Lutetium-PSMA therapy—a new therapeutic option in metastatic castration-resistant prostate cancer?

2018 ◽  
Vol 11 (4) ◽  
pp. 301-304
Author(s):  
Michael Ladurner ◽  
Wolfgang Horninger ◽  
Jasmin Bektic
Keyword(s):  
Prostate Cancer ◽  
Therapeutic Option ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant

scholarly journals Cotargeting Polo-Like Kinase 1 and the Wnt/β-Catenin Signaling Pathway in Castration-Resistant Prostate Cancer

2015 ◽  
Vol 35 (24) ◽  
pp. 4185-4198 ◽  
Author(s):  
Jie Li ◽  
Anju Karki ◽  
Kurt B. Hodges ◽  
Nihal Ahmad ◽  
Amina Zoubeidi ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Signaling Pathway ◽  
Glycogen Synthase ◽  
Therapeutic Option ◽  
Negative Regulator ◽  
Castration Resistant Prostate Cancer ◽  
Prostate Cancer Cells ◽  
Castration Resistant

The Wnt/β-catenin signaling pathway has been identified as one of the predominantly upregulated pathways in castration-resistant prostate cancer (CRPC). However, whether targeting the β-catenin pathway will prove effective as a CRPC treatment remains unknown. Polo-like kinase 1 (Plk1) is a critical regulator in many cell cycle events, and its level is significantly elevated upon castration of mice carrying xenograft prostate tumors. Indeed, inhibition of Plk1 has been shown to inhibit tumor growth in severalin vivostudies. Here, we show that Plk1 is a negative regulator of Wnt/β-catenin signaling. Plk1 inhibition or depletion enhances the level of cytosolic and nuclear β-catenin in human prostate cancer cells. Furthermore, inhibition of Wnt/β-catenin signaling significantly potentiates the antineoplastic activity of the Plk1 inhibitor BI2536 in both cultured prostate cancer cells and CRPC xenograft tumors. Mechanistically, axin2, a negative regulator of the β-catenin pathway, serves as a substrate of Plk1, and Plk1 phosphorylation of axin2 facilitates the degradation of β-catenin by enhancing binding between glycogen synthase kinase 3β (GSK3β) and β-catenin. Plk1-phosphorylated axin2 also exhibits resistance to Cdc20-mediated degradation. Overall, this study identifies a novel Plk1-Wnt signaling axis in prostate cancer, offering a promising new therapeutic option to treat CRPC.

Cabazitaxel multiple rechallenge in metastatic castration-resistant prostate cancer: A therapeutic option to increase overall survival?

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 97-97
Author(s):  
Cedric Pobel ◽  
Edouard Auclin ◽  
Diego Teyssonneau ◽  
Brigitte Laguerre ◽  
Mathilde Cancel ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Overall Survival ◽  
Therapeutic Option ◽  
Progression Free Survival ◽  
Median Number ◽  
Castration Resistant Prostate Cancer ◽  
Free Survival ◽  
Castration Resistant ◽  
Grade 3

97 Background: Cabazitaxel rechallenge could be a more efficient therapy with an acceptable toxicity than docetaxel in the treatment of patients with a metastatic castration resistant prostate cancer (mCRPC). The aim of this study was to assess the feasibility and efficacy of cabazitaxel multiple rechallenge. Methods: This is a multicenter, retrospective cohort study including patients from 9 centers in France who received 3 lines or more of cabazitaxel from February 2012 to July 2020. Cabazitaxel schedule differed between patients: 25 mg/m2 q3w, 20 mg/m2 q3w, 16 mg/m2 q2w or 10 mg/m2 weekly. Efficacy was assessed by overall survival (OS) and progression-free survival (PFS) from each cabazitaxel line start. Only toxicities grade ≥ 3 were reported. Results: Twenty-two patients were included. The median follow-up from mCRPC was 94.7 months, median age at initial diagnosis was 59.5 years old, median ISUP score at diagnosis was 4 and median PSA at diagnosis was 55 ng/ml. Median number of cabazitaxel cycles was 7 at first-line, 6 at first rechallenge, and 5 for subsequent rechallenges. Median OS from mCRPC diagnosis was 105 months. Median PFS from cabazitaxel line start was 11.8 months at first use, 9.6 for first rechallenge and 5.6 in second rechallenge (table). Only one case of febrile neutropenia and 6 events of grade ≥ 3 toxicity were reported. Conclusions: Cabazitaxel multiple rechallenge could efficiently extend OS with manageable toxicities for patients. Even if anti-PARP therapy and immunotherapy are promising treatments, cabazitaxel rechallenge could be also a relevant therapeutic option for long responder patients. Specific biomarkers should be explored to predict the efficacy of cabazitaxel rechallenge. [Table: see text]

scholarly journals Inhibitor of H3K27 demethylase JMJD3/UTX GSK-J4 is a potential therapeutic option for castration resistant prostate cancer

Oncotarget ◽  
2017 ◽  
Vol 8 (37) ◽  
pp. 62131-62142 ◽  
Author(s):  
Viacheslav M. Morozov ◽  
Ying Li ◽  
Matthew M. Clowers ◽  
Alexander M. Ishov
Keyword(s):  
Prostate Cancer ◽  
Therapeutic Option ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant

scholarly journals The 68Ga/177Lu-theragnostic concept in PSMA-targeting of metastatic castration–resistant prostate cancer: impact of post-therapeutic whole-body scintigraphy in the follow-up

2019 ◽  
Vol 47 (3) ◽  
pp. 695-712 ◽  
Author(s):  
Johanna Maffey-Steffan ◽  
Lorenza Scarpa ◽  
Anna Svirydenka ◽  
Bernhard Nilica ◽  
Christian Mair ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Therapeutic Option ◽  
Whole Body ◽  
Castration Resistant Prostate Cancer ◽  
The Third ◽  
Castration Resistant ◽  
Mixed Response ◽  
Pet Ct ◽  
Post Therapy

Abstract Introduction A new therapeutic option for metastatic castration–resistant prostate cancer (mCRPC) of heavily pre-treated patients lies in 177Lu-PSMA-617 radioligand therapy. Methods On the basis of PSMA-targeted 68Ga-PSMA-11 PET/CT, 32 consecutive mCRPC patients were selected for 177Lu-PSMA-617 therapy (6 GBq/cycle, 2 to 6 cycles, 6–10 weeks apart) and followed until death. Post-therapy whole-body (WB) dosimetry and 68Ga-PSMA-11 PET/CT data were compared and related to progression free and overall survival. Results 177Lu-PSMA-617 dosimetry after the first cycle indicated high tumor doses for skeletal (4.01 ± 2.64; range 1.10–13.00 Gy/GBq), lymph node (3.12 ± 2.07; range 0.70–8.70 Gy/GBq), and liver (2.97 ± 1.38; range 0.76–5.00 Gy/GBq) metastases whereas the dose for tissues/organs was acceptable in all patients for an intention-to-treat activity of 24 GBq. Any PSA decrease after the first cycle was found in 23/32 (72%), after the second cycle in 22/32 (69%), after the third cycle in 16/28 (57%), and after the fourth cycle in 8/18 (44%) patients. Post-therapy 24 h WB scintigraphy showed decreased tumor-to-background ratios in 24/32 (75%) after the first therapy cycle, after the second cycle in 17/29 (59%), and after the third cycle in 13/21 (62%) patients. The median PFS was 7 months and the median OS 12 months. In the group of PSA responders (n = 22) the median OS was 17 months versus 11 months in the group of non-responders (n = 10), p < 0.05. Decreasing SUVmax values were found for parotid (15.93 ± 6.23 versus 12.33 ± 4.07) and submandibular glands (17.65 ± 7.34 versus 13.12 ± 4.62) following treatment, along with transient (n = 6) or permanent (n = 2) xerostomia in 8/32 (25%) patients. In 3/32 patients, nephrotoxicity changed from Grade 2 to 3, whereas neither Grade 4 nephrotoxicity nor hematotoxicity was found. In most patients a good agreement was observed for the visual interpretation of the tracer accumulation between 24 h WB and PET/CT scans. However, no significance could be calculated for baseline-absorbed tumor doses and SUVmax values of tumor lesions. 5/32 (16%) patients showed a mixed response pattern, which resulted in disease progression over time. Conclusion Serial PSA measurements and post-therapy 24 h WB scintigraphy seems to allow a sufficiently accurate follow-up of 177Lu-PSMA-617-treated mCRPC patients whereas 68Ga-PSMA-11 PET/CT should be performed for patient selection and final response assessment.

scholarly journals Immune Checkpoint Inhibitors: A Promising Treatment Option for Metastatic Castration-Resistant Prostate Cancer?

2021 ◽  
Vol 22 (9) ◽  
pp. 4712
Author(s):  
Vicenç Ruiz de Porras ◽  
Juan Carlos Pardo ◽  
Lucia Notario ◽  
Olatz Etxaniz ◽  
Albert Font
Keyword(s):  
Prostate Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Therapeutic Option ◽  
Predictive Biomarkers ◽  
Current Status ◽  
Castration Resistant Prostate Cancer ◽  
Mechanisms Of Resistance ◽  
Castration Resistant

Since 2010, several treatment options have been available for men with metastatic castration-resistant prostate cancer (mCRPC), including immunotherapeutic agents, although the clinical benefit of these agents remains inconclusive in unselected mCRPC patients. In recent years, however, immunotherapy has re-emerged as a promising therapeutic option to stimulate antitumor immunity, particularly with the use of immune checkpoint inhibitors (ICIs), such as PD-1/PD-L1 and CTLA-4 inhibitors. There is increasing evidence that ICIs may be especially beneficial in specific subgroups of patients with high PD-L1 tumor expression, high tumor mutational burden, or tumors with high microsatellite instability/mismatch repair deficiency. If we are to improve the efficacy of ICIs, it is crucial to have a better understanding of the mechanisms of resistance to ICIs and to identify predictive biomarkers to determine which patients are most likely to benefit. This review focuses on the current status of ICIs for the treatment of mCRPC (either as monotherapy or in combination with other drugs), mechanisms of resistance, potential predictive biomarkers, and future challenges in the management of mCRPC.

Extraction of 223Radium by haemodialysis after treatment of metastatic castration-resistant prostate cancer

2017 ◽  
Vol 56 (03) ◽  
pp. 69-72
Author(s):  
Heiko Wissel ◽  
Thekla Wallbaum ◽  
Philipp Genseke ◽  
Dennis Kupitz ◽  
Jens Ricke ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Phase I ◽  
Activity Concentration ◽  
Therapeutic Option ◽  
Residual Activity ◽  
Activity Level ◽  
Castration Resistant Prostate Cancer ◽  
Faecal Excretion ◽  
Castration Resistant ◽  
Stage Renal Disease

Summary Aim: 223Radium-dichloride (223Ra) administration is an upcoming therapeutic option in patients with castration-resistant metastatic prostate cancer (mCRPC), whose renal and faecal excretion of 223Ra has been primarily estimated from data of a phase-I clinical trial in patients with normal renal function. In the rare case of concomitant renal insufficiency requiring haemodialysis (HD), an estimation of the contamination of dialysate would be beneficial. Methods: The excretion of 223Ra and its concentration in the dialysate in a patient with mCRPC and end-stage renal disease was examined for six consecutive treatment cycles. Dialysate samples were measured using a commercial system with NaI-scintillation detector. Results: HD showed a residual activity level in the remaining dialysate. The excreted activity was a median of 46.1 kBq (range = 42.0 83.4 kBq) and 11.2 kBq (range = 8.419.9 kBq) for the first (24 h post injection p.i.) and second HD (96 h p.i.), respectively. The activity concentration decreased significantly from a median of 4.18 kBq/l (range = 2.98-5.14 kBq/l) to 0.85 kBq/l (range=0.69-1.31 kBq/l, p < 0.0001). For all consecutive time points, the activity concentration further decreased significantly (p < 0.0001). The activity concentration of dialysate from HD performed 125.4 h p.i. [95 % confidence interval = 120.5-130.4 h p.i.] reached the threshold for unrestricted waste disposal. Conclusion: The observed extraction of 223Ra by HD exceeded the data determined from the phase-I study. The activity concentration in the dialysate observed for the first HD’s p.i. was above the threshold for unrestricted disposal of radioactive waste in Germany. Therefore, the specific requirement for waste handling has to be followed to fulfil the radiation protection regulations.

Radioligand Therapy With 177Lu-PSMA-617 as A Novel Therapeutic Option in Patients With Metastatic Castration Resistant Prostate Cancer

2016 ◽  
Vol 41 (7) ◽  
pp. 522-528 ◽  
Author(s):  
Kambiz Rahbar ◽  
Axel Bode ◽  
Matthias Weckesser ◽  
Nemanja Avramovic ◽  
Michael Claesener ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Therapeutic Option ◽  
Castration Resistant Prostate Cancer ◽  
Radioligand Therapy ◽  
Castration Resistant ◽  
Novel Therapeutic

scholarly journals Role of Chemotherapy and Mechanisms of Resistance to Chemotherapy in Metastatic Castration-Resistant Prostate Cancer

2016 ◽  
Vol 10s1 ◽  
pp. CMO.S34535 ◽  
Author(s):  
Vipin Lohiya ◽  
Jeanny B. Aragon-Ching ◽  
Guru Sonpavde
Keyword(s):  
Prostate Cancer ◽  
Potential Role ◽  
Therapeutic Option ◽  
Cross Resistance ◽  
Castration Resistant Prostate Cancer ◽  
Mechanisms Of Resistance ◽  
Castration Resistant ◽  
Phases Of Development ◽  
Resistance To Chemotherapy

Chemotherapy using the taxanes, docetaxel and cabazitaxel, remains an important therapeutic option in metastatic castration-resistant prostate cancer (CRPC). However, despite the survival benefits afforded by these agents, the survival increments are modest and resistance occurs universally. Efforts to overcome resistance to docetaxel by combining with biologic agents have heretofore been unsuccessful. Indeed, resistance to these taxanes is also associated with cross-resistance to the antiandrogen drugs, abiraterone and enzalutamide. Here, we discuss the various mechanisms of resistance to chemotherapy in metastatic CRPC and the potential role of emerging regimens and agents in varying clinical phases of development.

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