ATRi/ATMi/RLT; ATRi/PARPi/RLT) in mouse models with different capacities to repair damaged DNA (BRCA wildtype vs. mutant). In a related approach, project 6 focused on preventing tumor cells from actually repairing DNA that is damaged by PSMA-RLT. RLT was combined with an inhibitor of deoxycytidine kinase (dCki), a protein critical for the generation of the building blocks of DNA (deoxyribuncleoside triphosphates) whose balanced production and sufficient levels are required for accurate DNA repair and replication. A pilot study in a murine PC model indicated synergistic tumor growth inhibition by dCki plus 177Lu-PSMA. These results encouraged a currently ongoing, first full study in which sensitization of PC by dCki to PSMA-RLT is explored, and results are awaited for late spring 2019. To support the pre-clinical work with patient-derived data and thus, enhance its clinical relevance, a clinical protocol was devised in which pre- and post-treatment biopsies from patients undergoing PSMA-RLT will be analyzed by various “big data” approaches (phospho-proteomics, transcriptomics, genomics) (project 7). The resulting datasets will be bioinformatically integrated to yield patient-specific network maps of RLT responses in mCRPC. Patient recruitment is expected to commence in the weeks ahead. Collectively, my DFG funded research at UCLA yielded new experimental models that were used to elucidate causes for limited PSMA-RLT efficacy and tumor relapse in PC, and to establish rationally-designed, clinically viable combination therapies that significantly improve the efficacy of PSMA-RLT in mCRPC.
Projektbezogene Publikationen (Auswahl)
-
Establishing (177)Lu-PSMA-617 radioligand therapy in a syngeneic model of murine prostate cancer. J Nucl Med. 2017 Nov;58(11):1786-1792
Fendler WP, Stuparu AD, Evans-Axelsson S, Lückerath K, Wei L, Kim W, Poddar S, Said J, Radu CG, Eiber M, Czernin J, Slavik R, Herrmann K
-
Detection threshold and reproducibility of (68)Ga-PSMA11 PET/CT in a mouse model of prostate cancer. J Nucl Med. 2018 Sep;59(9):1392-1397
Lückerath K, Stuparu AD, Wei L, Kim W, Radu CG, Mona CE, Calais J, Rettig M, Reiter RE, Czernin J, Slavik R, Herrmann K, Eiber M, Fendler W
-
Preclinical evaluation of PSMA expression in response to androgen receptor blockade for theranostics in prostate cancer. EJNMMI Res. 2018 Oct 29;8(1):96
Lückerath K, Wei L, Fendler WP, Evans-Axelsson S, Stuparu AD, Slavik R, Mona CE, Calais J, Rettig M, Reiter RE, Herrmann K, Radu CG, Czernin J, Eiber M
