Prostate-specific membrane antigen (PSMA) targeting radioligands deliver radiation to PSMA-expressing cells. However, the relationship between PSMA levels and intralesion heterogeneity of PSMA expression, and cytotoxic radiation by radioligand therapy (RLT) is unknown. Here we investigate RLT efficacy as function of PSMA levels/cell, and the fraction of PSMA þ cells in a tumor.Experimental Design: RM1 cells expressing different levels of PSMA (PSMA À , PSMA þ , PSMA þþ , PSMA þþþ ; study 1) or a mix of PSMA þ and PSMA À RM1 (study 2, 4) or PC-3/PC-3-PIP (study 3) cells at various ratios were injected into mice. Mice received 177 Lu-(studies 1-3) or 225 Ac-(study 4) PSMA617. Tumor growth was monitored. Two days post-RLT, tumors were resected in a subset of mice. Radioligand uptake and DNA damage were quantified.Results: 177 Lu-PSMA617 efficacy increased with increasing PSMA levels (study 1) and fractions of PSMA positive cells (studies 2 , 3 ) in both, the RM1 and PC-3-PIP models. In tumors resected 2 days post-RLT, PSMA expression correlated with 177 Lu-PSMA617 uptake and the degree of DNA damage. Compared with 177 Lu-PSMA617, 225 Ac-PSMA617 improved overall antitumor effectiveness and tended to enhance the differences in therapeutic efficacy between experimental groups.Conclusions: In the current models, both the degree of PSMA expression and the fraction of PSMA þ cells correlate with 177 Lu-/ 225 Ac-PSMA617 tumor uptake and DNA damage, and thus, RLT efficacy. Low or heterogeneous PSMA expression represents a resistance mechanism to RLT.
Prostate-specific membrane antigen (PSMA)-targeted radionuclide therapy (RNT) may increase tumor immunogenicity. We aimed at exploiting this effect by combining RNT with immunotherapy in a mouse model of prostate cancer (PC). Methods: C57BL/6-mice bearing syngeneic RM1-PGLS tumors were treated with 225 Ac-PSMA617, an anti-PD-1 antibody, or both. Therapeutic efficacy was assessed by tumor volume measurements (CT), time to progression (TTP), and survival. Results: PSMA RNT or anti-PD-1 alone tended to prolong TTP (isotype control, 25 d; anti-PD-1, 33.5 d [P 5 0.0153]; RNT, 30 d [P 5 0.1038]) and survival (control, 28 d; anti-PD-1, 37 d [P 5 0.0098]; RNT, 32 d [P 5 0.1018]). Combining PSMA RNT and anti-PD-1 significantly improved disease control compared with either monotherapy. TTP was extended to 47.5 d (P # 0.0199 vs. monotherapies), and survival to 51.5 d (P # 0.0251 vs. monotherapies). Conclusion: PSMA RNT and PD-1 blockade synergistically improve therapeutic outcomes in our PC model, supporting the evaluation of RNT and immunotherapy combinations for PC patients.
Prostate-specific membrane antigen-targeted radioligand therapy (PSMA-RLT) is effective against prostate cancer (PCa), but all patients relapse eventually. Poor understanding of the underlying resistance mechanisms represents a key barrier to development of more effective RLT. We investigate the proteome and phosphoproteome in a mouse model of PCa to identify signaling adaptations triggered by PSMA-RLT.Experimental Design: Therapeutic efficacy of PSMA-RLT was assessed by tumor volume measurements, time to progression, and survival in C4-2 or C4-2 TP53-knockout tumor-bearing Nod scid gamma mice. Two days post-RLT, the (phospho)proteome was analyzed by mass spectrometry.Results: PSMA-RLT significantly improved disease control in a dose-dependent manner.(Phospho)proteomic datasets revealed activation of genotoxic stress response pathways, including deregulation of DNA damage/replication stress response, TP53, androgen receptor, PI3K/AKT, and MYC signaling. C4-2 TP53-knockout tumors were less sensitive to PSMA-RLT than parental counterparts, supporting a role for TP53 in mediating RLT responsiveness. Conclusions:We identified signaling alterations that may mediate resistance to PSMA-RLT in a PCa mouse model. Our data enable the development of rational synergistic RLT-combination therapies to improve outcomes for PCa patients.
<div>AbstractPurpose:<p>Prostate-specific membrane antigen (PSMA) targeting radioligands deliver radiation to PSMA-expressing cells. However, the relationship between PSMA levels and intralesion heterogeneity of PSMA expression, and cytotoxic radiation by radioligand therapy (RLT) is unknown. Here we investigate RLT efficacy as function of PSMA levels/cell, and the fraction of PSMA<sup>+</sup> cells in a tumor.</p>Experimental Design:<p>RM1 cells expressing different levels of PSMA (PSMA<sup>−</sup>, PSMA<sup>+</sup>, PSMA<sup>++</sup>, PSMA<sup>+++</sup>; study 1) or a mix of PSMA<sup>+</sup> and PSMA<sup>−</sup> RM1 (study 2, 4) or PC-3/PC-3-PIP (study 3) cells at various ratios were injected into mice. Mice received <sup>177</sup>Lu- (studies 1–3) or <sup>225</sup>Ac- (study 4) PSMA617. Tumor growth was monitored. Two days post-RLT, tumors were resected in a subset of mice. Radioligand uptake and DNA damage were quantified.</p>Results:<p><sup>177</sup>Lu-PSMA617 efficacy increased with increasing PSMA levels (study 1) and fractions of PSMA positive cells (studies 2, 3) in both, the RM1 and PC-3-PIP models. In tumors resected 2 days post-RLT, PSMA expression correlated with <sup>177</sup>Lu-PSMA617 uptake and the degree of DNA damage. Compared with <sup>177</sup>Lu-PSMA617, <sup>225</sup>Ac-PSMA617 improved overall antitumor effectiveness and tended to enhance the differences in therapeutic efficacy between experimental groups.</p>Conclusions:<p>In the current models, both the degree of PSMA expression and the fraction of PSMA<sup>+</sup> cells correlate with <sup>177</sup>Lu-/<sup>225</sup>Ac-PSMA617 tumor uptake and DNA damage, and thus, RLT efficacy. Low or heterogeneous PSMA expression represents a resistance mechanism to RLT.</p><p><i>See related commentary by Ravi Kumar and Hofman, p. 2774</i></p></div>
<p>PSMA expression is heterogenous in human PC</p>
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