Dual-mTOR Inhibitor Rapalink-1 Reduces Prostate Cancer Patient-Derived Xenograft Growth and Alters Tumor Heterogeneity.

La Manna, Federico; De Menna, Marta; Patel, Nikhil; Karkampouna, Sofia; De Filippo, Maria; Klima, Irena; Kloen, Peter; Beimers, Lijkele; Thalmann, George N.; Pelger, Rob C M; Jacinto, Estela; Kruithof-de Julio, Marianna (2020). Dual-mTOR Inhibitor Rapalink-1 Reduces Prostate Cancer Patient-Derived Xenograft Growth and Alters Tumor Heterogeneity. Frontiers in oncology, 10(1012), p. 1012. Frontiers Research Foundation 10.3389/fonc.2020.01012

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Bone metastasis is the leading cause of prostate cancer (PCa) mortality, frequently marking the progression to castration-resistant PCa. Dysregulation of the androgen receptor pathway is a common feature of castration-resistant PCa, frequently appearing in association with mTOR pathway deregulations. Advanced PCa is also characterized by increased tumor heterogeneity and cancer stem cell (CSC) frequency. CSC-targeted therapy is currently being explored in advanced PCa, with the aim of reducing cancer clonal divergence and preventing disease progression. In this study, we compared the molecular pathways enriched in a set of bone metastasis from breast and prostate cancer from snap-frozen tissue. To further model PCa drug resistance mechanisms, we used two patient-derived xenografts (PDX) models of bone-metastatic PCa, BM18, and LAPC9. We developed in vitro organoids assay and ex vivo tumor slice drug assays to investigate the effects of mTOR- and CSC-targeting compounds. We found that both PDXs could be effectively targeted by treatment with the bivalent mTORC1/2 inhibitor Rapalink-1. Exposure of LAPC9 to Rapalink-1 but not to the CSC-targeting drug disulfiram blocked mTORC1/2 signaling, diminished expression of metabolic enzymes involved in glutamine and lipid metabolism and reduced the fraction of CD44+ and ALDEFluorhigh cells, in vitro. Mice treated with Rapalink-1 showed a significantly delayed tumor growth compared to control and cells recovered from the tumors of treated animals showed a marked decrease of CD44 expression. Taken together these results highlight the increased dependence of advanced PCa on the mTOR pathway, supporting the development of a targeted approach for advanced, bone metastatic PCa.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Urologie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Urologie

04 Faculty of Medicine > Department of Dermatology, Urology, Rheumatology, Nephrology, Osteoporosis (DURN) > Clinic of Urology

UniBE Contributor:

La Manna, Federico; De Menna, Marta; Karkampouna, Sofia; De Filippo, Maria Rosaria; Klima, Irena; Thalmann, George and Kruithof-de Julio, Marianna

Subjects:

600 Technology > 610 Medicine & health

ISSN:

2234-943X

Publisher:

Frontiers Research Foundation

Language:

English

Submitter:

Jeannine Wiemann

Date Deposited:

04 Aug 2020 08:21

Last Modified:

09 Aug 2020 02:43

Publisher DOI:

10.3389/fonc.2020.01012

PubMed ID:

32656088

Uncontrolled Keywords:

ALDH PDX bone metastasis disulfiram mTOR prostate cancer

BORIS DOI:

10.7892/boris.145534

URI:

https://boris.unibe.ch/id/eprint/145534

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