Tasquinimod

Tasquinimod
Systematic (IUPAC) name
4-hydroxy-5-methoxy-N,1-dimethyl-2-oxo-N-[4-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide
Legal status
Legal status
  • Experimental
Pharmacokinetic data
Biological half-life 40 ± 16 hours[1]
Identifiers
CAS Number 254964-60-8 N
PubChem CID 54682876
IUPHAR/BPS 8098
ChemSpider 11444963 YesY
UNII 756U07KN1R YesY
ChEMBL CHEMBL2107784 YesY
Chemical data
Formula C20H17F3N2O4
Molar mass 406.355 g/mol
 NYesY (what is this?)

Tasquinimod (ABR-215050, CID 54682876) is a novel, oral drug currently being investigated for the treatment of solid tumors. Tasquinimod has been mostly studied in prostate cancer, but its mechanism of action suggests that it could be used to treat other cancers. Castration-resistant prostate cancer (CRPC), formerly called hormone-resistant or hormone-refractory prostate cancer, is prostate cancer that grows despite medical or surgical androgen deprivation therapy. Tasquinimod targets the tumor microenvironment and counteracts cancer development by inhibiting angiogenesis and metastasis and by modulating the immune system.[2][3][4][5] It is now in phase III development,[6][7] following successful phase II trial outcomes.[7][8][9]

History

Collaborative studies by laboratories at The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA, and Active Biotech Research AB, Lund, Sweden, identified tasquinimod as the lead agent for developing a treatment for prostate cancer.[2][10][11] Tasquinimod was one of several second-generation quinoline-3-carboxamide variants synthesized using the drug roquinimex as a starting point, and it performed well in pre-clinical studies of cancer models.[2][11][12][13]

In April 2011, Ipsen and Active Biotech entered into a broad partnership for the co-development of tasquinimod for the treatment of cancer. Active Biotech granted Ipsen exclusive rights to commercialize tasquinimod worldwide, except in North and South America and Japan where Active Biotech retained all commercial and marketing rights.[14]

Mechanism of action

Tasquinimod is a novel small-molecule inhibitor that targets the tumor microenvironment by controlling the accumulation and immunosuppressive, pro-angiogenic and pro-metastatic functions of regulatory myeloid cells (also called myeloid-derived suppressor cells).[2][4][5][15] It binds to and inhibits the interactions of S100A9, an immunomodulatory protein that promotes tumor development,[16] influences suppressive and pro-angiogenic cells in the tumor microenvironment,[16][17][18] and participates in the establishment of pre-metastatic niches.[17]

Tasquinimod may also target the tumor microenvironment by suppressing the tumor hypoxic response, in which genes involved in the adaptation and survival of cells during hypoxia are induced.[3] Tasquinimod reduces tumor angiogenesis; but its anti-angiogenic effects do not appear to be linked to vascular endothelial growth factor (VEGF) neutralization or VEGF receptor tyrosine kinase inhibition.[2][13]

Clinical studies

A randomized, double-blind, placebo-controlled phase II study comparing tasquinimod with placebo in 206 men with metastatic CRPC was completed in 2009.[8] The primary endpoint in the trial was to show a difference in the number of patients with disease progression at 6 months.[8] The proportion of patients who were disease progression-free after 6 months was 69% for patients treated with tasquinimod versus 37% for placebo-treated patients (p<0.001).[8] Median progression-free survival (PFS) was significantly improved in patients treated with tasquinimod compared with patients receiving placebo (7.6 vs 3.3 months; hazard ratio [HR] 0.57; 95% confidence interval [CI] 0.39, 0.85, p=0.0042).[8] Tasquinimod thus delayed disease progression by about 4.3 months. Overall survival (OS) observed for tasquinimod-treated patients was longer than previously reported in this patient population.[9] Median overall survival was 33.4 months for the tasquinimod group versus 30.4 months for the placebo group (p=0.49).[9] Using a multivariate analysis, treatment with tasquinimod was associated with an OS advantage with a HR of 0.64 (95% CI 0.42, 0.97, p=0.034).[9] It was hypothesized that the prolongation in PFS observed with tasquinimod treatment may lead to a survival advantage in men with metastatic CRPC. Also, a stronger trend for survival benefit was seen in patients with bone metastases; 34.2 for the tasquinimod group vs 27.1 months for the placebo group (HR 0.73, 95% CI 0.46, 1.17, p=0.19).[9]

Analysis of up to 3 years of safety data from phase II studies showed that treatment-related adverse events were mild to moderate, manageable and less frequent after 2 months of therapy.[7] Adverse events observed included gastrointestinal disorders, fatigue, musculoskeletal pain as well as elevations of some laboratory parameters.[7]

A phase III randomized controlled trial called 10TASQ10[6] to confirm tasquinimod’s effect on disease progression is ongoing. More than 1,200 patients with asymptomatic to mildly symptomatic metastatic CRPC were successfully enrolled in the study, as planned in the clinical protocol.[7] The study is expected to complete in 2016.[6] Other indications are currently under investigation.[6][19]

References

  1. ↑ Bratt, O; Häggman, M; Ahlgren, G; Nordle, Ö; Björk, A; Damber, J-E (2009). "Open-label, clinical phase I studies of tasquinimod in patients with castration-resistant prostate cancer". British Journal of Cancer 101 (8): 1233–40. doi:10.1038/sj.bjc.6605322. PMC: 2768463. PMID 19755981.
  2. 1 2 3 4 5 Isaacs, John T.; Pili, Roberto; Qian, David Z.; Dalrymple, Susan L.; Garrison, Jason B.; Kyprianou, Natasha; Björk, Anders; Olsson, Anders; Leanderson, Tomas (2006). "Identification of ABR-215050 as lead second generation quinoline-3-carboxamide anti-angiogenic agent for the treatment of prostate cancer". The Prostate 66 (16): 1768–78. doi:10.1002/pros.20509. PMID 16955399.
  3. 1 2 Isaacs, J. T.; Antony, L.; Dalrymple, S. L.; Brennen, W. N.; Gerber, S.; Hammers, H.; Wissing, M.; Kachhap, S.; Luo, J.; Xing, L.; Björk, P.; Olsson, A.; Björk, A.; Leanderson, T. (2012). "Tasquinimod is an Allosteric Modulator of HDAC4 Survival Signaling within the Compromised Cancer Microenvironment". Cancer Research 73 (4): 1386–99. doi:10.1158/0008-5472.CAN-12-2730. PMC: 3578133. PMID 23149916.
  4. 1 2 Källberg, Eva; Vogl, Thomas; Liberg, David; Olsson, Anders; Björk, Per; Wikström, Pernilla; Bergh, Anders; Roth, Johannes; Ivars, Fredrik; Leanderson, Tomas (2012). Lebedeva, Irina V, ed. "S100A9 Interaction with TLR4 Promotes Tumor Growth". PLoS ONE 7 (3): e34207. doi:10.1371/journal.pone.0034207. PMC: 3314596. PMID 22470535.
  5. 1 2 Jennbacken, Karin; Welén, Karin; Olsson, Anders; Axelsson, Bengt; Törngren, Marie; Damber, Jan-Erik; Leanderson, Tomas (2012). "Inhibition of metastasis in a castration resistant prostate cancer model by the quinoline-3-carboxamide tasquinimod (ABR-215050)". The Prostate 72 (8): 913–24. doi:10.1002/pros.21495. PMID 22287276.
  6. 1 2 3 4 Clinical trial number NCT01234311 for "A Study of Tasquinimod in Men With Metastatic Castrate Resistant Prostate Cancer" at ClinicalTrials.gov
  7. 1 2 3 4 5 "Active Biotech and Ipsen announce completion of recruitment of tasquinimod clinical phase III study in prostate cancer" (Press release). Active Biotech. Dec 10, 2012. Retrieved January 4, 2014.
  8. 1 2 3 4 5 Pili, R.; Häggman, M.; Stadler, W. M.; Gingrich, J. R.; Assikis, V. J.; Björk, A.; Nordle, O.; Forsberg, G.; Carducci, M. A.; Armstrong, A. J. (2011). "Phase II Randomized, Double-Blind, Placebo-Controlled Study of Tasquinimod in Men with Minimally Symptomatic Metastatic Castrate-Resistant Prostate Cancer". Journal of Clinical Oncology 29 (30): 4022–8. doi:10.1200/JCO.2011.35.6295. PMID 21931019.
  9. 1 2 3 4 5 Armstrong AJ, Häggman M, Stadler WM, et al. Tasquinimod and survival in men with metastatic castration-resistant prostate cancer: Results of long-term follow-up of a randomized phase II placebo-controlled trial. [Abstract no. 4550 plus poster]. American Society of Clinical Oncology Annual Meeting; 2012 June 1–5; Chicago. http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=114&abstractID=98057; http://activebiotech.com/file/asco-poster-os-2012-final.pdf
  10. ↑ Björk, Per; Björk, Anders; Vogl, Thomas; Stenström, Martin; Liberg, David; Olsson, Anders; Roth, Johannes; Ivars, Fredrik; Leanderson, Tomas (2009). Akira, Shizuo, ed. "Identification of Human S100A9 as a Novel Target for Treatment of Autoimmune Disease via Binding to Quinoline-3-Carboxamides". PLoS Biology 7 (4): e97. doi:10.1371/journal.pbio.1000097. PMC: 2671563. PMID 19402754.
  11. 1 2 Isaacs, John T (2010). "The long and winding road for the development of tasquinimod as an oral second-generation quinoline-3-carboxamide antiangiogenic drug for the treatment of prostate cancer". Expert Opinion on Investigational Drugs 19 (10): 1235–43. doi:10.1517/13543784.2010.514262. PMID 20836618.
  12. ↑ Dalrymple, Susan L.; Becker, Robin E.; Isaacs, John T. (2007). "The quinoline-3-carboxamide anti-angiogenic agent, tasquinimod, enhances the anti-prostate cancer efficacy of androgen ablation and taxotere without effecting serum PSA directly in human xenografts". The Prostate 67 (7): 790–7. doi:10.1002/pros.20573. PMID 17373719.
  13. 1 2 Olsson, Anders; Björk, Anders; Vallon-Christersson, Johan; Isaacs, John T; Leanderson, Tomas (2010). "Tasquinimod (ABR-215050), a quinoline-3-carboxamide anti-angiogenic agent, modulates the expression of thrombospondin-1 in human prostate tumors". Molecular Cancer 9: 107. doi:10.1186/1476-4598-9-107. PMC: 2885345. PMID 20470445.
  14. ↑ "Active Biotech and Ipsen enter into a broad partnership for the co- development and commercialization of TASQ in" (Press release). Active Biotech. Apr 18, 2011. Retrieved January 4, 2014.
  15. ↑ Murdoch, Craig; Muthana, Munitta; Coffelt, Seth B.; Lewis, Claire E. (2008). "The role of myeloid cells in the promotion of tumour angiogenesis". Nature Reviews Cancer 8 (8): 618–31. doi:10.1038/nrc2444. PMID 18633355.
  16. 1 2 Turovskaya, O.; Foell, D.; Sinha, P.; Vogl, T.; Newlin, R.; Nayak, J.; Nguyen, M.; Olsson, A.; Nawroth, P. P.; Bierhaus, A.; Varki, N.; Kronenberg, M.; Freeze, H. H.; Srikrishna, G. (2008). "RAGE, carboxylated glycans and S100A8/A9 play essential roles in colitis-associated carcinogenesis". Carcinogenesis 29 (10): 2035–43. doi:10.1093/carcin/bgn188. PMC: 2556970. PMID 18689872.
  17. 1 2 Rafii, Shahin; Lyden, David (2006). "S100 chemokines mediate bookmarking of premetastatic niches". Nature Cell Biology 8 (12): 1321–3. doi:10.1038/ncb1206-1321. PMC: 2955889. PMID 17139281.
  18. ↑ Sinha, P; Okoro, C; Foell, D; Freeze, HH; Ostrand-Rosenberg, S; Srikrishna, G (2008). "Proinflammatory S100 proteins regulate the accumulation of myeloid-derived suppressor cells". Journal of immunology 181 (7): 4666–75. doi:10.4049/jimmunol.181.7.4666. PMC: 2810501. PMID 18802069.
  19. ↑ Clinical trial number NCT01743469 for "A Study With Tasquinimod Treating Patients in Four Independent Cohorts of Hepatocellular, Ovarian, Renal Cell and Gastric Cancers" at ClinicalTrials.gov

External links

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