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Radionuclide-based Diagnosis and Therapy of Prostate Cancer
Published in Michael Ljungberg, Handbook of Nuclear Medicine and Molecular Imaging for Physicists, 2022
Sven-Erik Strand, Mohamed Altai, Joanna Strand, David Ulmert
The main problem with castrate-resistant PCa with metastatic spread is that conventional treatments with surgery, EBRT, or androgen deprivation treatments are ineffective. For example, novel agents’ abiraterone and enzalutamide provide limited survival benefits of only 3.9 and 4.8 months, respectively. Thus, the development of more effective therapies targeting metastases is needed.
Endocrine Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Abiraterone was discovered through research in the early 1990s led by Mike Jarman and colleagues at the Institute of Cancer Research (London, UK) to discover and develop new drug treatments for prostate cancer. A patent protecting the molecule was filed in 1993, and commercialization rights were assigned to (the then) British Technology Group (BTG) plc, a UK-based drug discovery company. BTG licensed abiraterone to Cougar Biotechnology which started development work, and Cougar was then acquired by Johnson & Johnson, which carried out the late-stage development work, and Janssen-Cilag (now part of the Johnson & Johnson Group) now markets the approved agent.
Basic Science and Molecular Oncology
Published in Manit Arya, Taimur T. Shah, Jas S. Kalsi, Herman S. Fernando, Iqbal S. Shergill, Asif Muneer, Hashim U. Ahmed, MCQs for the FRCS(Urol) and Postgraduate Urology Examinations, 2020
Paul Cleaveland, Vijay Sangar, Noel Clarke
Abiraterone inhibits CYP17 enzymes that are expressed in testicular, prostatic and adrenal tissues. The 17-alpha-hydroxylase component catalyses the conversion of pregnenolone and progesterone to their 17-alpha-hydroxy derivatives. 17,20-lyase catalyses the subsequent formation of dehydroepiandrosterone (DHEA) and androstenedione, which are androgens and precursors of testosterone. Abiraterone also acts as a partial AR antagonist.
Advances in adrenocortical carcinoma pharmacotherapy: what is the current state of the art?
Published in Expert Opinion on Pharmacotherapy, 2022
Valentina Cremaschi, Andrea Abate, Deborah Cosentini, Salvatore Grisanti, Elisa Rossini, Marta Laganà, Mariangela Tamburello, Antonella Turla, Sandra Sigala, Alfredo Berruti
Our group demonstrated an antitumor activity of abiraterone acetate, a drug currently in use in metastatic prostate cancer. Our preclinical in vitro and in vivo studies on ACC models indicated that the mechanism of abiraterone cytotoxic effect was the increase in intracellular progesterone concentrations [29,30], which could have an antineoplastic activity in ACC. This hypothesis was then validated by further studies demonstrating a direct cytotoxic effect of progesterone (alone or combined with mitotane) in different ACC cell models, expanding the experimental tools available to study at preclinical levels a phenotypically heterogenous disease such as ACC [31,32]. Interestingly, we demonstrated that progesterone was able to reduce the β-catenin nuclear translocation [31] in NCI-H295R cells that carry a β-catenin pathogenic mutation [33]. Moreover, on the basis of the detectable, albeit scarce, the presence of estrogen receptor β in different cellular models of ACC, we studied the combination of progesterone with the selective estrogen receptor modulator tamoxifen, which did not show superior cytotoxicity compared to progesterone alone [32]. These encouraging preclinical results of progesterone prompted us to design a randomized phase II clinical study aimed to explore the antitumor effect of the progestin analog megestrol acetate in ACC patients.
An up-to-date evaluation of abiraterone for the treatment of prostate cancer
Published in Expert Opinion on Pharmacotherapy, 2021
Jason Shpilsky, Julia Stevens, Glenn Bubley
Research on the role of abiraterone for the various settings of prostate cancer is ongoing, especially around sequencing of treatments. One multicenter open-label crossover trial sought to identify the most effective sequence of abiraterone and enzalutamide for mCRPC [31]. Patients who had not received prior treatment for their mCRPC (n = 202) were randomized to either abiraterone followed by enzalutamide upon progression (A→E) or enzalutamide followed by abiraterone (E→A). The primary endpoint was time to second PSA progression. A→E was associated with a longer median time to second PSA progression compared to the reverse sequence (19.3 vs 15.2 mos, HR 0.66, P = 0.036). This was driven by a lower PSA response to second-line abiraterone than to second-line enzalutamide (4% vs 36%, P < 0.001). Abiraterone appears to have poor effectiveness in patients who have progressed on an androgen receptor inhibitor such as enzalutamide, suggesting abiraterone should be considered for initial therapy.
Abiraterone acetate plus prednisone/prednisolone in hormone-sensitive and castration-resistant metastatic prostate cancer
Published in Expert Review of Precision Medicine and Drug Development, 2021
Jürgen E Gschwend, Kurt Miller
The outlook for patients with advanced CRPC has changed dramatically over the past years as drug development has shifted focus from standard chemotherapy to the rational development of targeted therapies based on a better understanding of the biology of disease progression. Since traditional ADT does not completely deplete intratumoral androgen synthesis or the expression of androgen receptor (AR) variants, one of the most successful targeted approaches to date is the inhibition of extragonadal and intratumoral androgen synthesis that contribute to prostate cancer growth. AA was the first anti-hormonal agent approved by the FDA designed to potently target both adrenal and tumor androgen production. With its distinct mode of action (CYP17 inhibition), abiraterone profoundly suppresses testosterone to lower levels than are generally seen with traditional AR blocking agents/antagonists [41].