Darolutamide Potentiates the Antitumor Efficacy of a PSMA-targeted Thorium-227 Conjugate by a Dual Mode of Action in Prostate Cancer Models

Hammer, Stefanie; Schlicker, Andreas; Zitzmann-Kolbe, Sabine; Baumgart, Simon J.; Hagemann, Urs B.; Scholz, Arne; Haendler, Bernard; Lejeune, Pascale; Karlsson, Jenny; Ellingsen, Christine; Hennekes, Hartwig; Nielsen, Carsten H.; Juul, Mark U.; Mumberg, Dominik; Schatz, Christoph A.

doi:10.1158/1078-0432.ccr-21-0342

Cited by 17 publications

(17 citation statements)

References 50 publications

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“…Our results demonstrate that these effects of topoisomerase-2 inhibition drive PSMA expression. This is in keeping with results from other groups reporting that BRCA2 CRISPR knockout and treatment with PSMA-TCC, an alpha particle emitting RLT toward PSMA, induce PSMA expression (24,25). Interestingly, our screen also identified that toposisomerase-1 inhibition and EGFR inhibition upregulate PSMA; as topoisomerase-1 inhibitors can also cause DNA single-and double-strand breaks this is perhaps not surprising (31).…”

Section: Discussionsupporting

confidence: 91%

“…We have previously demonstrated that mCRPC with DNA damage repair (DDR) defects, including deleterious alterations in BRCA2 and ATM, have significantly higher PSMA expression (15). Interestingly, preliminary studies suggest that BRCA2 CRISPR knockout and alpha emitting radioisotopes that result in DNA damage may upregulate PSMA (24,25). Overall, we hypothesized that these data support a functional role for PSMA in nucleotide pool maintenance and that the expression of PSMA is dynamic, not static in prostate cancer cells, with DNA damage-inducing agents increasing PSMA expression.…”

Section: Introductionmentioning

confidence: 99%

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Prostate-Specific Membrane Antigen Expression and Response to DNA Damaging Agents in Prostate Cancer

Sheehan

Neeb

Buroni

et al. 2022

Clinical Cancer Research

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Purpose: Prostate specific membrane antigen (PSMA) targeting therapies such as Lutetium-177 (177Lu)-PSMA-617 are impacting outcomes from metastatic castration-resistant prostate cancer (mCRPC). However, a significant subset of patients have prostate cancer cells lacking PSMA expression raising concerns about treatment resistance attributable at least in part to heterogeneous PSMA expression. We have previously demonstrated an association between high PSMA expression and DNA damage repair defects in mCRPC biopsies, and therefore hypothesized that DNA damage upregulates PSMA expression. Experimental Design: To test this relationship between PSMA and DNA damage we conducted a screen of 147 anticancer agents (NCI/NIH FDA-approved anticancer "Oncology Set") and treated tumor cells with repeated ionizing irradiation. Results: The topoisomerase-2 inhibitors, daunorubicin and mitoxantrone, were identified from the screen to upregulate PSMA protein expression in castration-resistant LNCaP95 cells; this result was validated in vitro in LNCaP, LNCaP95 and 22Rv1 cell lines, and in vivo using an mCRPC patient-derived xenograft model CP286 identified to have heterogeneous PSMA expression. Since double strand DNA break induction by topoisomerase-2 inhibitors upregulated PSMA, we next studied the impact of ionizing radiation on PSMA expression; this also upregulated PSMA protein expression in a dose-dependent fashion. Conclusions: The results presented herein are the first, to our knowledge, to demonstrate that PSMA is upregulated in response to double-strand DNA damage by anticancer treatment. These data support the study of rational combinations that maximize the antitumor activity of PSMA targeted therapeutic strategies by upregulating PSMA.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Prostate-Specific Membrane Antigen Expression and Response to DNA Damaging Agents in Prostate Cancer

Sheehan

Neeb

Buroni

et al. 2022

Clinical Cancer Research

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“…The ARI darolutamide is approved for non-metastatic CRPC in key markets ( 78 , 79 ) and more recently for use in combination with docetaxel for metastatic hormone-sensitive prostate cancer in the United States ( 79 ). Darolutamide has been shown to induce PSMA expression in prostate cancer cell lines and xenografts ( 80 , 81 ), providing a rationale for combining the drug with a PSMA-TTC. In prostate cancer xenograft models, darolutamide-mediated increase of PSMA expression facilitated tumor uptake of PSMA-TTC, and darolutamide also impaired PSMA-TTC-mediated induction of DNA damage repair genes ( 80 ).…”

Section: Ttcs In Combination With Other Cancer Therapiesmentioning

confidence: 99%

“…Darolutamide has been shown to induce PSMA expression in prostate cancer cell lines and xenografts ( 80 , 81 ), providing a rationale for combining the drug with a PSMA-TTC. In prostate cancer xenograft models, darolutamide-mediated increase of PSMA expression facilitated tumor uptake of PSMA-TTC, and darolutamide also impaired PSMA-TTC-mediated induction of DNA damage repair genes ( 80 ). Furthermore, the combination of PSMA-TTC plus darolutamide demonstrated synergistic inhibition of tumor growth in xenograft models ( 80 ).…”

Section: Ttcs In Combination With Other Cancer Therapiesmentioning

confidence: 99%

“…In prostate cancer xenograft models, darolutamide-mediated increase of PSMA expression facilitated tumor uptake of PSMA-TTC, and darolutamide also impaired PSMA-TTC-mediated induction of DNA damage repair genes ( 80 ). Furthermore, the combination of PSMA-TTC plus darolutamide demonstrated synergistic inhibition of tumor growth in xenograft models ( 80 ). The tumor inhibitory activity of the combination was also more notable than either agent alone in xenograft models that were either resistant to the ARI enzalutamide ( 80 ) or hormone independent ( 81 ).…”

Section: Ttcs In Combination With Other Cancer Therapiesmentioning

confidence: 99%

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Targeted thorium-227 conjugates as treatment options in oncology

et al. 2023

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Targeted alpha therapy (TAT) is a promising approach for addressing unmet needs in oncology. Inherent properties make α-emitting radionuclides well suited to cancer therapy, including high linear energy transfer (LET), penetration range of 2–10 cell layers, induction of complex double-stranded DNA breaks, and immune-stimulatory effects. Several alpha radionuclides, including radium-223 (223Ra), actinium-225 (225Ac), and thorium-227 (227Th), have been investigated. Conjugation of tumor targeting modalities, such as antibodies and small molecules, with a chelator moiety and subsequent radiolabeling with α-emitters enables specific delivery of cytotoxic payloads to different tumor types. 223Ra dichloride, approved for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) with bone-metastatic disease and no visceral metastasis, is the only approved and commercialized alpha therapy. However, 223Ra dichloride cannot currently be complexed to targeting moieties. In contrast to 223Ra, 227Th may be readily chelated, which allows radiolabeling of tumor targeting moieties to produce targeted thorium conjugates (TTCs), facilitating delivery to a broad range of tumors. TTCs have shown promise in pre-clinical studies across a range of tumor-cell expressing antigens. A clinical study in hematological malignancy targeting CD22 has demonstrated early signs of activity. Furthermore, pre-clinical studies show additive or synergistic effects when TTCs are combined with established anti-cancer therapies, for example androgen receptor inhibitors (ARI), DNA damage response inhibitors such as poly (ADP)-ribose polymerase inhibitors or ataxia telangiectasia and Rad3-related kinase inhibitors, as well as immune checkpoint inhibitors.

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Association of multiple trace metals in scalp hair with glioma risk: the mediating role of inflammation

Yan,

You,

Wang

et al. 2024

Ann Clin Transl Neurol

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ObjectiveTo explore the relationship between 35 trace metals in scalp hair and the glioma risk as well as the potential mediating roles of 27 plasma inflammatory cytokines.MethodsA case–control study involving 228 participants was performed in southeastern China. Trace metals in scalp hair were analyzed using inductively coupled plasma mass spectrometry, and multiplex cytokines were detected based on Luminex® technology. The least absolute shrinkage and selection operator (LASSO) regression in combination with four machine learning methods were used to select trace metals associated with gliomas. The joint exposure effect of trace metals was estimated using the generalized weighted quantile sum (gWQS) regression and quantile‐based g‐computation (qgcomp) algorithms.ResultsBoth LASSO regression and random forest algorithms identified five trace metals (gadolinium [Gd], lithium [Li], thulium [Tm], thorium [Th], and molybdenum [Mo]) associated with gliomas. After adjustments for potential confounders, Gd (odds ratio [OR] = 2.84, 95% confidence interval [CI]: 1.89–4.43) and Li (OR = 1.77, 95% CI: 1.04–3.02) concentrations were positively associated with glioma risk, while Tm (OR = 0.36, 95% CI: 0.17–0.73) and Th (OR = 0.45, 95% CI: 0.28–0.71) exhibited inverse associations. Both gWQS and qgcomp algorithms showed Gd contributed most to the mixture effect. Moreover, there was a significant interaction between Gd and Tm or Th on glioma risk (p < 0.05). Notably, granulocyte–macrophage colony‐stimulating factor (GM‐CSF) mediated the association between Gd exposure and glioma risk by 25.75%.InterpretationThese findings suggest potential associations of certain trace metals, especially for Gd, with glioma risk, and may provide new insights into the mechanisms underlying from an inflammatory response perspective.

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Darolutamide Potentiates the Antitumor Efficacy of a PSMA-targeted Thorium-227 Conjugate by a Dual Mode of Action in Prostate Cancer Models

Cited by 17 publications

References 50 publications

Prostate-Specific Membrane Antigen Expression and Response to DNA Damaging Agents in Prostate Cancer

Prostate-Specific Membrane Antigen Expression and Response to DNA Damaging Agents in Prostate Cancer

Targeted thorium-227 conjugates as treatment options in oncology

Association of multiple trace metals in scalp hair with glioma risk: the mediating role of inflammation

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