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

Rebello, Richard J.; Kusnadi, Eric; Cameron, Donald P.; Pearson, Helen; Lesmana, Analia; Devlin, Jennifer R.; Drygin, Denis; Clark, Ashlee K.; Porter, Laura H.; Pedersen, John; Sandhu, Shahneen; Risbridger, Gail P.; Pearson, Richard B.; Hannan, Ross D.; Furic, Luc

doi:10.1158/1078-0432.ccr-16-0124

Cited by 62 publications

(64 citation statements)

References 48 publications

(64 reference statements)

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“…The concept of a ceiling on the nuclear DNA/cytoplasm volume relationship is not unique to skeletal muscle and is actually a primary driver of cell division in mitotically active mononucleated cells. In fact, some current strategies in cancer-targeting therapeutics are focused on disrupting the protein synthetic machinery in cancer cells to limit cellular hypertrophy, thereby mitigating proliferation (Devlin et al 2016; Rebello et al 2016). …”

Section: Muscle Stem (Satellite) Cell Activitymentioning

confidence: 99%

Molecular Regulation of Exercise-Induced Muscle Fiber Hypertrophy

Bamman

Roberts

Adams

2017

Cold Spring Harb Perspect Med

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Skeletal muscle hypertrophy is a widely sought exercise adaptation to counteract the muscle atrophy of aging and disease, or to improve athletic performance. While this desired muscle enlargement is a well-known adaptation to resistance exercise training (RT), the mechanistic underpinnings are not fully understood. The purpose of this review is thus to provide the reader with a summary of recent advances in molecular mechanisms—based on the most current literature—that are thought to promote RT-induced muscle hypertrophy. We have therefore focused this discussion on the following areas of fertile investigation: ribosomal function and biogenesis, muscle stem (satellite) cell activity, transcriptional regulation, mechanotransduction, and myokine signaling.

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Section: Muscle Stem (Satellite) Cell Activitymentioning

confidence: 99%

Molecular Regulation of Exercise-Induced Muscle Fiber Hypertrophy

Bamman

Roberts

Adams

2017

Cold Spring Harb Perspect Med

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“…However, such studies are now being extended to various solid organ malignancies including metastatic/recurrent/locally advanced/unresectable triple negative breast cancer which is currently recruiting through the Canadian Cancer Trials group (NCT02719977). This is a logical extension as there is preliminary data for efficacy of CX-5461 in solid tumours, with pre-clinical data suggesting a role in prostate cancer[14]. Similarly, studies in PDAC cell lines have also shown promise[76], as documented by Drygin et al[76] using MIA PaCa-2 cell lines.…”

Section: Ribosome Biogenesismentioning

confidence: 97%

“…To this end, novel approaches that are non, or at least minimally genotoxic are of particular interest. The potential advantages observed with targeted therapies in reducing systemic side effects and improving outcomes for other malignancies have gained interest in the realm of PDAC and will be briefly discussed in this review with a particular focus on the emerging role of nucleolar stress pathway and ribosome biogenesis as a potential treatment option given its promising results in the management of haematological malignancies and prostate cancer[12-14]. …”

Section: Introductionmentioning

confidence: 99%

Advanced pancreatic ductal adenocarcinoma - Complexities of treatment and emerging therapeutic options

Diwakarla¹,

Hannan²,

Hein³

et al. 2017

WJG

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Pancreatic ductal adenocarcinoma is a devastating disease with a poor prognosis regardless of stage. To date the mainstay of therapy for advanced disease has been chemotherapy with little incremental improvements in outcome. Despite extensive research investigating new treatment options the current practices continue to utilise fluorouracil or gemcitabine containing combinations. The need for novel therapeutic approaches is mandated by the ongoing poor survival rates associated with this disease. One such approach may include manipulation of ribosome biogenesis and the nucleolar stress response, which has recently been applied to haematological malignancies such as lymphoma and prostate cancer with promising results. This review will focus on the current therapeutic options for pancreatic ductal adenocarcinoma and the complexities associated with developing novel treatments, with a particular emphasis on the role of the nucleolus as a treatment strategy.

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“…Recently, Rebello et al [167] reported the efficacy of a combination of RNA polymerase I (Rpol I) and proto-oncogene serine/threonine-protein (PIM) kinase inhibitors (CX-5461 and CX-6258) for MYC-driven prostate cancer. They showed that c-MYC is related to both Rpol I and PIM kinase activation, which were significantly inhibited by both drugs in Hi-MYC mice [167]. …”

Section: Development Of Novel Drugsmentioning

confidence: 99%

Crosstalk of the Androgen Receptor with Transcriptional Collaborators: Potential Therapeutic Targets for Castration-Resistant Prostate Cancer

Obinata

Takayama

Takahashi

et al. 2017

Cancers

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Prostate cancer is the second leading cause of death from cancer among males in Western countries. It is also the most commonly diagnosed male cancer in Japan. The progression of prostate cancer is mainly influenced by androgens and the androgen receptor (AR). Androgen deprivation therapy is an established therapy for advanced prostate cancer; however, prostate cancers frequently develop resistance to low testosterone levels and progress to the fatal stage called castration-resistant prostate cancer (CRPC). Surprisingly, AR and the AR signaling pathway are still activated in most CRPC cases. To overcome this problem, abiraterone acetate and enzalutamide were introduced for the treatment of CRPC. Despite the impact of these drugs on prolonged survival, CRPC acquires further resistance to keep the AR pathway activated. Functional molecular studies have shown that some of the AR collaborative transcription factors (TFs), including octamer transcription factor (OCT1), GATA binding protein 2 (GATA2) and forkhead box A1 (FOXA1), still stimulate AR activity in the castration-resistant state. Therefore, elucidating the crosstalk between the AR and collaborative TFs on the AR pathway is critical for developing new strategies for the treatment of CRPC. Recently, many compounds targeting this pathway have been developed for treating CRPC. In this review, we summarize the AR signaling pathway in terms of AR collaborators and focus on pyrrole-imidazole (PI) polyamide as a candidate compound for the treatment of prostate cancer.

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

Abstract: 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.

Cited by 62 publications

References 48 publications

Molecular Regulation of Exercise-Induced Muscle Fiber Hypertrophy

Molecular Regulation of Exercise-Induced Muscle Fiber Hypertrophy

Advanced pancreatic ductal adenocarcinoma - Complexities of treatment and emerging therapeutic options

Crosstalk of the Androgen Receptor with Transcriptional Collaborators: Potential Therapeutic Targets for Castration-Resistant Prostate Cancer

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