Targeted α Therapies for the Treatment of Bone Metastases

Zustovich, Fable; Barsanti, Roberto

doi:10.3390/ijms19010074

Cited by 24 publications

(13 citation statements)

References 41 publications

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“…When given to CRPC patients, radium-223 dichloride significantly improves overall survival irrespective of prior docetaxel use, while alleviating pain linked to bone metastases and with a favorable safety profile [ 121 , 122 , 123 ]. It was originally approved by the FDA in 2013 for CRPC patients with bone metastases and no known visceral metastatic disease [ 14 , 124 ].…”

Section: Treatment Options and Potential Novel Therapiesmentioning

confidence: 99%

Recent Advances in Prostate Cancer Treatment and Drug Discovery

Nevedomskaya

Baumgart

Haendler

2018

IJMS

209

174

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Novel drugs, drug sequences and combinations have improved the outcome of prostate cancer in recent years. The latest approvals include abiraterone acetate, enzalutamide and apalutamide which target androgen receptor (AR) signaling, radium-223 dichloride for reduction of bone metastases, sipuleucel-T immunotherapy and taxane-based chemotherapy. Adding abiraterone acetate to androgen deprivation therapy (ADT) in order to achieve complete androgen blockade has proven highly beneficial for treatment of locally advanced prostate cancer and metastatic hormone-sensitive prostate cancer (mHSPC). Also, ADT together with docetaxel treatment showed significant benefit in mHSPC. Ongoing clinical trials for different subgroups of prostate cancer patients include the evaluation of the second-generation AR antagonists enzalutamide, apalutamide and darolutamide, of inhibitors of the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) pathway, of inhibitors of DNA damage response, of targeted alpha therapy and of prostate-specific membrane antigen (PSMA) targeting approaches. Advanced clinical studies with immune checkpoint inhibitors have shown limited benefits in prostate cancer and more trials are needed to demonstrate efficacy. The identification of improved, personalized treatments will be much supported by the major progress recently made in the molecular characterization of early- and late-stage prostate cancer using “omics” technologies. This has already led to novel classifications of prostate tumors based on gene expression profiles and mutation status, and should greatly help in the choice of novel targeted therapies best tailored to the needs of patients.

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Section: Treatment Options and Potential Novel Therapiesmentioning

confidence: 99%

Recent Advances in Prostate Cancer Treatment and Drug Discovery

Nevedomskaya

Baumgart

Haendler

2018

IJMS

209

174

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“…Therefore, in comparison to beta decay, alpha decay can cause a high quantity of DNA double strand breaks in a short range and holds the promise of a higher level of induced DNA damage per cell. Actinium-225, lead-212, thorium-227, bismuth-213, and astatine-211 are alpha emitting radionuclides that are being explored (pre)clinically for PSMA-TAT [54,80,82,83]. These studies all prove the increased therapeutic effectiveness of alpha-radiation compared to beta-radiation.…”

Section: Varying Radionuclides For Psma-trtmentioning

confidence: 99%

The Future of PSMA-Targeted Radionuclide Therapy: An Overview of Recent Preclinical Research

et al. 2019

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Prostate specific membrane antigen (PSMA) has become a major focus point in the research and development of prostate cancer (PCa) imaging and therapeutic strategies using radiolabeled tracers. PSMA has shown to be an excellent target for PCa theranostics because of its high expression on the membrane of PCa cells and the increase in expression during disease progression. Therefore, numerous PSMA-targeting tracers have been developed and (pre)clinically studied with promising results. However, many of these PSMA-targeting tracers show uptake in healthy organs such as the salivary glands, causing radiotoxicity. Furthermore, not all patients respond to PSMA-targeted radionuclide therapy (TRT). This created the necessity of additional preclinical research studies in which existing tracers are reevaluated and new tracers are developed in order to improve PSMA-TRT by protecting the (PSMA-expressing) healthy organs and improving tumor uptake. In this review we will give an overview of the recent preclinical research projects regarding PCa-TRT using PSMA-specific radiotracers, which will give an indication of where the PSMA-TRT research movement is going and what we can expect in future clinical trials.

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“…Ra, the first a-emitter approved by the FDA, takes advantage of radium's bone mimetic properties for the treatment of patients with castrate-resistant prostate cancer with bone metastases (15,16). The established clinical efficacy of 223 Ra has led to significant interest in expanding the use of a-particles to target cancers other than those that are localized in bone.…”

mentioning

confidence: 99%

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

et al. 2019

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Targeted a-particle-emitting radionuclides have great potential for the treatment of a broad range of cancers at different stages of progression. A platform that accurately measures cancer cellular sensitivity to a-particle irradiation could guide and accelerate clinical translation. Here, we performed highcontent profiling of cellular survival following exposure to a-particles emitted from radium-223 (223 Ra) using 28 genetically diverse human tumor cell lines. Significant variation in cellular sensitivity across tumor cells was observed. 223 Ra was significantly more potent than sparsely ionizing irradiation, with a median relative biological effectiveness of 10.4 (IQR: 8.4-14.3). Cells that are the most resistant to g radiation, such as Nrf2 gain-of-function mutant cells, were sensitive to a-particles. Combining these profiling results with genetic features, we identified several somatic copy-number alterations, gene mutations, and the basal expression of gene sets that correlated with radiation survival. Activating mutations in PIK3CA, a frequent event in cancer, decreased sensitivity to 223 Ra. The identification of cellular and genetic determinants of sensitivity to 223 Ra may guide the clinical incorporation of targeted a-particle emitters in the treatment of several cancer types. Significance: These findings address limitations in the preclinical guidance and prediction of radionuclide tumor sensitivity by identifying intrinsic cellular and genetic determinants of cancer cell survival following exposure to a-particle irradiation. See related commentary by Sgouros, p. 5479

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Targeted α Therapies for the Treatment of Bone Metastases

Cited by 24 publications

References 41 publications

Recent Advances in Prostate Cancer Treatment and Drug Discovery

Recent Advances in Prostate Cancer Treatment and Drug Discovery

The Future of PSMA-Targeted Radionuclide Therapy: An Overview of Recent Preclinical Research

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

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