Management of men with metastatic castration-resistant prostate cancer following potent androgen receptor inhibition: a review of novel investigational therapies

Labriola, Matthew; Atiq, Saad; Hirshman, Nathan; Bitting, Rhonda L.

doi:10.1038/s41391-020-00299-9

Cited by 21 publications

(21 citation statements)

References 82 publications

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“…This number is expected to increase as the population grows and life expectancy increases [ 1 ]. Approximately 10–20% of the estimated cases develop into castration-resistant prostate cancer within 5 years of diagnosis, and more than 80% develop into metastatic castration-resistant prostate cancer (mCRPC) [ 2 ]. Nowadays, mCRPC patients are treated with hormone therapy and chemotherapy, which can have severe side effects.…”

Section: Introductionmentioning

confidence: 99%

Development of [225Ac]Ac-PSMA-I&T for Targeted Alpha Therapy According to GMP Guidelines for Treatment of mCRPC

et al. 2021

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Recently, promising results of the antitumor effects were observed in patients with metastatic castration-resistant prostate cancer treated with 177Lu-labeled PSMA-ligands. Radionuclide therapy efficacy may even be improved by using the alpha emitter Ac-225. Higher efficacy is claimed due to high linear energy transfer specifically towards PSMA positive cells, causing more double-strand breaks. This study aims to manufacture [225Ac]Ac-PSMA-I&T according to good manufacturing practice guidelines for the translation of [225Ac]Ac-PSMA-I&T into a clinical phase 1 dose escalation study. Quencher addition during labeling was investigated. Quality control of [225Ac]Ac-PSMA-I&T was based on measurement of Fr-221 (218 keV), in equilibrium with Ac-225 in approximately six half-lives of Fr-221 (T½ = 4.8 min). Radio-(i)TLC methods were utilized for identification of the different radiochemical forms, gamma counter for concentration determination, and HPGe-detector for the detection of the radiochemical yield. Radiochemical purity was determined by HPLC. The final patient dose was prepared and diluted with an optimized concentration of quenchers as during labeling, with an activity of 8–12 MBq (±5%), pH > 5.5, 100 ± 20 μg/dose, PSMA-I&T, radiochemical yield >95%, radiochemical purity >90% (up to 3 h), endotoxin levels of <5 EU/mL, osmolarity of 2100 mOsmol, and is produced according to current guidelines. The start of the phase I dose escalation study is planned in the near future.

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Section: Introductionmentioning

confidence: 99%

Development of [225Ac]Ac-PSMA-I&T for Targeted Alpha Therapy According to GMP Guidelines for Treatment of mCRPC

et al. 2021

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“…To check if the top 50 pathways had been reported to be involved in CBZ‐resistance, we performed a MEDLINE search using the search terms “CBZ” and “the name of each pathway.” As a result, PI3K signaling pathway and autophagy‐related protein signaling pathway were found to be possibly related to CBZ‐resistance. Of the two pathways, we focused on the PI3K signaling pathway, because it is one of the most frequently activated signaling pathways in CRPC 17,18 and its inhibitors are in clinical use for cancer therapy 19 . To examine the cytotoxic effect of ZSTK474, one of PI3K inhibitors that are used in clinical trials, 22Rv1 and 22Rv1CR cells were treated with ZSTK474 alone or in combination of CBZ.…”

Section: Resultsmentioning

confidence: 99%

Proteomic analysis of extracellular vesicles identified PI3K pathway as a potential therapeutic target for cabazitaxel‐resistant prostate cancer

et al. 2021

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Background Cabazitaxel (CBZ) is now widely used for prostate cancer (PC) patients resistant to docetaxel (DOC), however, most patients eventually acquire resistance. It will, therefore, be of great benefit to discover novel therapeutic target for the resistance. We aimed to identify candidate therapeutic targets for CBZ‐resistance by proteomic analysis of extracellular vesicles (EVs) isolated from serum of DOC‐resistant PC patients who later developed CBZ‐resistance as well as those harvested from culture medium of DOC‐ and CBZ‐resistant PC cell lines. Methods Using T‐cell immunoglobulin domain and mucin domain‐containing protein 4 (Tim4) conjugated to magnetic beads, EVs were purified from serum of PC patients with DOC‐resistance that was collected before and after acquiring CBZ‐resistance and conditioned medium of DOC‐resistant (22Rv1DR) and CBZ‐resistant (22Rv1CR) PC cell lines. Protein analysis of EVs was performed by nanoLC‐MS/MS, followed by a comparative analysis of protein expression and network analysis. The cytotoxic effect of a phosphatidylinositol‐3‐kinase (PI3K) inhibitor, ZSTK474, was evaluated by WST‐1 assay. The expression and phosphorylation of PI3K and PTEN were examined by western blot analysis. Results Among differentially regulated proteins, 77 and 61 proteins were significantly increased in EVs from CBZ‐resistant PC cell line and patients, respectively. A comparison between the two datasets revealed that six proteins, fructose‐bisphosphate aldolase, cytosolic nonspecific dipeptidase, CD63, CD151, myosin light chain 9, and peroxiredoxin‐6 were elevated in EVs from both cell line and patients. Network analysis of the increased EV proteins identified pathways associated with CBZ‐resistance including PI3K signaling pathway. ZSTK474 significantly inhibited growth of 22Rv1CR cells and improved their sensitivity to CBZ. In 22Rv1CR cells, PI3K was activated and PTEN that inhibits PI3K was deactivated. Conclusions Proteomic analysis of serum EVs was successfully accomplished by using Tim‐4 as a tool to isolate highly purified EVs. Our results suggest that the combination use of CBZ and PI3K inhibitor could be a promising treatment option for CBZ‐resistant PC patients.

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“…Prostate cancer is the second most common cancer in men worldwide, with an estimated 1.3 million new cases and 359,000 deaths in 2018 [ 1 ]. The tumors of 10–20% of prostate cancer patients become refractory to androgen deprivation therapy and progress as metastatic castration-resistant prostate cancer (mCRPC) [ 2 , 3 ]. Bone metastases dominate, but lymph node and visceral metastases are also frequent in mCRPC patients [ 4 , 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

Preclinical and Clinical Status of PSMA-Targeted Alpha Therapy for Metastatic Castration-Resistant Prostate Cancer

Juzeniene

Stenberg

Bruland

et al. 2021

Cancers

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Bone, lymph node, and visceral metastases are frequent in castrate-resistant prostate cancer patients. Since such patients have only a few months’ survival benefit from standard therapies, there is an urgent need for new personalized therapies. The prostate-specific membrane antigen (PSMA) is overexpressed in prostate cancer and is a molecular target for imaging diagnostics and targeted radionuclide therapy (theragnostics). PSMA-targeted α therapies (PSMA-TAT) may deliver potent and local radiation more selectively to cancer cells than PSMA-targeted β- therapies. In this review, we summarize both the recent preclinical and clinical advances made in the development of PSMA-TAT, as well as the availability of therapeutic α-emitting radionuclides, the development of small molecules and antibodies targeting PSMA. Lastly, we discuss the potentials, limitations, and future perspectives of PSMA-TAT.

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Management of men with metastatic castration-resistant prostate cancer following potent androgen receptor inhibition: a review of novel investigational therapies

Cited by 21 publications

References 82 publications

Development of [225Ac]Ac-PSMA-I&T for Targeted Alpha Therapy According to GMP Guidelines for Treatment of mCRPC

Development of [225Ac]Ac-PSMA-I&T for Targeted Alpha Therapy According to GMP Guidelines for Treatment of mCRPC

Proteomic analysis of extracellular vesicles identified PI3K pathway as a potential therapeutic target for cabazitaxel‐resistant prostate cancer

Preclinical and Clinical Status of PSMA-Targeted Alpha Therapy for Metastatic Castration-Resistant Prostate Cancer

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