Preclinical Assessment of the Combination of PSMA-Targeting Radionuclide Therapy with PARP Inhibitors for Prostate Cancer Treatment

Abstract

Prostate specific membrane antigen targeted radionuclide therapy (PSMA-TRT) is a promising novel treatment for prostate cancer (PCa) patients. However, PSMA-TRT cannot be used for curative intent yet, thus additional research on how to improve the therapeutic efficacy is warranted. A potential way of achieving this, is combining TRT with poly ADP-ribosylation inhibitors (PARPi), which has shown promising results for TRT of neuroendocrine tumor cells. Currently, several clinical trials have been initiated for this combination for PCa, however so far, no evidence of synergism is available for PCa. Therefore, we evaluated the combination of PSMA-TRT with three classes of PARPi in preclinical PCa models. In vitro viability and survival assays were performed using PSMA-expressing PCa cell lines PC3-PIP and LNCaP to assess the effect of increasing concentrations of PARPi veliparib, olaparib or talazoparib in combination with PSMA-TRT compared to single PARPi treatment. Next, DNA damage analyses were performed by quantifying the number of DNA breaks by immunofluorescent stainings. Lastly, the potential of the combination treatments was studied in vivo in mice bearing PC3-PIP xenografts. Our results show that combining PSMA-TRT with PARPi did not synergistically affect the in vitro clonogenic survival or cell viability. DNA-damage analysis revealed only a significant increase in DNA breaks when combining PSMA-TRT with veliparib and not in the other combination treatments. Moreover, PSMA-TRT with PARPi treatment did not improve tumor control compared to PSMA-TRT monotherapy. Overall, the data presented do not support the assumption that combining PSMA-TRT with PARPi leads to a synergistic antitumor effect in PCa. These results underline that extensive preclinical research using various PCa models is imperative to validate the applicability of the combination strategy for PCa, as it is for other cancer types.

Pharmacological Optimization of PSMA-Based Radioligand Therapy

“…Radiosensitizing agents, immune modulators, high-dose vitamin C and polyadenosine-diphosphate-ribose polymerase (PARP) inhibitors may have synergistic effects when combined with PSMA-targeted radioligands [ 63 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 ]. The mechanism of action of radiosensitizing agents may be to dysregulate the cell cycle, resulting in oxygenated stress and thereby inducing cytotoxicity and inhibiting DNA repair mechanisms [ 74 ].…”

“…Combining PARP inhibitors with RLT should theoretically increase cytotoxicity by inhibiting the repair mechanism [ 84 ]. However, PARP inhibitors did not significantly contribute to less tumor growth or better survival in PC3-PIP xenograft mice [ 85 ]. Clinical trials in humans combining 177 Lu-PSMA with PARP-inhibitors are ongoing (NCT03874884, Lu-PARP trial).…”

Patient outcomes following a response biomarker-guided approach to treatment using 177Lu-PSMA-I&T in men with metastatic castrate-resistant prostate cancer (Re-SPECT)

“…Measures that address causes of treatment resistance (PARP inhibitors, targeted alpha therapies) may help improve responses in RG 3. [19][20][21] A higher proportion of men in RG 1 were chemotherapy naïve, potentially explaining the better treatment response rates in this group. However, these men were older, many considered not suitable for chemotherapy.…”

Understanding the Radiobiological Mechanisms Induced by 177Lu-DOTATATE in Comparison to External Beam Radiation Therapy

“…Nevertheless, in patients, the dose to achieve efficient radiosensitization must always be balanced against drug toxicities. The absence of 177 Lu-labelled Prostate-Specific Membrane Antigen (PSMA) radiosensitization by different PARP inhibitors in prostate cancer cell lines was reported in a recent study [ 32 ]. Additional studies are needed to decipher PARPi optimal conditions for efficient RNT radiosensitization.…”