Short Communication

Lessons from Targeting the Endothelin Axis in Myeloma and Prostate Cancer

Panagiotis J Vlachostergios1*, Christos N Papandreou2
1Division of Hematology and Medical Oncology, Weill Cornell Medicine, USA
2Department of Medical Oncology, Faculty of Medicine, Aristotle University of Thessaloniki, Greece


*Corresponding author: Panagiotis J. Vlachostergios, Division of Hematology and Medical Oncology, Weill Cornell Medicine, Meyer Cancer Center, New York, USA

Published: 18 Feb, 2018
Cite this article as: Vlachostergios PJ, Papandreou CN. Lessons from Targeting the Endothelin Axis in Myeloma and Prostate Cancer. Clin Oncol. 2018; 3: 1412.

Short Communication

Endothelin (ET) and other neuropeptides are potent mitogens for both benign and malignant cells through G-protein receptor binding and signal transduction [1]. Aberrant expression of several components of the endothelin axis, including Endothelin (ET) and its receptors, ET-A and ETB is found in different tumors types, including Prostate Cancer (PC) [1]. Evidence of increased paracrine and autocrine signaling through the endothelin axis in PC cells has triggered clinical testing of endothelin receptor inhibitors. However, lack of clinical benefit has prevented further development of this approach [2-5]. At the cellular level, we previously reported ET-induced upregulation of proteasome activity and associated proliferative and antiapoptotic effects in androgen-independent PC cells [6]. These effects were reversed with the use of the proteasome inhibitor bortezomib [7]. However, bortezomib failed to demonstrate clinical activity in prostate cancer patients, therefore its clinical use for inhibiting the endothelin axis could not be supported in that setting [8-11].
Nevertheless, in Multiple Myeloma (MM) bortezomib is a very active drug and often consists the backbone for most myeloma treatment regimens [12-14]. We have previously revealed the over expression of ET-B in MM mediating resistance to bortezomib via upregulation of proteasome activity and resultant MAPK pathway activation [15].
In their recent work, published in the British Journal of Haematology, Russignan et al [16]. further complemented these findings by reporting ET-B over expression in human malignant plasma cells compared to healthy donors. Moreover, the addition of an ET receptor antagonist to bortezomib enhanced the cytotoxic effect on myeloma cells [15,16].
In conclusion, the rational for ET receptor antagonism in myeloma has been documented. Therefore, design and conduction of a clinical trial combining bortezomib and a non-selective ET receptor antagonist, for example bosentan, or a selective ETB receptor antagonist, appears to be a reasonable next step and holds promise for further improving outcomes of MM patients.


References

  1. Bagnato A, Loizidou M, Pflug BR, Curwen J, Growcott J. Role of the endothelin axis and its antagonists in the treatment of cancer. Br J Pharmacol. 2011;163(2):220-33.
  2. Qi P, Chen M, Zhang LX, Song RX, He ZH, Wang ZP. A Meta-Analysis and Indirect Comparison of Endothelin A Receptor Antagonist for Castration-Resistant Prostate Cancer. PLoS One. 2015;10(7):e0133803.
  3. Quinn DI, Tangen CM, Hussain M, Lara PN, Goldkorn A, Moinpour CM. Docetaxel and atrasentan versus docetaxel and placebo for men with advanced castration-resistant prostate cancer (SWOG S0421): a randomised phase 3 trial. Lancet Oncol. 2013;14(9):893-900.
  4. Fizazi K, Higano CS, Nelson JB, Gleave M, Miller K, Morris T, et al. Phase III, randomized, placebo-controlled study of docetaxel in combination with zibotentan in patients with metastatic castration-resistant prostate cancer. J Clin Oncol. 2013;31(14):1740-7.
  5. Nelson JB, Fizazi K, Miller K, Higano C, Moul JW, Akaza H, et al. Phase 3, randomized, placebo-controlled study of zibotentan (ZD4054) in patients with castration-resistant prostate cancer metastatic to bone. Cancer. 2012;118(22):5709-18.
  6. Patrikidou A, Vlachostergios PJ, Voutsadakis IA, Hatzidaki E, Valeri RM, Destouni C, et al. Inverse baseline expression pattern of the NEP/neuropeptides and NFκB/proteasome pathways in androgen-dependent and androgen-independent prostate cancer cells. Cancer Cell Int. 2011;11(1):13.
  7. Tsapakidis K, Vlachostergios PJ, Voutsadakis IA, Befani CD, Patrikidou A, Hatzidaki E, et al. Bortezomib reverses the proliferative and antiapoptotic effect of neuropeptides on prostate cancer cells. Int J Urol. 2012;19(6):565-74.
  8. Papandreou CN, Logothetis CJ. Bortezomib as a potential treatment for prostate cancer. Cancer Res. 2004;64(15):5036-43.
  9. Papandreou CN, Daliani DD, Nix D, Yang H, Madden T, Wang X, et al. Phase I trial of the proteasome inhibitor bortezomib in patients with advanced solid tumors with observations in androgen-independent prostate cancer. J Clin Oncol. 2004 ;22(11):2108-21.
  10. Dreicer R, Petrylak D, Agus D, Webb I, Roth B. Phase I/II study of bortezomib plus docetaxel in patients with advanced androgenindependent prostate cancer. Clin Cancer Res. 2007;13(4):1208-15.
  11. Morris MJ, Kelly WK, Slovin S, Ryan C, Eicher C, Heller G, et al. A phase II trial of bortezomib and prednisone for castration resistant metastatic prostate cancer. J Urol. 2007;178(6):2378-83.
  12. Aguiar PM, de Mendonça Lima T, Colleoni GWB, Storpirtis S. Efficacy and safety of bortezomib, thalidomide, and lenalidomide in multiple myeloma: An overview of systematic reviews with meta-analyses. Crit Rev Oncol Hematol. 2017;113:195-212.
  13. Moreau P, Touzeau C. Multiple myeloma: from front-line to relapsed therapies. Am Soc Clin Oncol Educ Book. 2015:e504-11.
  14. Moreau P, Richardson PG, Cavo M, Orlowski RZ, San Miguel JF, Palumbo A, et al. Proteasome inhibitors in multiple myeloma: 10 years later. Blood. 2012;120(5):947-59.
  15. Vaiou M, Pangou E, Liakos P, Sakellaridis N, Vassilopoulos G, Dimas K, et al. Endothelin-1 (ET-1) induces resistance to bortezomib in human multiple myeloma cells via a pathway involving the ETB receptor and upregulation of proteasomal activity. J Cancer Res Clin Oncol. 2016;142(10):2141-58.
  16. Russignan A, Spina C, Tamassia N, Cassaro A, Rigo A, Bagnato A, et al. Endothelin-1 receptor blockade as new possible therapeutic approach in multiple myeloma. Br J Haematol. 2017 ;178(5):781-93.