The future of prostate cancer precision medicine: anti-ERG therapies
Editorial

The future of prostate cancer precision medicine: anti-ERG therapies

Mani Roshan-Moniri, Michael Hsing, Paul S. Rennie, Artem Cherkasov, Michael E. Cox

Vancouver Prostate Centre and the Department of Urologic Sciences, University of British Columbia, Vancouver, Canada

Correspondence to: Michael E. Cox. Vancouver Prostate Centre and the Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia V6H 3Z6, Canada. Email: mcox@prostatecentre.com; Artem Cherkasov. Vancouver Prostate Centre and the Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia V6H 3Z6, Canada. Email: acherkasov@prostatecentre.com.

Comment on: Wang X, Qiao Y, Asangani IA, et al. Development of Peptidomimetic Inhibitors of the ERG Gene Fusion Product in Prostate Cancer. Cancer Cell 2017;31:532-548.e7.


Submitted Aug 11, 2017. Accepted for publication Aug 14, 2017.

doi: 10.21037/tcr.2017.08.30


Prostate cancer (PCa), the most common, non-cutaneous male malignancy (1), is primarily driven by androgen signaling. Thus, clinical management of the disseminated disease is dominated by ever-improving androgen receptor (AR) pathway inhibitors (ARPIs) that have contributed to 30–40% decline in disease-specific mortality observed over the last two decades (2). Nonetheless nearly all ARPI therapy patients eventually develop resistance to these agents (2,3), calling for the development of novel targeted therapeutics for additional molecular lesions in PCa.

Although confounded by disease heterogeneity, PCas harbor a number of specific genomic alterations linked to the disease occurrence, progression, and outcome (1,3,4). Some of the most prevalent lesions correlated with metastatic castration-resistant PCa (mCRPC) include: AR overexpression and mutations, loss/mutations of key tumor suppressors [including TP53, RB and phosphatase tensin homologue (PTEN) among others], and prominent gene fusions that direct aberrant expression of members of the E26 transformation-specific (ETS) family, such as TMPRSS2-ERG (5,6). These fusion events have been observed in approximately half of PCas, and represent the most common PCa-associated abnormality documented to date (7).

ERG is one of several members of the ETS transcription factor family known to have oncogenic potential (8,9) and the fusion of androgen-responsive elements of TMPRSS2 with open reading frame sequences of ERG (TMPRSS2-ERG) directs aberrant AR-driven ERG expression (1). It is broadly accepted that TMPRSS2-ERG rearrangements represent early events in PCa initiation and are strongly associated with higher Gleason score, aggressive disease, and poor prognosis due to activation of aberrant ERG-driven transcriptional programs that promote migration, invasion and epithelial-mesenchymal transition (10). Importantly, ERG expression has been shown to persist during disease progression and to regulate taxane sensitivity in PCa. Thus, it is expected that therapeutic targeting of ERG could have immense clinical significance (11).

While TMPRSS2-ERG diagnostic and prognostic methods undergo very active development, there are yet no approved ERG-directed therapeutics. The absence of agents targeting any ETS factors makes developing therapeutics targeting these major oncoproteins a critical step towards new therapeutics for PCa and other ETS factor-driven malignancies. With urine tests available to detect the TMPRSS2-ERG fusion event (12,13), the development of ERG-targeted drugs would offer a specific ‘precision medicine’ approach for PCa patients. Here we discuss the recent report by Wang et al. “Development of Peptidomimetic Inhibitors of the ERG Gene Fusion Product in Prostate Cancer” (14), and that effort to develop such needed ERG-targeted therapy.

Using a phage display random peptide library screen, Wang et al. identified ERG inhibitory peptides (EIP) that bound directly to the DNA binding (ETS)-domain of ERG and disrupt ERG-ETS domain/DNA interactions. Mutagenesis of the ETS domain and peptides demonstrated reciprocal requirements for the selective affinity. Furthermore, cell permeable peptides prepared via conjugation of HIV-TAT sequence to EIPs retained ERG-ETS affinity, exhibited nuclear co-localization with ERG, and blocked invasive properties of ERG-expressing PCa models. While retro-inverso (RI) EIP versions exhibited no significant effect on angiogenesis in several models, they promoted ERG degradation, decreased ERG target gene expression, offered improved stability when delivered via intraperitoneal administration, and demonstrated inhibition of tumor growth and metastasis.

The results of this study represent a significant step towards the development of an ERG-targeted therapeutic and bolster the ever-increasing recognition of the importance of persistent ERG expression in TMPRSS2-ERG PCas. The lack of overt murine toxicity of the developed candidates is encouraging; however, there is a need to characterize the affinity of these peptides with other ETS family members since these genes are involved in maintenance and oncogenesis in several tissue types and target selective peptidomimetic agents would undoubtedly be of value. The details of molecular interactions between the developed EIPs and ERG-ETS target as well as the specifics of the competition with DNA binding remain to be described. For the latter, as for any mutational efficacy study, the lack of observed activity in the binding assay needs to be considered with respect to differential domain folding, or indirect allosteric changes to the protein structure. Finally, ERG is a key regulator of fate determination and differentiation of several tissues, including chondrogenesis (15), hematopoiesis (10) and, as tested by Wang et al., endothelial development. It is perplexing that a potent ERG antagonist would not exhibit an impact on the array of angiogenic assays performed.

As has been previously reviewed (16,17), peptidomimetics have several advantages and disadvantages in their use as therapeutic agents. While complexity of peptide-based therapeutics affords their high target affinity and specificity, as well as generally low side effect and toxicity, the important issues of tissue accumulation of the corresponding drug candidates, their metabolic stability and solubility, membrane permeability and delivery obstacles, along with rapid clearance and high cost of development, represent well-known drawbacks for their clinical development (16). With that being said, it is important to stipulate that the use of peptides as ERG-directed therapeutic agents represents an exciting avenue for PCa treatment and that result by Wang et al. provide an important stepping stone for overcoming limitations associated with the use of peptides as therapeutic agents.

On another hand, it should also be noted that there are concurrent efforts to develop small molecule ERG antagonists as a more clinically viable alternative for peptide-based agents. The first reported small molecule ERG inhibitor YK-4-279 was initially discovered as an antagonist for FLI1 protein, a close homologue of ERG and a known oncotarget implicated in Ewing’s sarcoma (18-21). The pre-clinical development of its derivative TK216 is currently in phase 1 trial (ClinicalTrials.gov Identifier: NCT02657005) (22) that is expected to significantly impact the future development of ETS targeted therapies.

Other recent efforts to directly target ERG protein with small molecules include rational computer-aided discovery of a compound VPC-18005. It has been shown that this compound directly binds the ERG-ETS domain and suppresses ERG transcriptional activity at low micromolar concentrations, while it is also capable of suppressing metastatic potential of ERG-expressing PCa cells (23). Other small molecules include ERGi-USU, a small molecule that can selectively suppress growth of ERG-expressing cancer cells (24), and heterocyclic dithiophene diamidines that target the ETS consensus DNA motif to block ERG-DNA interactions (25).

To conclude, it is important to outline, that therapeutic targeting of ERG, as well as other oncogenic ETS family members represents a promising avenue for the development of novel precision oncology strategies. It is anticipated that an entirely novel class of ERG inhibitors (whether peptide- or small molecule-based) are urgently needed and can be used as alternative or complimentary agents for the current ARPIs and chemotherapeutics to treat PCa even in its most deadly resistant and metastatic form.


Acknowledgments

Funding: This work was support provided by Terry Fox New Frontiers Program Project Grant (#1062), and Canadian Institute of Health Research Project Grant (CIHR #364578) to ME Cox, Prostate Cancer Foundation of British Columbia Grant-in-Aid Award, and CIHR Banting and Best Doctoral Fellowship (#347940) to M Roshan-Moniri.


Footnote

Provenance and Peer Review: This article was commissioned and reviewed by the Section Editor Peng Zhang (Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, China).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tcr.2017.08.30). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.


References

  1. Cancer Genome Atlas Research Network. The Molecular Taxonomy of Primary Prostate Cancer. Cell 2015;163:1011-25. [Crossref] [PubMed]
  2. Chang AJ, Autio KA, Roach M 3rd, et al. High-risk prostate cancer-classification and therapy. Nat Rev Clin Oncol 2014;11:308-23. [Crossref] [PubMed]
  3. Robinson D, Van Allen EM, Wu YM, et al. Integrative clinical genomics of advanced prostate cancer. Cell 2015;161:1215-28. [Crossref] [PubMed]
  4. Yadav SS, Li J, Lavery HJ, et al. Next-generation sequencing technology in prostate cancer diagnosis, prognosis, and personalized treatment. Urol Oncol 2015;33:267.e1-13. [Crossref] [PubMed]
  5. Narod SA, Seth A, Nam R. Fusion in the ETS gene family and prostate cancer. Br J Cancer 2008;99:847-51. [Crossref] [PubMed]
  6. Seth A, Watson DK. ETS transcription factors and their emerging roles in human cancer. Eur J Cancer 2005;41:2462-78. [Crossref] [PubMed]
  7. Tomlins SA, Rhodes DR, Perner S, et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 2005;310:644-8. [Crossref] [PubMed]
  8. Lawlor ER, Sorensen PH. Twenty Years on: What Do We Really Know about Ewing Sarcoma and What Is the Path Forward? Crit Rev Oncog 2015;20:155-71. [Crossref] [PubMed]
  9. Sizemore GM, Pitarresi JR, Balakrishnan S, et al. The ETS family of oncogenic transcription factors in solid tumours. Nat Rev Cancer 2017;17:337-51. [Crossref] [PubMed]
  10. Adamo P, Ladomery MR. The oncogene ERG: a key factor in prostate cancer. Oncogene 2016;35:403-14. [Crossref] [PubMed]
  11. Galletti G, Matov A, Beltran H, et al. ERG induces taxane resistance in castration-resistant prostate cancer. Nat Commun 2014;5:5548. [Crossref] [PubMed]
  12. Sanguedolce F, Cormio A, Brunelli M, et al. Urine TMPRSS2: ERG Fusion Transcript as a Biomarker for Prostate Cancer: Literature Review. Clin Genitourin Cancer 2016;14:117-21. [Crossref] [PubMed]
  13. Tomlins SA, Day JR, Lonigro RJ, et al. Urine TMPRSS2:ERG Plus PCA3 for Individualized Prostate Cancer Risk Assessment. Eur Urol 2016;70:45-53. [Crossref] [PubMed]
  14. Wang X, Qiao Y, Asangani IA, et al. Development of Peptidomimetic Inhibitors of the ERG Gene Fusion Product in Prostate Cancer. Cancer Cell 2017;31:532-548.e7. [Crossref] [PubMed]
  15. Flajollet S, Tian TV, Huot L, et al. Increased adipogenesis in cultured embryonic chondrocytes and in adult bone marrow of dominant negative Erg transgenic mice. PLoS One 2012;7:e48656 [Crossref] [PubMed]
  16. Marqus S, Pirogova E, Piva TJ. Evaluation of the use of therapeutic peptides for cancer treatment. J Biomed Sci 2017;24:21. [Crossref] [PubMed]
  17. Craik DJ, Fairlie DP, Liras S, et al. The future of peptide-based drugs. Chem Biol Drug Des 2013;81:136-47. [Crossref] [PubMed]
  18. Winters B, Brown L, Coleman I, et al. Inhibition of ERG Activity in Patient-derived Prostate Cancer Xenografts by YK-4-279. Anticancer Res 2017;37:3385-96. [PubMed]
  19. Rahim S, Minas T, Hong SH, et al. A small molecule inhibitor of ETV1, YK-4-279, prevents prostate cancer growth and metastasis in a mouse xenograft model. PLoS One 2014;9:e114260 [Crossref] [PubMed]
  20. Rahim S, Beauchamp EM, Kong Y, et al. YK-4-279 inhibits ERG and ETV1 mediated prostate cancer cell invasion. PLoS One 2011;6:e19343 [Crossref] [PubMed]
  21. Erkizan HV, Kong Y, Merchant M, et al. A small molecule blocking oncogenic protein EWS-FLI1 interaction with RNA helicase A inhibits growth of Ewing's sarcoma. Nat Med 2009;15:750-6. [Crossref] [PubMed]
  22. TK216 in Patients With Relapsed or Refractory Ewing Sarcoma. Bethesda (MD): National Library of Medicine (US). 2016. Available online: https://clinicaltrials.gov/ct2/show/study/NCT02657005
  23. Butler MS, Roshan-Moniri M, Hsing M, et al. Discovery and characterization of small molecules targeting the DNA-binding ETS domain of ERG in prostate cancer. Oncotarget 2017;8:42438-54. [PubMed]
  24. Mohamed AA, Xavier CP, Sukumar G, et al. Abstract 1183: Structure-activity studies and biological evaluations of ERGi-USU, a highly selective inhibitor for ERG-positive prostate cancer cells. Cancer Res 2017;77:Abstract nr 1183.
  25. Nhili R, Peixoto P, Depauw S, et al. Targeting the DNA-binding activity of the human ERG transcription factor using new heterocyclic dithiophene diamidines. Nucleic Acids Res 2013;41:125-38. [Crossref] [PubMed]
Cite this article as: Roshan-Moniri M, Hsing M, Rennie PS, Cherkasov A, Cox ME. The future of prostate cancer precision medicine: anti-ERG therapies. Transl Cancer Res 2017;6(Suppl 7):S1136-S1138. doi: 10.21037/tcr.2017.08.30

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