Patient-derived Models of Abiraterone- and Enzalutamide-resistant Prostate Cancer Reveal Sensitivity to Ribosome-directed Therapy

Lawrence, Mitchell G.; Obinata, Daisuke; Sandhu, Shahneen; Selth, Luke A.; Wong, Stephen Q.; Porter, Laura H.; Lister, Natalie; Pook, David; Pezaro, Carmel; Goode, David; Rebello, Richard J.; Clark, Ashlee K.; Papargiris, Melissa; Gramberg, Jenna Van; Hanson, Adrienne R.; Banks, Patricia; Wang, Hong; Niranjan, Birunthi; Keerthikumar, Shivakumar; Hedwards, Shelley; Huglo, Alisee; Yang, Rendong; Henzler, Christine; Li, Yingming; López-Campos, Fernando; Castro, Elena; Toivanen, Roxanne; Azad, Arun; Bolton, Damien; Goad, Jeremy; Grummet, Jeremy; Harewood, Laurence; Kourambas, John; Lawrentschuk, Nathan; Moon, Daniel; Murphy, Declan; Sengupta, Shamik; Snow, Ross; Thorne, Heather; Mitchell, Catherine; Pedersen, John; Clouston, David; Norden, Sam; Ryan, Andrew; Dehm, Scott M.; Tilley, Wayne D.; Pearson, Richard B.; Hannan, Ross D.; Frydenberg, Mark; Furic, Luc; Taylor, Renea A.; Risbridger, Gail P.

doi:10.1016/j.eururo.2018.06.020

Cited by 92 publications

(148 citation statements)

References 46 publications

(61 reference statements)

Supporting

Mentioning

132

Contrasting

Unclassified

Order By: Relevance

“…Nine PDXs from the MURAL collection were cryopreserved, including the PDX used in the previous experiments. The cohort included three PDXs of castrate‐sensitive localized prostate cancer and six PDXs of metastatic CRPC growing in intact host mice supplemented with testosterone . Three of the CRPC PDXs were also serially passaged in castrated host mice (Table ).…”

Section: Resultsmentioning

confidence: 99%

“…Experiments with the MURAL cohort of PDXs were conducted according to animal ethics approval from Monash University (MARP/2014/085 and MARP/2018/087). Serially transplantable PDXs of localized and metastatic prostate cancer were established and characterized by MURAL, as previously reported . In brief, tumor tissue was implanted under the renal capsule of 6 to 8‐week‐old male non‐obese diabetic severe‐combined immune‐deficient gamma (NSG) mice.…”

Section: Methodsmentioning

confidence: 99%

“…This is evident by the low numbers of prostate cancer PDXs in international consortia, including the EurOPDX consortium, JAX Laboratories and BioMedical Research PDX encyclopedia, where prostate cancer PDXs constitute only 1% of the collection in some cases . To address this problem, academic groups developed a repertoire of serially transplantable PDX of prostate cancer, resulting in over 100 authenticated PDXs, including those from the Living Tumor Laboratory, the LuCaP series, the MD Anderson (MDA PCa) series, the Johns Hopkins University cohort, our recently published collection from the Melbourne Urological Research Alliance (MURAL), and others . The take rates for establishing these serially transplantable PDX were 10% to 40% and they often had long latency times of up to 12 months after initial grafting .…”

Section: Introductionmentioning

confidence: 99%

“…As the number of prostate cancer PDXs increases, the process of maintaining them becomes more laborious and time consuming. PDXs are often maintained by continually repassaging them into new host mice, which can be as often as every few weeks for fast growing tumors . Therefore, the ability to store PDXs through cryopreservation would decrease the workload of maintaining them.…”

Section: Introductionmentioning

confidence: 99%

“…Research Alliance (MURAL), and others. [4][5][6][7] The take rates for establishing these serially transplantable PDX were 10% to 40% and they often had long latency times of up to 12 months after initial grafting. 4 Therefore, given the difficulty in establishing serially transplantable PDXs, it is important to maximize their preservation and maintain them for ongoing prostate cancer research.…”

mentioning

confidence: 99%

See 4 more Smart Citations

Establishing a cryopreservation protocol for patient‐derived xenografts of prostate cancer

et al. 2019

Self Cite

View full text Add to dashboard Cite

Background Serially transplantable patient‐derived xenografts (PDXs) are invaluable preclinical models for studying tumor biology and evaluating therapeutic agents. As these models are challenging to establish from prostate cancer specimens, the ability to preserve them through cryopreservation has several advantages for ongoing research. Despite this, there is still uncertainty about the ability to cryopreserve PDXs of prostate cancer. This study compared three different cryopreservation protocols to identify a method that can be used to reproducibly cryopreserve a diverse cohort of prostate cancer PDX models. Methods One serially transplantable prostate cancer PDX from the Melbourne Urological Research Alliance cohort was used to compare three cryopreservation protocols: slow freezing in fetal calf serum (FCS) with 10% dimethyl sulfoxide (DMSO), FCS with 10% DMSO supplemented with the Rho‐associated kinase (ROCK) inhibitor Y‐27632 and vitrification. The efficiency of the slow freezing protocols was then assessed in 17 additional prostate cancer PDXs. Following cryopreservation, PDXs were re‐established in host mice that were either intact and supplemented with testosterone or castrated. Graft take rate, tumor growth, histological features, and transcriptome profiles before and after cryopreservation were compared. Results Slow freezing maintained the viability and histological features of prostate cancer PDXs, and the addition of a ROCK inhibitor increased their growth following cryopreservation. Using the slow freezing method, we re‐established 100% of PDXs grown in either testosterone‐supplemented or castrated host mice. Importantly, the long‐term tumor growth rate and transcriptome profile were maintained following cryopreservation. Conclusion This study has identified a protocol to reliably cryopreserve and re‐establish a diverse cohort of serially transplantable PDXs of prostate cancer. This study has the potential to significantly improve the practicality of maintaining PDX models. Cryopreservation may also increase the accessibility of these important resources and provide new opportunities for preclinical studies on a broader spectrum of prostate tumors.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Establishing a cryopreservation protocol for patient‐derived xenografts of prostate cancer

et al. 2019

Self Cite

View full text Add to dashboard Cite

show abstract

PIM protein kinases regulate the level of the long noncoding RNA H19 to control stem cell gene transcription and modulate tumor growth

et al. 2020

View full text Add to dashboard Cite

The proviral integration site for Moloney murine leukemia virus (PIM) serine/threonine kinases have an oncogenic and prosurvival role in hematological and solid cancers. However, the mechanism by which these kinases drive tumor growth has not been completely elucidated. To determine the genes controlled by these protein kinases, we carried out a microarray analysis in T‐cell acute lymphoblastic leukemia (T‐ALL) comparing early progenitor (ETP‐ALL) cell lines whose growth is driven by PIM kinases to more mature T‐ALL cells that have low PIM levels. This analysis demonstrated that the long noncoding RNA (lncRNA) H19 was associated with increased PIM levels in ETP‐ALL. Overexpression or knockdown of PIM in these T‐ALL cell lines controlled the level of H19 and regulated the methylation of the H19 promoter, suggesting a mechanism by which PIM controls H19 transcription. In these T‐ALL cells, the expression of PIM1 induced stem cell gene expression (SOX2, OCT‐4, and NANOG) through H19. Identical results were found in prostate cancer (PCa) cell lines where PIM kinases drive cancer growth, and both H19 and stem cell gene levels. Small molecule pan‐PIM inhibitors (PIM‐i) currently in clinical trials reduced H19 expression in both of these tumor types. Importantly, the knockdown of H19 blocked the ability of PIM to induce stem cell genes in T‐ALL cells, suggesting a novel signal transduction cascade. In PCa, increases in SOX2 levels have been shown to cause both resistance to the androgen deprivation therapy (ADT) and the induction of neuroendocrine PCa, a highly metastatic form of this disease. Treatment of PCa cells with a small molecule pan‐PIM‐i reduced stem cell gene transcription and enhanced ADT, while overexpression of H19 suppressed the ability of pan‐PIM‐i to regulate hormone blockade. Together, these results demonstrate that the PIM kinases control the level of lncRNA H19, which in turn modifies stem cell gene transcription regulating tumor growth.

show abstract

TAS3681, an androgen receptor antagonist, prevents drug resistance driven by aberrant androgen receptor signaling in prostate cancer

Yoshida,

Kajiwara,

Seki

et al. 2024

Molecular Oncology

View full text Add to dashboard Cite

Second‐generation androgen receptor (AR) signaling inhibitors (ARSIs), such as abiraterone and enzalutamide, prolong the life of patients with castration‐resistant prostate cancer (CRPC). However, patients receiving ARSIs ultimately develop resistance through various complex mechanisms, including AR mutations, constitutively active AR‐splice variants (AR‐Vs), and AR overexpression. Here, we characterized a novel AR pure antagonist, TAS3681, which inhibits AR transcriptional activity and downregulates AR‐full length (AR‐FL) and AR‐Vs. TAS3681 reduced the protein levels of AR‐FL and AR‐Vs including AR‐V7 in enzalutamide‐resistant cells (SAS MDV No. 3‐14), in vitro and in vivo, showing strong antitumor efficacy in an AR‐V7‐positive xenograft model. In AR‐overexpressing VCaP (prostate cancer) cells, conversely to enzalutamide, TAS3681 effectively suppressed cell proliferation and downregulated AR expression. Importantly, TAS3681 blocked the transcriptional activity of various mutant ARs, including mutations F877L/T878A and H875Y/T878A, which confer resistance to enzalutamide, and V716M and H875Y mutations, which confer resistance to darolutamide. Our results demonstrate that TAS3681 suppresses the reactivation of AR signaling, which causes resistance to ARSIs, via a newly identified mechanism of action. Therefore, TAS3681 could be a new therapeutic option for CRPC treatment.

show abstract

Patient-derived Models of Abiraterone- and Enzalutamide-resistant Prostate Cancer Reveal Sensitivity to Ribosome-directed Therapy

Abstract: Diverse types of therapy-resistant prostate cancers are sensitive to a new combination of drugs that inhibit protein synthesis pathways in cancer cells.

Cited by 92 publications

References 46 publications

Establishing a cryopreservation protocol for patient‐derived xenografts of prostate cancer

Establishing a cryopreservation protocol for patient‐derived xenografts of prostate cancer

PIM protein kinases regulate the level of the long noncoding RNA H19 to control stem cell gene transcription and modulate tumor growth

TAS3681, an androgen receptor antagonist, prevents drug resistance driven by aberrant androgen receptor signaling in prostate cancer

Contact Info

Product

Resources

About