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Prostate Cancer
Published in Karl H. Pang, Nadir I. Osman, James W.F. Catto, Christopher R. Chapple, Basic Urological Sciences, 2021
Karl H. Pang, James W.F. Catto
ADT aims to lower/block androgen activity:Lowering testosteroneBilateral orchidectomy to remove testosterone-producing Leydig cells.GHRH agonist: downregulates GnRH receptors.GHRH antagonist: blocks GnRH receptors.CYP17A1 inhibitor (Abiraterone): inhibits androgen synthesis.Blocking androgen effectNon-steroidal anti-androgens (Bicalutamide): block androgen receptors.
Endocrine Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Other NSAAs are being developed at the time of writing. For example, proxalutamide is a close analog of enzalutamide (GT-0918), and is being developed by Suzhou Kintor Pharmaceuticals for the treatment of prostate cancer. It is reported to be more potent than bicalutamide and enzalutamide in inhibiting AR-mediated gene transcription, and to have low central nervous system penetration. Proxalutamide entered Phase II clinical trials for prostate cancer in 2017. Another NSAA, seviteronel (VT-464), has a novel structure unrelated to other NSAAs, and is being developed by Viamet Pharmaceuticals and Innocrin Pharmaceuticals for the treatment of prostate and breast cancer. It is a CYP17A1 inhibitor and works by inhibiting the biosynthesis of androgens and estrogens. Seviteronel entered Phase II clinical trials for both prostate cancer and breast cancer in 2017.
Introduction to Human Cytochrome P450 Superfamily
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
To date, there are seven crystal structures of CYP17A1 in the PDB in complex with an inhibitor or substrate (4NKZ, 4NKY, 4NKX, 4NKW, 4NKV, 3SWZ, and 3RUK). The structures in complex with either abiraterone or TOK-001 (another CYP17A1 inhibitor) were first reported in 2012 (DeVore and Scott 2012b). Both of these inhibitors bind the heme iron, forming a 60° angle above the heme plane and packing against the central I helix with the 3p-OH interacting with Asn202 in the F helix. Similar binding modes are observed with CYP17A1 substrates such as pregnenolone, progesterone, and 17α-hydroxypregnenolone (Petrunak et al. 2014). This binding mode differs substantially from those that are predicted by homology models and from steroids in other CYP enzymes with known structures, and some features of this binding mode are more similar to steroid receptors (DeVore and Scott 2012b). The overall structures of CYP17A1 provide a rationale for understanding many mutations that are associated with steroidogenic diseases, and the active site reveals multiple steric and hydrogen-bonding features that will facilitate a better understanding of the enzyme’s dual hydroxylase and lyase catalytic activities.
The dawn of targeted therapies for triple negative breast cancer (TNBC): a snapshot of investigational drugs in phase I and II trials
Published in Expert Opinion on Investigational Drugs, 2020
My-my Huynh, Mary Rose Pambid, Aarthi Jayanthan, Andrew Dorr, Gerrit Los, Sandra E. Dunn
AR+ TNBC represents a subgroup of cancers that have an even worse prognosis than AR- TNBC [63]. These AR+ cases fall into the luminal androgen receptor (LAR) molecular TNBC subtype, uniquely characterized by having high expression of genes in hormone regulated pathways [4]. Therefore, the AR inhibitor enzalutamide, which has been used successfully in castration resistant prostate cancer, is now being tested in an ongoing phase I trial (NCT02689427) in combination with paclitaxel as neoadjuvant therapy in AR+ TNBC. Another antiandrogen that has been successful in prostate cancer, bicalutamide, is in a phase II study in combination with ribociclib, a CDK4/6 inhibitor (NCT03090165). The modest response to treatment with antiandrogens alone has led to this combination, as it is hypothesized based on preclinical data in prostate cells, that CDK4/6 inhibition overcomes resistance mechanisms to antiandrogen therapy [64]. Other strategies for targeting the hormonal synthesis pathways in TNBC include several phase II trials testing orteronel, a nonsteroidal CYP17A1 inhibitor, that is important in androgen synthesis. These trials include orteronel, as a monotherapy in metastatic disease (NCT01990209) and in combination with enzalutamide in early stage TNBC (NCT02750358). This same combination is also being explored in advanced TNBC (NCT01889238).
Abiraterone acetate in combination with prednisone in the treatment of prostate cancer: safety and efficacy
Published in Expert Review of Anticancer Therapy, 2020
Cécile Manceau, Loic Mourey, Damien Pouessel, Guillaume Ploussard
The natural evolution of the metastatic prostate cancer is often marked by an initial response phase to abiraterone followed by relapsed disease progression in long-term patients and ultimately results in a disease non-responsive to abiraterone. However, some CRPC patients exhibit primary resistance where the commencement of AA treatment is not associated with decreasing PSA, other clinical and/or imaging progression. This phenomenon was reported in less than 10% of chemotherapy naïve patients with mCRPC [27] and less than 40% of patients with mCRPC after chemotherapy [8]. As resistance mechanisms to CYP17A1 inhibitor are still poorly understood, AR activity appears to be restored. Animal models, tumor biopsy mRNA or liquid biopsy of patients who had developed resistance to CYP17A1 inhibitor were studied. A few mechanisms were suspected; progesterone driven mutation, AR mutation, amplification, AR enhancer mutations, AR splice variants [37], AR activation by exogenous corticosteroids and steroids precursors upstream of CYP17A1, androgen biosynthesis pathway upregulation, glucocorticoids, and glucocorticoid receptor overexpression [3].
The addition of apalutamide to ADT in the treatment of metastatic castration-sensitive prostate cancer: safety and efficacy
Published in Expert Review of Anticancer Therapy, 2020
Pedro Barata, Umang Swami, Neeraj Agarwal
Subsequently, abiraterone acetate, an irreversible CYP17A1 inhibitor, which was already approved for mCRPC in pre and post-docetaxel setting [23,24], demonstrated significant improvement in overall survival and quality of life of patients with mCSPC, in LATITUDE and arm G of the STAMPEDE trials [7,8]. While LATITUDE trial only included patients with high-risk mCSPC defined as those with two of the following risk factors: Gleason ≥8; presence of ≥3 bone lesions; or visceral disease, in the STAMPEDE study, patients were not selected based on volume or risk status. Results of these two trials showed that the upfront use of abiraterone acetate in addition to ADT improved overall survival in all patients with mCSPC[25]. Of interest, the magnitude of benefit observed with abiraterone acetate was very similar to the one observed with upfront docetaxel and the optimal regimen of choice is a matter of debate, due to different toxicity profiles of both therapies, including duration of treatment, patient comorbidities, physicians' preferences, and financial constraints associated with an oral drug [26].