Therapeutic Potential of PARP Inhibitors in the Treatment of Metastatic Castration-Resistant Prostate Cancer

Jang, Albert; Sartor, Oliver; Barata, Pedro C.; Fletcher, Sean A.

doi:10.3390/cancers12113467

Cited by 17 publications

(7 citation statements)

References 71 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In recent years a new therapy based on the use of PARP inhibitors (PARPis) was developed. Jang et al analyzed the mechanism of action and rationale for the use of PARPis, alone or in combination with other therapies especially in patients with metastatic castration-resistant PCa (mCRPC) [ 91 ]. The previously cited review evaluated several studies based on the use of two types of PARPis, Olaparib, and Rucaparib, which have produced encouraging results.…”

Section: Theranostic Pet Tracersmentioning

confidence: 99%

Prognostic and Theranostic Applications of Positron Emission Tomography for a Personalized Approach to Metastatic Castration-Resistant Prostate Cancer

Filippi

Frantellizzi

Chiaravalloti

et al. 2021

IJMS

View full text Add to dashboard Cite

Metastatic castration-resistant prostate cancer (mCRPC) represents a condition of progressive disease in spite of androgen deprivation therapy (ADT), with a broad spectrum of manifestations ranging from no symptoms to severe debilitation due to bone or visceral metastatization. The management of mCRPC has been profoundly modified by introducing novel therapeutic tools such as antiandrogen drugs (i.e., abiraterone acetate and enzalutamide), immunotherapy through sipuleucel-T, and targeted alpha therapy (TAT). This variety of approaches calls for unmet need of biomarkers suitable for patients’ pre-treatment selection and prognostic stratification. In this scenario, imaging with positron emission computed tomography (PET/CT) presents great and still unexplored potential to detect specific molecular and metabolic signatures, some of whom, such as the prostate specific membrane antigen (PSMA), can also be exploited as therapeutic targets, thus combining diagnosis and therapy in the so-called “theranostic” approach. In this review, we performed a web-based and desktop literature research to investigate the prognostic and theranostic potential of several PET imaging probes, such as 18F-FDG, 18F-choline and 68Ga-PSMA-11, also covering the emerging tracers still in a pre-clinical phase (e.g., PARP-inhibitors’ analogs and the radioligands binding to gastrin releasing peptide receptors/GRPR), highlighting their potential for defining personalized care pathways in mCRPC

show abstract

Section: Theranostic Pet Tracersmentioning

confidence: 99%

Prognostic and Theranostic Applications of Positron Emission Tomography for a Personalized Approach to Metastatic Castration-Resistant Prostate Cancer

Filippi

Frantellizzi

Chiaravalloti

et al. 2021

IJMS

View full text Add to dashboard Cite

show abstract

“…Published biomarker outcomes are used in clinical guidelines, drug labels, and research. For example, the olaparib drug label references the PROfound trial data (de Bono et al, 2020 ; Hussain et al, 2020 ; FDA, 2020 ), and multiple publications have reviewed PARP inhibitors in mCRPC (Luo and Antonarakis, 2019 ; Antonarakis et al, 2020a ; Jang et al, 2020 ). These activities involve a redundant, error-prone, time-consuming, and laborious data aggregation step.…”

Section: Introductionmentioning

confidence: 99%

“…Many of these analyses focus on comparisons between the AR-directed (ARD) therapies abiraterone acetate + prednisone/enzalutamide and PARP inhibitors (PARPi) olaparib, rucaparib, veliparib, niraparib, and talazoparib. HRD specifically is widely recognized to mediate PARPi survival benefit, potentially via synthetic lethality (Jang et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Applications for open access normalized synthesis in metastatic prostate cancer trials

Luechtefeld¹,

Bozada²,

Goel

et al. 2022

Front. Artif. Intell.

Self Cite

View full text Add to dashboard Cite

Recent metastatic castration-resistant prostate cancer (mCRPC) clinical trials have integrated homologous recombination and DNA repair deficiency (HRD/DRD) biomarkers into eligibility criteria and secondary objectives. These trials led to the approval of some PARP inhibitors for mCRPC with HRD/DRD indications. Unfortunately, biomarker-trial outcome data is only discovered by reviewing publications, a process that is error-prone, time-consuming, and laborious. While prostate cancer researchers have written systematic evidence reviews (SERs) on this topic, given the time involved from the last search to publication, an SER is often outdated even before publication. The difficulty in reusing previous review data has resulted in multiple reviews of the same trials. Thus, it will be useful to create a normalized evidence base from recently published/presented biomarker-trial outcome data that one can quickly update. We present a new approach to semi-automating normalized, open-access data tables from published clinical trials of metastatic prostate cancer using a data curation and SER platform. Clinicaltrials.gov and Pubmed.gov were used to collect mCRPC clinical trial publications with HRD/DRD biomarkers. We extracted data from 13 publications covering ten trials that started before 22nd Apr 2021. We extracted 585 hazard ratios, response rates, duration metrics, and 543 adverse events. Across 334 patients, we also extracted 8,180 patient-level survival and biomarker values. Data tables were populated with survival metrics, raw patient data, eligibility criteria, adverse events, and timelines. A repeated strong association between HRD and improved PARP inhibitor response was observed. Several use cases for the extracted data are demonstrated via analyses of trial methods, comparison of treatment hazard ratios, and association of treatments with adverse events. Machine learning models are also built on combined and normalized patient data to demonstrate automated discovery of therapy/biomarker relationships. Overall, we demonstrate the value of systematically extracted and normalized data. We have also made our code open-source with simple instructions on updating the analyses as new data becomes available, which anyone can use even with limited programming knowledge. Finally, while we present a novel method of SER for mCRPC trials, one can also implement such semi-automated methods in other clinical trial domains to advance precision medicine.

show abstract

“…Prostate cancer is the most common malignancies and the second leading cause of cancer-associated mortality in men ( 1 ). Despite that androgen-deprivation therapy results in long-lasting responses, the disease inevitably progresses to metastatic castration-resistant prostate cancer (mCRPC) that is associated with poor prognosis ( 2 , 3 ). The proteasome is a validated target for cancer therapy.…”

Section: Introductionmentioning

confidence: 99%

miR-33b-3p Acts as a Tumor Suppressor by Targeting DOCK4 in Prostate Cancer

Zhang

et al. 2021

Front. Oncol.

View full text Add to dashboard Cite

Despite that androgen-deprivation therapy results in long-lasting responses, the disease inevitably progresses to metastatic castration-resistant prostate cancer. In this study, we identified miR-33b-3p as a tumor suppressor in prostate cancer. miR-33b-3p was significantly reduced in prostate cancer tissues, and the low expression of miR-33b-3p was correlated with poor overall survival of prostate cancer patients. Overexpression of miR-33b-3p inhibited both migration and invasion of highly metastatic prostate cancer cells whereas inhibition of miR-33b-3p promoted those processes in lowly metastatic cells. The in vivo results demonstrate that miR-33b-3p suppresses metastasis of tail vein inoculated prostate cancer cells to lung and lymph nodes in mice. DOCK4 was validated as the direct target of miR-33b-3p. miR-33b-3p decreased the expression of DOCK4 and restoration of DOCK4 could rescue miR-33b-3p inhibition on cell migration and invasion. Moreover, downregulation of miR-33b-3p was induced by bortezomib, the clinically used proteasome inhibitor, and overexpression of miR-33b-3p enhanced the insufficient inhibition of bortezomib on migration and invasion as well as metastasis of prostate cancer cells. In summary, our findings demonstrate that miR-33b-3p suppresses metastasis by targeting DOCK4 in prostate cancer. Our results suggest that enhancing miR-33b-3p expression may provide a promising therapeutic strategy for overcoming that proteasome inhibitor’s poor efficacy against metastatic prostate cancer.

show abstract

Therapeutic Potential of PARP Inhibitors in the Treatment of Metastatic Castration-Resistant Prostate Cancer

Cited by 17 publications

References 71 publications

Prognostic and Theranostic Applications of Positron Emission Tomography for a Personalized Approach to Metastatic Castration-Resistant Prostate Cancer

Prognostic and Theranostic Applications of Positron Emission Tomography for a Personalized Approach to Metastatic Castration-Resistant Prostate Cancer

Applications for open access normalized synthesis in metastatic prostate cancer trials

miR-33b-3p Acts as a Tumor Suppressor by Targeting DOCK4 in Prostate Cancer

Contact Info

Product

Resources

About