Cellular and Genetic Determinants of the Sensitivity of Cancer to α-Particle Irradiation

Yard, Brian D.; Gopal, Priyanka; Bannik, Kristina; Siemeister, Gerhard; Hagemann, Urs B.; Abazeed, Mohamed E.

doi:10.1158/0008-5472.can-19-0859

Cited by 28 publications

(27 citation statements)

References 54 publications

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“…These are particularly difficult for cells to repair and the highly localized energy of alpha emitters make them particularly attractive for the treatment of small volume metastases (26). In contrast, beta emitters induce mainly single-strand DNA breaks and mechanisms of resistance applicable for these are not valid for alpha emitters as recently demonstrated in an in vitro cell line screen (27).…”

Section: Discussionmentioning

confidence: 99%

Preclinical Efficacy of a PSMA-Targeted Thorium-227 Conjugate (PSMA-TTC), a Targeted Alpha Therapy for Prostate Cancer

Hammer¹,

Hagemann²,

Zitzmann-Kolbe³

et al. 2020

Clinical Cancer Research

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◥Purpose: Prostate-specific membrane antigen (PSMA) is an attractive target for radionuclide therapy of metastatic castrationresistant prostate cancer (mCRPC). PSMA-targeted alpha therapy (TAT) has shown early signs of activity in patients with prostate cancer refractory to beta radiation. We describe a novel, antibody-based TAT, the PSMA-targeted thorium-227 conjugate PSMA-TTC (BAY 2315497) consisting of the alpha-particle emitter thorium-227 complexed by a 3,2-HOPO chelator covalently linked to a fully human PSMA-targeting antibody.Experimental Design: PSMA-TTC was characterized for affinity, mode of action, and cytotoxic activity in vitro. Biodistribution, pharmacokinetics, and antitumor efficacy were investigated in vivo using cell line and patient-derived xenograft (PDX) models of prostate cancer.Results: PSMA-TTC was selectively internalized into PSMApositive cells and potently induced DNA damage, cell-cycle arrest, and apoptosis in vitro. Decrease in cell viability was observed dependent on the cellular PSMA expression levels. In vivo, PSMA-TTC showed strong antitumor efficacy with T/C values of 0.01 to 0.31 after a single injection at 300 to 500 kBq/kg in subcutaneous cell line and PDX models, including models resistant to standard-of-care drugs such as enzalutamide. Furthermore, inhibition of both cancer and cancer-induced abnormal bone growth was observed in a model mimicking prostate cancer metastasized to bone. Specific tumor uptake and efficacy were demonstrated using various PSMA-TTC doses and dosing schedules. Induction of DNA double-strand breaks was identified as a key mode of action for PSMA-TTC both in vitro and in vivo.Conclusions: The strong preclinical antitumor activity of PSMA-TTC supports its clinical evaluation, and a phase I trial is ongoing in mCRPC patients (NCT03724747).

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Section: Discussionmentioning

confidence: 99%

Preclinical Efficacy of a PSMA-Targeted Thorium-227 Conjugate (PSMA-TTC), a Targeted Alpha Therapy for Prostate Cancer

Hammer¹,

Hagemann²,

Zitzmann-Kolbe³

et al. 2020

Clinical Cancer Research

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“…TTCs may be less susceptible to the development of acquired resistance compared with cytotoxic chemotherapy drugs or inhibitors of specific signaling molecules and, therefore, may be beneficial in early and late treatment lines. 26,97 Future clinical studies designed to investigate the toxicity profiles of TTCs will be of paramount importance in determining the full potential of this class of cancer therapy. The MoA of TTCs offers the potential for new combinations with a range of current and emerging therapies, including inhibitors of the DDR pathway and potentially immune TARGETED THORIUM-227 CONJUGATES IN PRECISION ONCOLOGY checkpoint inhibitors for the effective treatment of patients with a variety of tumor types.…”

Section: Summary and Future Perspectivesmentioning

confidence: 99%

“…TTCs, therefore, represent a new promising class of TAT for cancer therapy capable of delivering a high-energy a-particle radiation to tumors by targeting antigens specifically expressed or overexpressed on cancer versus healthy tissue. 3,4 Resistance to therapy, which develops to some cancer drugs, is unlikely to occur to a-particle-emitting radionuclides, 26 although a high prevalence of mutations in the DNA damage response (DDR) genes was reported in a small group of patients who had not responded to 225 Ac-prostate-specific membrane antigen (PSMA)-617 treatment. 27 Moreover, the high energy of a particles, delivered within a small area in the tumor, damage cancer cells independently of local oxygen levels, thus overcoming hypoxia-induced resistance to therapy.…”

Section: Introductionmentioning

confidence: 99%

Advances in Precision Oncology: Targeted Thorium-227 Conjugates As a New Modality in Targeted Alpha Therapy

Hagemann

Wickstroem

Hammer

et al. 2020

Cancer Biotherapy and Radiopharmaceuticals

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Targeted alpha therapy (TAT) offers the potential for the targeted delivery of potent a-particle-emitting radionuclides that emit high linear energy transfer radiation. This leads to a densely ionizing radiation track over a short path. Localized radiation induces cytotoxic, difficult-to-repair, clustered DNA double-strand breaks (DSBs). To date, radium-223 (223 Ra) is the only TAT approved for the treatment of patients with metastatic castration-resistant prostate cancer. Thorium-227 (227 Th), the progenitor nuclide of 223 Ra, offers promise as a wider-ranging alternative due to the availability of efficient chelators, such as octadentate 3,2-hydroxypyridinone (3,2-HOPO). The 3,2-HOPO chelator can be readily conjugated to a range of targeting moieties, enabling the generation of new targeted thorium-227 conjugates (TTCs). This review provides a comprehensive overview of the advances in the preclinical development of TTCs for hematological cancers, including CD22-positive B cell cancers and CD33-positive leukemia, as well as for solid tumors overexpressing renal cell cancer antigen CD70, membrane-anchored glycoprotein mesothelin in mesothelioma, prostate-specific membrane antigen in prostate cancer, and fibroblast growth factor receptor 2. As the mechanism of action for TTCs is linked to the formation of DSBs, the authors also report data supporting combinations of TTCs with inhibitors of the DNA damage response pathways, including those of the ataxia telangiectasia and Rad3-related protein, and poly-ADP ribose polymerase. Finally, emerging evidence suggests that TTCs induce immunogenic cell death through the release of danger-associated molecular patterns. Based on encouraging preclinical data, clinical studies have been initiated to investigate the safety and tolerability of TTCs in patients with various cancers.

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“…To avoid these relapses, the idea would be to eliminate the residual cancer cells by using TAT after the first lines of treatment. Indeed, few resistances to alpha particles have been reported in the literature due to their high cytotoxic potential [37][38][39].…”

Section: Discussionmentioning

confidence: 99%

Targeted-Alpha-Therapy Combining Astatine-211 and anti-CD138 Antibody in a Preclinical Syngeneic Mouse Model of Multiple Myeloma Minimal Residual Disease

Gouard

Maurel

Marionneau-Lambot

et al. 2020

Cancers

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Despite therapeutic progress in recent years with the introduction of targeted therapies (daratumumab, elotuzumab), multiple myeloma remains an incurable cancer. The question is therefore to investigate the potential of targeted alpha therapy, combining an anti-CD138 antibody with astatine-211, to destroy the residual cells that cause relapses. A preclinical syngeneic mouse model, consisting of IV injection of 1 million of 5T33 cells in a KaLwRij C57/BL6 mouse, was treated 10 days later with an anti-mCD138 antibody, called 9E7.4, radiolabeled with astatine-211. Four activities of the 211At-9E7.4 radioimmunoconjugate were tested in two independent experiments: 370 kBq (n = 16), 555 kBq (n = 10), 740 kBq (n = 17) and 1100 kBq (n = 6). An isotype control was also tested at 555 kBq (n = 10). Biodistribution, survival rate, hematological parameters, enzymatic hepatic toxicity, histological examination and organ dosimetry were considered. The survival median of untreated mice was 45 days after engraftment. While the activity of 1100 kBq was highly toxic, the activity of 740 kBq offered the best efficacy with 65% of overall survival 150 days after the treatment with no evident sign of toxicity. This work demonstrates the pertinence of treating minimal residual disease of multiple myeloma with an anti-CD138 antibody coupled to astatine-211.

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Cellular and Genetic Determinants of the Sensitivity of Cancer to α-Particle Irradiation

Cited by 28 publications

References 54 publications

Preclinical Efficacy of a PSMA-Targeted Thorium-227 Conjugate (PSMA-TTC), a Targeted Alpha Therapy for Prostate Cancer

Preclinical Efficacy of a PSMA-Targeted Thorium-227 Conjugate (PSMA-TTC), a Targeted Alpha Therapy for Prostate Cancer

Advances in Precision Oncology: Targeted Thorium-227 Conjugates As a New Modality in Targeted Alpha Therapy

Targeted-Alpha-Therapy Combining Astatine-211 and anti-CD138 Antibody in a Preclinical Syngeneic Mouse Model of Multiple Myeloma Minimal Residual Disease

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