castrate resistant
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2022 ◽  
Vol 10 (1) ◽  
Author(s):  
Nikki L. Raftopulos ◽  
Tinashe C. Washaya ◽  
Andreas Niederprüm ◽  
Antonia Egert ◽  
Mariam F. Hakeem-Sanni ◽  
...  

Abstract Background Prostate cancer growth is driven by androgen receptor signaling, and advanced disease is initially treatable by depleting circulating androgens. However, prostate cancer cells inevitably adapt, resulting in disease relapse with incurable castrate-resistant prostate cancer. Androgen deprivation therapy has many side effects, including hypercholesterolemia, and more aggressive and castrate-resistant prostate cancers typically feature cellular accumulation of cholesterol stored in the form of cholesteryl esters. As cholesterol is a key substrate for de novo steroidogenesis in prostate cells, this study hypothesized that castrate-resistant/advanced prostate cancer cell growth is influenced by the availability of extracellular, low-density lipoprotein (LDL)-derived, cholesterol, which is coupled to intracellular cholesteryl ester homeostasis. Methods C4-2B and PC3 prostate cancer cells were cultured in media supplemented with fetal calf serum (FCS), charcoal-stripped FCS (CS-FCS), lipoprotein-deficient FCS (LPDS), or charcoal-stripped LPDS (CS-LPDS) and analyzed by a variety of biochemical techniques. Cell viability and proliferation were measured by MTT assay and Incucyte, respectively. Results Reducing lipoprotein availability led to a reduction in cholesteryl ester levels and cell growth in C4-2B and PC3 cells, with concomitant reductions in PI3K/mTOR and p38MAPK signaling. This reduced growth in LPDS-containing media was fully recovered by supplementation of exogenous low-density lipoprotein (LDL), but LDL only partially rescued growth of cells cultured with CS-LPDS. This growth pattern was not associated with changes in androgen receptor signaling but rather increased p38MAPK and MEK1/ERK/MSK1 activation. The ability of LDL supplementation to rescue cell growth required cholesterol esterification as well as cholesteryl ester hydrolysis activity. Further, growth of cells cultured in low androgen levels (CS-FCS) was suppressed when cholesteryl ester hydrolysis was inhibited. Conclusions Overall, these studies demonstrate that androgen-independent prostate cancer cell growth can be influenced by extracellular lipid levels and LDL-cholesterol availability and that uptake of extracellular cholesterol, through endocytosis of LDL-derived cholesterol and subsequent delivery and storage in the lipid droplet as cholesteryl esters, is required to support prostate cancer cell growth. This provides new insights into the relationship between extracellular cholesterol, intracellular cholesterol metabolism, and prostate cancer cell growth and the potential mechanisms linking hypercholesterolemia and more aggressive prostate cancer.


Cureus ◽  
2021 ◽  
Author(s):  
Syed Ehsanullah ◽  
Syeda Zarmeena Rashid ◽  
Saiyed Abdullah A Ehsanullah

2021 ◽  
Author(s):  
Jingsong Zhang ◽  
Jessica Cunningham ◽  
Joel Brown ◽  
Robert A Gatenby

Background We present a multidisciplinary approach to clinical trial design and analysis in a pilot study (NCT02415621) in which evolution-based mathematical models guide patient-specific dosing for Abiraterone treatment in men with castrate resistant metastatic prostate cancer. Methods Abiraterone plus prednisone were administered intermittently based on an evolutionary mathematical model. Outcomes are compared to historical controls and a matched contemporaneous cohort who met trial eligibility but received SOC dosing. Longitudinal cohort data allowed modification of pre-trial model parameter estimates. Model simulations of each patient using updated parameters critically evaluated trial design. Results Trial patients, on average, received no abiraterone during 59% of time on treatment. Median Time to Radiographic Progression (TTP) was 30.4 months compared to 14.3 months in the contemporaneous SOC group (p<0.001). All patients in the SOC group have progressed but 4 in the adaptive cohort remain on treatment at >1800 days. Longitudinal trial data found the competition coefficient ratio (αRS/αSR) of sensitive and resistant populations, a critical factor in intratumoral evolution, was 2 to 3-fold higher than pre-trial estimates. Computer simulations using the corrected parameter unexpectedly demonstrated optimal cycling can reduce the resistant cells. Longitudinal data from 4 trial patients who remain on treatment are consistent with model predictions. Modeling results predict protocol changes that will allow similar outcomes in most patients. Conclusions Administration of abiraterone using evolution-based mathematical models decreased drug dosing and increased radiographic TTP. Integration of mathematical models into trial design identifies novel insights into key treatment parameters and provides optimization strategies for follow-up investigations.


2021 ◽  
Vol 12 (8) ◽  
pp. S30
Author(s):  
M. Parthipan ◽  
N. Toledano ◽  
G. Feng ◽  
H. Breunis ◽  
U. Emmenegger ◽  
...  

Genes ◽  
2021 ◽  
Vol 12 (12) ◽  
pp. 1900
Author(s):  
Luiz Paulo Chaves ◽  
Camila Morais Melo ◽  
Fabiano Pinto Saggioro ◽  
Rodolfo Borges dos Reis ◽  
Jeremy Andrew Squire

Prostate cancers may reactivate a latent embryonic program called the epithelial–mesenchymal transition (EMT) during the development of metastatic disease. Through EMT, tumors can develop a mesenchymal phenotype similar to cancer stem cell traits that contributes to metastasis and variation in therapeutic responses. Some of the recurrent somatic mutations of prostate cancer affect EMT driver genes and effector transcription factors that induce the chromatin- and androgen-dependent epigenetic alterations that characterize castrate-resistant prostate cancer (CRPC). EMT regulators in prostate cancer comprise transcription factors (SNAI1/2, ZEB1, TWIST1, and ETS), tumor suppressor genes (RB1, PTEN, and TP53), and post-transcriptional regulators (miRNAs) that under the selective pressures of antiandrogen therapy can develop an androgen-independent metastatic phenotype. In prostate cancer mouse models of EMT, Slug expression, as well as WNT/β-Catenin and notch signaling pathways, have been shown to increase stemness potential. Recent single-cell transcriptomic studies also suggest that the stemness phenotype of advanced prostate cancer may be related to EMT. Other evidence correlates EMT and stemness with immune evasion, for example, activation of the polycomb repressor complex I, promoting EMT and stemness and cytokine secretion through RB1, TP53, and PRC1. These findings are helping clinical trials in CRPC that seek to understand how drugs and biomarkers related to the acquisition of EMT can improve drug response.


2021 ◽  
Vol 22 (22) ◽  
pp. 12095
Author(s):  
Kristin A. Plichta ◽  
Stephen A. Graves ◽  
John M. Buatti

Theranostics, a combination of therapy and diagnostics, is a field of personalized medicine involving the use of the same or similar radiopharmaceutical agents for the diagnosis and treatment of patients. Prostate-specific membrane antigen (PSMA) is a promising theranostic target for the treatment of prostate cancers. Diagnostic PSMA radiopharmaceuticals are currently used for staging and diagnosis of prostate cancers, and imaging can predict response to therapeutic PSMA radiopharmaceuticals. While mainly used in the setting of metastatic, castrate-resistant disease, clinical trials are investigating the use of PSMA-based therapy at earlier stages, including in hormone-sensitive or hormone-naïve prostate cancers, and in oligometastatic prostate cancers. This review explores the use of PSMA as a theranostic target and investigates the potential use of PSMA in earlier stage disease, including hormone-sensitive metastatic prostate cancer, and oligometastatic prostate cancer.


2021 ◽  
Vol 143 ◽  
pp. 112226
Author(s):  
Eric Zhuang ◽  
Edward Uchio ◽  
Michael Lilly ◽  
Xiaolin Zi ◽  
John P. Fruehauf

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