Establishment and characterization of a hormone dependent, PSA/PSMA positive prostate PDX model

Wick, Macdonald; Quinn, Mark; Mangold, Aaron R.; Gamez, Lizette; Díaz, Ana Patricia Ovejero; Vaught, Teresa L.; Reyna, Juan A.; Tolcher, Anthony W.; Rasco, Drew W.; Patnaik, Akash; Papadopoulos, K.

doi:10.1016/s0959-8049(16)32935-5

Cited by 4 publications

(5 citation statements)

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“…Next, we evaluated the in vivo efficacy of the PSMA-TTC and darolutamide combination in the high PSMA-expressing (Supplementary Fig. S2A and S2C), hormone-dependent, castration-, and enzalutamide-sensitive ( 14 ) ST1273 prostate cancer PDX model. In the first ST1273 efficacy study, the antitumor efficacy of a fixed, intermediate PSMA-TTC dose (250 kBq/kg) in combination with varying doses of darolutamide (15, 30, or 100 mg/kg, twice daily) was evaluated.…”

Section: Resultsmentioning

confidence: 99%

“…For the in vitro experiments, LNCaP and VCaP cells were supplemented with 0.1 nmol/L of the synthetic androgen agonist R1881. The patient-derived xenograft (PDX) prostate cancer model ST1273 ( 14 ) was obtained from South Texas Accelerated Research Therapeutics and KUCaP-1 ( 15 ) from O. Ogawa (University of Kyoto, Kyoto, Japan). The LuCaP 86 and LuCaP 58 PDX models were obtained from E. Corey (University of Washington, Seattle, WA).…”

Section: Methodsmentioning

confidence: 99%

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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

Hammer¹,

Schlicker²,

Zitzmann-Kolbe³

et al. 2021

Clinical Cancer Research

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Most patients with prostate cancer undergoing antiandrogen treatment will develop resistance, and thus, novel effective treatments are needed. Here, we explore the combination of the antibody-based targeted alpha therapy PSMA-TTC and the androgen receptor inhibitor darolutamide in preclinical prostate cancer models. This combination is well-tolerated and exhibits synergistic antitumor efficacy. We demonstrate a dual mode-ofaction for this combination treatment, where androgen inhibition (1) induces PSMA expression, resulting in increased PSMA-TTC tumor uptake and enhanced efficacy in a model with low baseline PSMA expression, and (2) prevents the expression of DNA repair pathway genes, leading to increased DNA damage and antitumor efficacy in combination with PSMA-TTC in a model with high baseline PSMA expression. Altogether, our preclinical data suggest that PSMA-TTC and darolutamide combination therapy may be a highly effective treatment option for prostate cancer and support the clinical development of PSMA-TTC in combination with androgen receptor inhibitors, such as darolutamide.Research.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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

Hammer¹,

Schlicker²,

Zitzmann-Kolbe³

et al. 2021

Clinical Cancer Research

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“…LNCaP-luc cells were generated by transfecting LNCaP cells with the luciferase gene at NMI. The patient-derived xenograft (PDX) prostate cancer model ST1273 (18) Matched samples of primary tumors and lymph node metastases from prostate cancer patients were obtained from Provitro AG.…”

Section: Cell Lines Tumor Models and Human Cancer Samplesmentioning

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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“…The androgen-sensitive ST1273 [19] and the androgenindependent KUCaP-1 [20] patient-derived xenograft (PDX) PrCa models were obtained from START (San Antonio, TX, USA) and O. Ogawa (University of Kyoto, Kyoto, Japan), respectively.…”

Section: Compounds Cell Lines and Tumor Modelsmentioning

confidence: 99%

Mono- and multimeric PSMA-targeting small molecule-thorium-227 conjugates for optimized efficacy and biodistribution in preclinical models

Böhnke,

Indrevoll,

Hammer

et al. 2023

Eur J Nucl Med Mol Imaging

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Purpose PSMA (prostate-specific membrane antigen) is highly expressed on prostate cancer (PrCa) cells and extensively used as a homing target for PrCa treatment. Most prominently, PSMA-targeting conjugate PSMA-617, carrying a DOTA chelator and labeled with therapeutic radionuclides like beta-emitting lutetium-177 or alpha-emitting actinium-225, has shown clinical activity in PrCa patients. We sought to develop PSMA-targeting small molecule (SMOL) conjugates that show high uptake in PSMA-expressing tumors and fast clearance, and can easily be labeled with the alpha emitter thorium-227 (half-life 18.7 days). Methods A novel linker motif with improved competition against 3H-PSMA-617 on PSMA-expressing LNCaP cells was identified. A 2,3-hydroxypyridinone chelator modified with carboxyl groups (carboxy-HOPO) with increased hydrophilicity and robust labeling with thorium-227 was developed and allowed the synthesis of mono-, di-, tri-, and tetrameric conjugates. The resulting monomeric and multimeric PSMA SMOL-TTCs (targeted thorium conjugate) were evaluated for cellular binding, internalization, and antiproliferative activity. The in vivo antitumor efficacy of the PSMA SMOL-TTCs was determined in ST1273 and KUCaP-1 PrCa models in mice, and their biodistribution was assessed in cynomolgus monkeys, minipigs, and mice. Results The monomeric and multimeric PSMA SMOL conjugates were readily labeled with thorium-227 at room temperature and possessed high stability and good binding, internalization, and antiproliferative activity in vitro. In vivo, the monomeric, dimeric, and trimeric PSMA SMOL-TTCs showed fast clearance, potent antitumor efficacy, and high uptake and retention in prostate tumors in mice. No major uptake or retention in other organs was observed beyond kidneys. Low uptake of free thorium-227 into bone confirmed high complex stability in vivo. Salivary gland uptake remained inconclusive as mini pigs were devalidated as a relevant model and imaging controls failed in cynomolgus monkeys. Conclusion Monomeric and multimeric PSMA SMOL-TTCs show high tumor uptake and fast clearance in preclinical models and warrant further therapeutic exploration.

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Establishment and characterization of a hormone dependent, PSA/PSMA positive prostate PDX model

Cited by 4 publications

References 0 publications

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

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

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

Mono- and multimeric PSMA-targeting small molecule-thorium-227 conjugates for optimized efficacy and biodistribution in preclinical models

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