Reference Detail

Ref Type

Journal Article

PMID

(27486174)

Authors

Rebello RJ, Kusnadi E, Cameron DP, Pearson HB, Lesmana A, Devlin JR, Drygin D, Clark AK, Porter L, Pedersen J, Sandhu S, Risbridger GP, Pearson RB, Hannan RD, Furic L

Title

The Dual Inhibition of RNA Pol I Transcription and PIM Kinase as a New Therapeutic Approach to Treat Advanced Prostate Cancer.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	22	22	2016 Nov 15	5539-5552	Clin Cancer Res

URL

Abstract Text

The MYC oncogene is frequently overexpressed in prostate cancer. Upregulation of ribosome biogenesis and function is characteristic of MYC-driven tumors. In addition, PIM kinases activate MYC signaling and mRNA translation in prostate cancer and cooperate with MYC to accelerate tumorigenesis. Here, we investigate the efficacy of a single and dual approach targeting ribosome biogenesis and function to treat prostate cancer.The inhibition of ribosomal RNA (rRNA) synthesis with CX-5461, a potent, selective, and orally bioavailable inhibitor of RNA polymerase I (Pol I) transcription, has been successfully exploited therapeutically but only in models of hematologic malignancy. CX-5461 and CX-6258, a pan-PIM kinase inhibitor, were tested alone and in combination in prostate cancer cell lines, in Hi-MYC- and PTEN-deficient mouse models and in patient-derived xenografts (PDX) of metastatic tissue obtained from a patient with castration-resistant prostate cancer.CX-5461 inhibited anchorage-independent growth and induced cell-cycle arrest in prostate cancer cell lines at nanomolar concentrations. Oral administration of 50 mg/kg CX-5461 induced TP53 expression and activity and reduced proliferation (MKI67) and invasion (loss of ductal actin) in Hi-MYC tumors, but not in PTEN-null (low MYC) tumors. While 100 mg/kg CX-6258 showed limited effect alone, its combination with CX-5461 further suppressed proliferation and dramatically reduced large invasive lesions in both models. This rational combination strategy significantly inhibited proliferation and induced cell death in PDX of prostate cancer.Our results demonstrate preclinical efficacy of targeting the ribosome at multiple levels and provide a new approach for the treatment of prostate cancer. Clin Cancer Res; 22(22); 5539-52. ©2016 AACR.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
PTEN loss	prostate cancer	predicted - sensitive	CX-6258	Preclinical	Actionable	In a preclinical study, CX-6258 treatment resulted in decreased carcinoma in situ in PTEN deficient transgenic animal model of prostate cancer (PMID: 27486174).	27486174
PTEN loss	prostate cancer	no benefit	CX-5461	Preclinical	Actionable	In a preclinical study, CX-5461 treatment did not result in histological change in PTEN deficient transgenic animal model of prostate cancer (PMID: 27486174).	27486174
PTEN loss	prostate cancer	predicted - sensitive	CX-5461 + CX-6258	Preclinical	Actionable	In a preclinical study, CX-6258 and CX-5461 combination treatment resulted in decreased tumor burden in PTEN deficient transgenic animal model of prostate cancer (PMID: 27486174).	27486174