http://www.gotoper.com/publications/ajho/2015/2015dec/aurora-kinase-inhibitors-in-breast-cancer-treatment

Review Article


Author: Mateusz Opyrchal, MD, PhD; Kothai Divya Guruswamy Sangameswaran, MBBS; Thaer Khoury, MD, FCAP; Patrick Boland, MD; Evanthia Galanis, MD; Tufia C. Haddad, MD; Antonino B. D’Assoro, MD, PhD



Breast cancer, despite many medical advances, remains a major health problem in the United States and worldwide. De novo and acquired resistance to systemic therapy remains a significant issue contributing to poor clinical outcomes. It is most evident in patients with metastatic disease, as these breast cancer cells develop resistance to sequential therapies, ultimately leading to disease progression and death. Novel approaches to both prevent and overcome resistance to breast cancer therapies are in development and urgently needed.

Pre-Clinical Studies of Aurora-A Kinase in Breast Cancer

Aurora-A kinase (AURKA) belongs to the family of serine-threonine kinases that play an integral part in cell cycle regulation by recruiting the cyclin B1/CDK1 complex and committing cells to mitosis.1-3 AURKA overexpression in murine fibroblasts and breast epithelial cells results in centrosome amplification and aneuploidy, suggesting it plays an important role in malignant transformation.4,5 AURKA is expressed in multiple carcinomas including breast cancer.6-9 AURKA overexpression has been associated with centrosome amplification and DNA instability.10-12 It has been proposed that cancer cells may overexpress AURKA through a switch in mRNA transcription through cap to internal ribosome entry site (IRES)-dependent translation, which allows for change in transcriptional regulation and increased mRNA production.13 The non-mitotic function of AURKA has been implicated in breast cancer progression and resistance to chemotherapy agents through epithelial to mesenchymal transition and the acquisition of stem cell-like characteristics.14,15 Breast cancer cells with stem cell-like properties have been associated with resistance to standard therapies, tumor progression and onset of distant metastasis.16-19 AURKA can activate NOTCH signaling, a pathway implicated in breast cancer cells acquiring stem cell-like properties.15,20 The NOTCH pathway has furthermore been shown to be important in mammary carcinomas in tumorigenesis,21 development of resistance to endocrine treatments,22 and cross-talk with the HER2 signaling pathway.23,24 Therefore, increasing interest in targeting AURKA for the treatment of breast cancer has evolved. There are several compounds targeting AURKA in clinical development, with the most advanced being alisertib (MLN8237), a selective AURKA inhibitor. Other compounds, targeting AURKA selectively or as part of their broader activity, are under evaluation in pre-clinical and early clinical testing (Table 1).25


Translational Studies With AURKA Inhibitors in Breast Cancer

Increased expression of both mRNA and protein correlates with worse clinical outcomes in patients with estrogen receptor positive (ER+), HER2-negative breast cancer; in cohorts of triple-negative breast cancer, the same analyses have yielded mixed results.26-30 AURKA has been identified as a relevant therapeutic target in ER+, endocrine resistant, breast cancer cell lines in a genetic screen by Thrane et al.31 Experimental testing has shown that AURKA activation has been associated with resistance to endocrine therapies in ER+ breast cancer models.32-34 Aurora-A and B have been identified through the kinase inhibitor screen as targets for the treatment of aromatase inhibitor-resistant breast cancer cells.34 One proposed mechanism of AURKA causing resistance to endocrine therapies is down-regulation of the ERα through expansion of a sub-population of ERlow/- tumor-initiating cells.32 An alternative proposed mechanism is through direct phosphorylation of ERα.33 Importantly, inhibition of AURKA either resulted in growth arrest or restored sensitivity to estrogen blockade in ER+ breast cancer cells and increased efficacy of hormonal therapies in in vitro and in vivo models of ER+ breast cancer.32-34
 
Inhibition of AURKA results in reversal of mesenchymal phonotype and reduction of cancer stem cell-like cells with increased sensitivity to chemotherapy agents.14,35 The combination of AURKA inhibitors with chemotherapy was much more effective than either treatment when compared in various breast cancer models with anthracyclines36 and taxanes.37 AURKA inhibitors may target cancer cells with increased propensity for metastasis and treatment-resistance either directly or through interference with the NOTCH signaling pathway.
 

Clinical Studies With Aurora Inhibitors in Breast Cancer

Alisertib is an orally administered, small molecule inhibitor highly selective for AURKA.38 The safety and tolerability of alisertib has been investigated in multiple phase I clinical trials in patients with hematologic and solid malignancies. In a first-in-human trial performed by Dees et al, 87 patients with solid malignancies (3 with breast cancer) were treated at escalating doses of 2 different formulations of alisertib from 5 mg to 150 mg twice daily for 7, 14, or 21 consecutive days followed by 14 days of recovery. The recommended phase II dose (RP2D) was 50 mg twice daily for 7 days with a 14-day recovery. The most common adverse events were fatigue, nausea, and neutropenia. Twenty patients achieved stable disease (SD) for a period greater than 3 months, with 1 patient achieving partial response lasting for over a year.39 Cervantes et al corroborated the RP2D results in a separate, dose escalation phase I study in 59 adults with advanced solid malignancies (one with breast cancer).40 Pharmacokinetic studies revealed fast absorption, and at the RP2D the steady-state concentration exceeded that associated with saturating pharmacodynamic effects and preclinical activity. There was one partial response, and 22 (37%) patients achieved SD, 6 of whom (10%) maintained it for a period > 6 months.40 A third phase I trial of 58 patients with refractory hematologic malignancies supported the same RP2D, and it further determined enteric coated tablets to be the preferred formulation.35 Hematological toxicities were the most frequent dose-limiting toxicities (DLTs), particularly neutropenia. There were also DLTs of stomatitis and skin toxicities.35,39,40
 
A phase II trial reported by Melichar et al investigated the efficacy of single-agent alisertib in patients with pre-treated breast cancer, small-cell lung cancer, non-small-cell lung cancer, head and neck squamous cell carcinoma, and gastro-esophageal adenocarcinoma.41 There were 53 patients with breast cancer treated and 49 were evaluable for response. Of these, 26 patients had hormone receptor positive (HR+), HER2-negative breast cancer, 9 had HER2-positive breast cancer, and 14 had HR-negative, HER2-negative breast cancer. The majority of the breast cancer patients (80%) had received 4 or more prior treatment regimens. Of all patients, 9 (18%) had an objective response. Of those with HR+ disease, 6 (23%) had an objective response, 8 (31%) achieved SD at least 6 months, and PFS was 7.9 months. In the small HER2-positive cohort, response rates were similar though the duration of response was longer at 11.2 months, an impressive finding given the absence of concurrent HER2-directed therapy. In this heavily pre-treated population, the overall results were very encouraging and the authors concluded that further investigation was recommended, especially in HR+ and HER2-positive patient populations.41
 
Grade 3-4 drug-related neutropenia was reported in 53% of patients with breast cancer; however, febrile neutropenia was only reported in 4% of this cohort. Thrombocytopenia, skin toxicities, and infections were also reported in a small percentage of patients.
 
In 2014, a phase I trial of alisertib in combination with fulvestrant in endocrine-resistant breast cancer (NCT02219789) was the first dedicated breast cancer trial with an AURKA inhibitor to be open to enrollment; this trial remains active but is no longer recruiting.
 
Other active and planned trials specifically in the breast cancer patient population are listed in Table 2. Alisertib has been combined with taxanes in early clinical trials that form the basis for future trials in patients with breast cancer, and specifically with triple-negative breast cancer (TNBC).42,43

Conclusion

There are promising data to support the development of breast cancer therapeutics targeting the inhibition of Aurora kinase. Promising single-agent activity has been observed with the selective Aurora-A kinase inhibitor alisertib, and there is particular interest to evaluate these agents in combination with endocrine therapy in HR+ disease and with HER2-directed therapies in HER2+ disease, given the non-overlapping toxicities. Beyond the molecular subtypes of breast cancer, the pre-clinical data that suggest AURKA inhibition reduces the sub-population of breast cancer stem cell-like cells is indeed encouraging and suggest a role for this class of drugs to be combined with other agents that target the main tumor bulk. Triple-negative breast cancers in particular have been shown to have a higher percentage of stem cell-like population leading to worse clinical ooutcomes44-47 and decreasing the metastatic potential of breast cancer cells. New treatment options in this patient population are sorely needed, and we will await any hints of activity in any future clinical trials, including ongoing and planned clinical trials with alisertib; another specific AURKA inhibitor, TAS-119; and pan-Aurora kinase inhibitors, as correlative studies from the phase II study of alisertib in all solid tumors.
 
Affiliations: Mateusz Opyrchal, MD, PhD, Kothai Divya Guruswamy Sangameswaran, MBBS, Thaer Khoury, MD, FCAP, and Patrick Boland, MD, are from Roswell Park Cancer Institute, Buffalo, NY. Evanthia Galanis, MD, Tufia C. Haddad, MD, and Antonino B. D’Assoro, MD, PhD, are from Mayo Clinic, Rochester, Minnesota
 
Disclosure: Dr. Opyrchal reports no disclosures.
 
Address correspondence to: Mateusz Opyrchal, MD, PhD, Assistant Professor of Oncology, Breast Service, Department of Medicine, Roswell Park Cancer Institute, Carlton House - A-414, Elm & Carlton Sts., Buffalo, NY, 14263, Phone: 716-845-4695, Fax: 716-845-3423, email: Mateusz.Opyrchal@RoswellPark.org

References

  1. Marumoto T, Honda S, Hara T, et al. Aurora-A kinase maintains the fidelity of early and late mitotic events in HeLa cells. J Biol Chem. 2003; 278(51):51786-51795.
  2. Portier N, Audhya A, Maddox PS, Green RA, Dammermann A, Desai A, Oegema K. A microtubule-independent role for centrosomes and aurora a in nuclear envelope breakdown. Dev Cell. 2007;12(4):515-529.
  3. Hirota T, Kunitoku N, Sasayama T, et al. Aurora-A and an interacting activator, the LIM protein Ajuba, are required for mitotic commitment in human cells. Cell. 2003;114(5):585-598.
  4. Zhou H, Kuang J, Zhong L, et al. Tumour amplified kinase STK15/BTAK induces centrosome amplification, aneuploidy and transformation. Nat Genet. 1998; 20(2):189-193.
  5. Goepfert TM, Adigun YE, Zhong L, Gay J, Medina D, Brinkley WR. Centrosome amplification and overexpression of aurora A are early events in rat mammary carcinogenesis. Cancer Res. 2002;62(14):4115-4122.
  6. Tanaka T, Kimura M, Matsunaga K, Fukada D, Mori H, Okano Y. Centrosomal kinase AIK1 is overexpressed in invasive ductal carcinoma of the breast. Cancer Res. 1999;59(9):2041-2044.
  7. Sakakura C, Hagiwara A, Yasuoka R, et al. Tumour-amplified kinase BTAK is amplified and overexpressed in gastric cancers with possible involvement in aneuploid formation. Br J Cancer. 2001;84(6):824-831.
  8. Gritsko TM, Coppola D, Paciga JE, et al. Activation andoverexpression of centrosome kinase BTAK/Aurora-A in human ovarian cancer. Clin Cancer Res. 2003;9(4):1420-1426.
  9. Staff S, Isola J, Jumppanen M, Tanner M. Aurora-A gene is frequently amplified in basal-like breast cancer. Oncol Rep. 2010;23(2):307-312.
  10. D’Assoro AB, Lingle WL, Salisbury JL. Centrosome amplification and the development of cancer. Oncogene. 2002; 21(40):6146-6153.
  11. Chou CH, Yang NK, Liu TY, et al. Chromosome instability modulated by BMI1-AURKA signaling drives progression in head and neck cancer. Cancer Res. 2013;73(2):953-966.
  12. Goepfert TM, Moreno-Smith M, Edwards DG, et al. Loss of chromosomal integrity drives rat mammary tumorigenesis. Int J Cancer. 2007;120(5):985-994.
  13. Dobson T, Chen J, Krushel LA. Dysregulating IRES-dependent translation contributes to overexpression of oncogenic Aurora A Kinase. Mol Cancer Res. 2013;11(8):887-900.
  14. D’Assoro AB, Liu T, Quatraro C, et al. The mitotic kinase Aurora—a promotes distant metastases by inducing epithelial-to-mesenchymal transition in ERalpha(+) breast cancer cells. Oncogene. 2014;33(5):599-610.
  15. Regan JL, Sourisseau T, Soady K, et al. Aurora A kinase regulates mammary epithelial cell fate by determining mitotic spindle orientation in a Notch-dependent manner. Cell Rep. 2013;4(1):110-123.
  16. Creighton CJ, Li X, Landis M, Dixon JM, et al. Residual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features. Proc Natl Acad Sci USA. 2009;106(33):13820-13825.
  17. Piva M, Domenici G, Iriondo O, et al. Sox2 promotes tamoxifen resistance in breast cancer cells. EMBO Mol Med. 2014;6(1):66-79.
  18. Giancotti FG. Mechanisms governing metastatic dormancy and reactivation. Cell. 2013;155(4):750-764.
  19. Oskarsson T, Acharyya S, Zhang XH, et al. Breast cancer cells produce tenascin C as a metastatic niche component to colonize the lungs. Nat Med. 2011;17(7):867-874.
  20. Takebe N, Harris PJ, Warren RQ, Ivy SP. Targeting cancer stem cells by inhibiting Wnt, Notch, and Hedgehog pathways. Nat Rev Clin Oncol. 2011;8(2):97-106.
  21. Gallahan D, Callahan R. The mouse mammary tumor associated gene INT3 is a unique member of the NOTCH gene family (NOTCH4). Oncogene. 1997;14(16):1883-1890.
  22. Rizzo P, Miao H, D’Souza G, et al. Cross-talk between notch and the estrogen receptor in breast cancer suggests novel therapeutic approaches. Cancer Res. 2008;68(13):5226-5235.
  23. Osipo C, Patel P, Rizzo P, et al. ErbB-2 inhibition activates Notch-1 and sensitizes breast cancer cells to a gamma-secretase inhibitor. Oncogene. 2008; 27(37):5019-5032.
  24. Baker AT, Zlobin A, Osipo C. Notch-EGFR/HER2 Bidirectional Crosstalk in Breast Cancer. Front. Oncol 2014;12:4:360.
  25. Cheung CH, Sarvagalla S, Lee JY, Huang YC, Coumar MS. Aurora kinase inhibitor patents and agents in clinical testing: an update (2011 - 2013). Expert Opin Ther Pat. 2014;24(9):1021-1038.
  26. Yamamoto S, Yamamoto-Ibusuki M, Yamamoto Y, Fujiwara S, Iwase H. A comprehensive analysis of Aurora A; transcript levels are the most reliable in association with proliferation and prognosis in breast cancer. BMC Cancer. 2013;13:217.
  27. Xu J, Wu X, Zhou WH, et al. Aurora-A identifies early recurrence and poor prognosis and promises a potential therapeutic target in triple negative breast cancer. PloS One. 2013;8(2):e56919.
  28. Tokes AM, Szasz AM, Geszti F, et al. Expression of proliferation markers Ki67, cyclin A, geminin and aurora-kinase A in primary breast carcinomas and corresponding distant metastases. J Clin Pathol. 2015;68(4):274-282.
  29. Ali HR, Dawson SJ, Blows FM, Provenzano E, Pharoah PD, Caldas C. Aurora kinase A outperforms Ki67 as a prognostic marker in ER-positive breast cancer. Br J Cancer. 2012;106(11):1798-1806.
  30. Siggelkow W, Boehm D, Gebhard S, et al. Expression of aurora kinase A is associated with metastasis-free survival in node-negative breast cancer patients. BMC Cancer. 2012;12;562.
  31. Thrane S, Pedersen AM, Thomsen MB, et al. A kinase inhibitor screen identifies Mcl-1 and Aurora kinase A as novel treatment targets in antiestrogen-resistant breast cancer cells. Oncogene. 2015;34(32);4199-4210.
  32. Opyrchal M, Salisbury JL, Zhang S, et al. Aurora-A mitotic kinase induces endocrine resistance through down-regulation of ERalpha expression in initially ERalpha+ breast cancer cells. PloS One. 2014;9(5):e96995.
  33. Zheng XQ, Guo JP, Yang H, et al. Aurora-A is a determinant of tamoxifen sensitivity through phosphorylation of ERa in breast cancer. Oncogene. 2014;33(42):4985-4996.
  34. Hole S, Pedersen AM, Lykkesfeldt AE, Yde CW. Aurora kinase A and B as new treatment targets in aromatase inhibitor-resistant breast cancer cells. Breast Cancer Res Treat. 2015;149(3):715-726.
  35. Kelly KR, Shea TC, Goy A, et al. Phase I study of MLN8237— investigational Aurora A kinase inhibitor—in relapsed/refractory multiple myeloma, non-Hodgkin lymphoma and chronic lymphocytic leukemia. Invest New Drugs. 2014;32(3):489-499.
  36. Zheng FM, Long ZJ, Hou ZJ, et al. A novel small molecule aurora kinase inhibitor attenuates breast tumor-initiating cells and overcomes drug resistance. Mol Cancer Ther. 2014;13(8):1991-2003.
  37. Huck JJ, Zhang M, Mettetal J, et al. Translational exposure-efficacy modeling to optimize the dose and schedule of taxanes combined with the investigational Aurora A kinase inhibitor MLN8237 (alisertib). Mol Cancer Ther. 2014;13(9):2170-2183.
  38. Manfredi MG, Ecsedy JA, Chakravarty A, et al. Characterization of Alisertib (MLN8237), an investigational small-molecule inhibitor of aurora A kinase using novel in vivo pharmacodynamic assays. Clin Cancer Res. 2011;17(24):7614-7624.
  39. Dees EC, Cohen RB, von Mehren M, et al. Phase I study of aurora A kinase inhibitor MLN8237 in advanced solid tumors: safety, pharmacokinetics, pharmacodynamics, and bioavailability of two oral formulations. Clin Cancer Res. 2012;18(17):4775-4784.
  40. Cervantes A, Elez E, Roda D, et al. Phase I pharmacokinetic/ pharmacodynamic study of MLN8237, an investigational, oral, selective aurora a kinase inhibitor, in patients with advanced solid tumors. Clin Cancer Res. 2012;18(17):4764-4774.
  41. Melichar B, Adenis A, Lockhart AC, et al. Safety and activity of alisertib, an investigational aurora kinase A inhibitor, in patients with breast cancer, small-cell lung cancer, non-small-cell lung cancer, head and neck squamous-cell carcinoma, and gastro-oesophageal adenocarcinoma: a five-arm phase 2 study. Lancet Oncol. 2015;16(4):395-405.
  42. Jeffrey E, Xiaofei Z, Jay M, et al. Rational dose and schedule selection for the combination of paclitaxel and the investigational agent alisertib in recurrent ovarian cancer: optimization of therapeutic index based on translational hematological toxicity and exposure-efficacy modeling. AACR 104th Annual Meeting 2013; Apr 6-10, 2013.
  43. Falchook GS, Goff BA, Kurzrock R, et al. Phase I/II study of weekly paclitaxel with or without MLN8237 (alisertib), an investigational aurora A kinase inhibitor, in patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer (OC), or breast cancer (BrC): phase I results. J Clin Oncol. 2012;30. Abstract 5021.
  44. Idowu MO, Kmieciak M, Dumur C, et al. CD44(+)/CD24(-/ low) cancer stem/progenitor cells are more abundant in triple-negative invasive breast carcinoma phenotype and are associated with poor outcome. Hum Pathol. 2012;43(3):364-373.
  45. Sheridan C, Kishimoto H, Fuchs RK, et al. CD44+/CD24-breast cancer cells exhibit enhanced invasive properties: an early step necessary for metastasis. Breast Cancer Res. 2006;8(5):R59.
  46. Honeth G, Bendahl PO, Ringner M, et al. The CD44+/ CD24- phenotype is enriched in basal-like breast tumors. Breast Cancer Res. 2008;10(3):R53.
  47. Giatromanolaki A, Sivridis E, Fiska A, Koukourakis MI. The CD44+/CD24- phenotype relates to ‘triple-negative’ state and unfavorable prognosis in breast cancer patients. Med Oncol. 2011;28(3):745-752.