Anti-androgen therapy is commonly used to treat patients with advanced prostate cancer at stages where the disease has spread to the bones.
However, new research reveals that anti-androgen treatment can actually facilitate prostate cancer cells to adapt and grow in the bone tumor microenvironment model, which has been developed by QUT biomedical scientists led by Dr Nathalie Bock.
Dr. Bock, under the mentorship of Distinguished Professor Dietmar Hutmacher, from QUT Centre for Biomedical Technologies, has focused her research on bone metastases from breast and prostate cancers.
She developed 3-D miniature bone-like tissue models in which 3-D printed biomimetic scaffolds are seeded with patient-derived bone cells and tumor cells to be used as clinical and preclinical drug testing tools.
The research team investigated their hypothesis that traditional anti-androgen therapy had limited effect in the microenvironment of prostate cancer bone tumors. The team’s findings are published in Science Advances.
“We wanted to see if the therapy could be a contributor of cancer cells’ adaptive responses that fuelled bone metastasis,” Professor Hutmacher said.
“We developed an all-human, microtissue-engineered model of metastatic tissue using human bone-forming cells, prostate cancer cells and 3-D printing.”
Cancer biologist Distinguished Professor Judith Clements said the team bioengineered the microenvironment of a bone tumor to assess the effects of two clinically routinely used anti-androgen therapies—enzalutamide and bicalutamide—on the tumor cells.
“We found that the interactions between the cancer cells, the bone and the anti-androgens significantly impacted the progress of cancer in the mineralised microenvironment of bone tumors,” Professor Clements said.
“This means that the efficacy of these therapies is compromised in the presence of the bone microenvironment.”
Professor Hutmacher said an important outcome of the study was the need to upscale the bone tumor microenvironment model platform and make it available to other research groups.
“This would enable the prostate cancer research community to develop therapies for a more effective treatment of advanced prostate cancer.”
In future, Dr. Bock will use her model with patient-derived cells from patients undergoing prostatectomy, so that it could be used as a personalized preclinical diagnostic and drug testing tool.
“By screening existing and novel drugs using the bone tumor model in the laboratory, doctors will be able to treat individual patients with an anti-cancer therapy that can best suit their clinical need,” Dr. Bock said.
“This has the potential to considerably improve the quality of life of patients, because patients will not have to trial a succession of drugs, each of which carry the potential of severe side-effects, and which may not work for them.”
This research was supported by the National Health & Medical Research Council of Australia, Australian Research Council and the Prostate Cancer Foundation of Australia.
Prostate Cancer Foundation of Australia CEO Professor Jeff Dunn AO said the findings were significant.
“This is an important discovery that will help us to better target treatments for men with different types of prostate cancer,” he said.
“The findings also demonstrate the importance of ongoing research to improve our understanding of how different treatments impact disease progression and spread.
“Notably, Australia has one of the highest incidence rates of prostate cancer internationally, with 1 in every 6 Australian men likely to be diagnosed during their lifetime and around 17,000 men diagnosed each year.
“While survival rates for prostate cancer are high, with over 95% of men likely to survive at least five years, we must keep up the pace of work to find curative treatments, especially for advanced disease in the bone.
“There can be no doubt that this research will build on previous discoveries to help us save lives by stopping cancer from spreading and claiming the lives of more than 3,000 men a year, as is currently the case.
“We commend the research team and congratulate PCFA grant recipient Dr. Nathalie Bock for her research achievements.
“This is Australian research excellence at its finest,” he said.
Prostate cancer (PCa) is the most common non-cutaneous cancer among men. Although it is slow growing, often with no symptoms and being highly treatable in early stages, the American Cancer Society predicts in 2020 that there will be around 33,000 deaths due to PCa . Most of these deaths occur from advanced forms of PCa called castration-resistant PCa (CRPC).
CRPC can be metastatic (mCRPC) or non-metastatic CRPC (nmCRPC), which grows aggressively and results in shorter overall survival (OS). Treatment for early PCa includes attempts at curative therapies such surgery, cryotherapy, proton therapy, and/or radiation therapy, sometimes followed by adjuvant pharmacotherapy in high-risk patients such as chemotherapy, androgen-deprivation therapy (ADT), and/or hormone therapies.
However, when curative and adjuvant therapies fail, as judged by rising prostate-specific antigen (PSA) levels or metastasis, currently available hormone therapies (various forms of indirect or direct androgen receptor (AR) antagonism) are employed to delay progression of (but cannot cure) PCa.
More than 90% of the early stage PCas are primarily dependent on the androgens, namely, testosterone (1) and dihydrotestosterone (DHT) (2) (Figure 1), for growth . Androgenic hormones bind to the AR, a member of the hormone receptor family of ligand-activated transcription factors, in the cytoplasm and promote translocation of the AR into the nucleus.
In the nucleus, the AR binds to DNA regions called androgen response elements (AREs), which are palindromic sequences, recruits cofactors, and general transcription machinery, and that promote transcription and translation of the target genes . AR is the primary therapeutic target in PCa and CRPC [4,5]. Although the early stage PCa is AR-driven in more than 90% of the cases, this percentage decreases in later stages of CRPC and mCRPC, where still around 70–80% of the cases require AR for growth [2,6,7]. Still, this is considered as a high percentage reliant on a single therapeutic target, and hence the preponderance of therapeutic modalities target antagonism of the AR axis.
Resistance to ADT such as gonadotropin-releasing hormone agonist or antagonist (or alternatively surgical castration) results in progression to CRPC. Subsequent or concomitant resistance to AR blocking agents such as the androgen synthesis inhibitor; abiraterone; and/or antiandrogens such enzalutamide (3), apalutamide (4), or darolutamide is inevitable.
Several mechanisms have been attributed to these resistances including overexpression of the AR, mutations in the AR ligand-binding domain (LBD), loss of AR (neuroendocrine PCa), constitutively active AR splice variants (AR-SVs), increase in intratumoral hormonal synthesis, and activation of growth factor pathways .
Over time, as the AR milieu present in the PCa becomes complex and heterogeneous, patients become refractory to AR blocking agents . The AR-SVs have emerged as critical players in the development and progression of mCRPCs. Among AR-SVs identified to date, AR-V7, also known as AR3, is one of the most abundant and frequently found forms in both PCa cell lines and human prostate tumors .
Notably, the lack of LBD indicates that all Food and Drug Administration (FDA)-approved AR blocking agents will have no efficacy in inhibiting AR-SVs. Genomic events leading to AR-SV expression could act as novel biomarkers of disease progression that may guide the optimal use of current and next-generation AR-targeted therapy .
Endocrine therapy-resistant PCa cells generated by chronic treatment with 3 or abiraterone showed enhanced AR-V7 protein expression [11,12]. Knockdown of AR-V7 by small interfering RNA (siRNA) in abiraterone-resistant CWR22Rv1 and C4-2B enzalutamide (MDV3100)-resistant (MDVR) cells restored their sensitivity to abiraterone, indicating that AR-V7 is involved in abiraterone resistance. Moreover, an FDA-approved anthelminthic drug, niclosamide (5) , has been previously identified as a potent inhibitor of AR-V7, re-sensitizes resistant cells to 3 or abiraterone treatment in vitro and in vivo [13,14].
Future Antiandrogen Design and Screening Paradigms
Thus far, all approved antiandrogens are competitive HBP ligands that function by denying access of endogenous androgens to the HBP pocket. As discussed above, this approach seems limited in view of the extreme complexity and highly regulated nature of AR biology and the known resistance mechanisms that these agents elicit. AR agonist activity requires a functional LBD to bind agonist and induce the N/C global conformation, homodimerize, and translocate to the nucleus to recruit coregulatory proteins to either AF-1 or AF-2, and this is further modulated by growth regulatory kinase signaling cascades.
The complexity provides multiple points to interfere with AR activity without resorting to blocking HBP binding, and early attempts to explore non-competitive direct-acting AR inhibitors that bind to novel sites of action are discussed above; however, no non-competitive antagonist has been successfully trialed. Further, some LBD (competitive ligands) or NTD-binding AR ligands also have the ability to degrade AR-FL or AR-SV, providing additional advantages in AR axis suppression over traditional canonical antiandrogens.
The field of noncanonical inhibitors and SARDs have exerted AR antagonism profiles commensurate in scope to the function of the site blocked , but are thus far limited by binding affinity and/or absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties.
The molecular structure details of full-length AR in its global agonist and antagonist conformations are not available, and AR biology, in many ways, is still poorly understood. This complexity and still emerging molecular basis of AR biology presents an opportunity for medicinal chemists willing to target nonconventional binding sites. In conclusion, the field of AR-targeted therapeutics to treat advanced PCa is entering a very exciting decade and the patients will see more mechanistically advanced drugs in the market that will provide them extended benefits.
reference link : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7924596/
More information: Nathalie Bock et al, In vitro engineering of a bone metastases model allows for study of the effects of antiandrogen therapies in advanced prostate cancer, Science Advances (2021). DOI: 10.1126/sciadv.abg2564