IP Library › Granted Patent US 12,201,599
Granted Patent B2
US 12,201,599 · App. 16/757,595 · Granted Jan 21, 2025

Compositions and methods for inhibiting blood cancer cell growth

Inventors: Alli Murugesan (Saint John, CA); Anthony Reiman (Saint John, CA); Mohamed Touaibia (Dieppe, CA)
Assignee: THE UNIVERSITY OF NEW BRUNSWICK UNIVERSITÉ DE MONCTON
A61K31/216A61P35/00
View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 12,201,599
App. No.
16/757,595
Granted
Jan 21, 2025
Kind
B2
Abstract

Methods, compositions and uses for inhibiting the growth in blood cancer cells with one or more of caffeic acid (3,4-dihydroxycinnamic acid) phenethyl ester (CAPE), CAPE analogue MT30, and CAPE analogue GL8. The blood cancer cells can be myeloma, lymphoma and leukemia cells. The methods, compositions and uses can be in conjunction with the use of an IMiD to treat a patient. The compositions can include a pharmaceutically acceptable carrier, adjuvant or vehicle, a pharmaceutically acceptable salt or dietary supplement.

Claims (23)

1. A composition for inhibiting the growth of blood cancer cells comprising:

a therapeutically effective amount of a caffeic acid (3,4-dihydroxycinnamic acid) phenethyl ester (CAPE) analogue, according to the formulae:

wherein the blood cancer cells are not leukemia cells, and

wherein the caffeic acid (3,4-dihydroxycinnamic acid) phenethyl ester (CAPE) analogue is present in the range of 5 μM-25 μM.

2. The composition of claim 1 , wherein the blood cancer cells are myeloma cells.

3. The composition of claim 2 , wherein the myeloma cells are immune-modulatory drug (IMiD) resistant.

4. The composition of claim 2 , wherein the myeloma cells are lenalidomide resistant.

5. The composition of claim 1 , wherein the blood cancer cells are lymphoma cells.

6. The composition of claim 5 , wherein the lymphoma cells are diffused large B-cell Lymphoma.

7. The composition of claim 1 , wherein the composition is a pharmaceutical composition.

8. The composition of claim 7 , the composition further comprising a pharmaceutically acceptable carrier.

9. A composition for inhibiting the growth of blood cancer cells comprising:

a therapeutically effective amount of a caffeic acid (3,4-dihydroxycinnamic acid) phenethyl ester (CAPE) analogue selected from the group consisting of MT30, and GL8, according to the formulae:

and further comprising a therapeutically effective amount of lenalidomide.

10. The composition of claim 9 , wherein the caffeic acid (3,4-dihydroxycinnamic acid) phenethyl ester (CAPE) analogue is present at a concentration in the range of 5 μM-25 μM.

11. The composition of claim 9 , wherein the lenalidomide is present at a concentration in the range of 0.001-100 μM.

12. The composition of claim 9 , wherein the composition is a pharmaceutical composition.

13. The composition of claim 12 , the composition further comprising a pharmaceutically acceptable carrier.

14. A composition for inhibiting the growth of blood cancer cells comprising:

a therapeutically effective amount of a caffeic acid (3,4-dihydroxycinnamic acid) phenethyl ester (CAPE) analogue according to the formulae:

15. The composition of claim 14 , wherein the caffeic acid (3,4-dihydroxycinnamic acid) phenethyl ester (CAPE) analogue is present in the range of 5 μM-25 μM.

16. The composition of claim 14 , wherein the composition is a pharmaceutical composition.

17. The composition of claim 16 , the composition further comprising a pharmaceutically acceptable carrier.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 24, 2021
From: MURUGESAN, ALLI; REIMAN, ANTHONY; TOUAIBIA, MOHAMED
To: THE UNIVERSITY OF NEW BRUNSWICK; UNIVERSITÉ DE MONCTON
Reel/Frame 055394/0851 →
Continuity (2)
Provisional Application 62575136 · Oct 20, 2017
Related Publication 20200268700A1 · Aug 27, 2020
References Cited (82)
US 5981583A · Aggarwal et al. · 1999 [cited by applicant]
US 8450337B2 · Priebe et al. · 2013 [cited by applicant]
US 20170042865A1 · Zaid et al. · 2017 [cited by applicant]
CN 107157978 · 2017 [cited by applicant]
JP 2003119169 · 2003 [cited by applicant]
JP 2010180167 · 2010 [cited by examiner]
WO 2017147718 · 2017 [cited by applicant]
Etzenhouser et al., Bioorg. Med. Chem., 2001, 9, 199-209. [cited by examiner]
JP2010180167-machine-translation, 2010, machine translation of JP2010180167. [cited by examiner]
Zhu YX, Kortuem KM, Stewart AK. Molecular mechanism of action of immune-modulatory drugs thalidomide, lenalidomide and pomalidomide in multiple myeloma. Leuk Lymphoma. 2013; 54: 683-687. [cited by applicant]
Marin, E.H. and Wang, X. Anti-Cancer Effect of Fluorinated Caffeic Acid Phenethyl Ester on Multiple Myeloma Cells. The FASEB Journal, vol. 31, No. 1, Supplement Ib533. Apr. 2017. [cited by applicant]
Boudreau LH, Maillet J, LeBlanc LM, Jean-Francois J, Touaibia M, et al. (2012) Caffeic Acid Phenethyl Ester and Its Amide Analogue Are Potent Inhibitors of Leukotriene Biosynthesis in Human Polymorphonuclear Leukocytes.… [cited by applicant]
Etzenhouser, B. et al. “Mechanism of Toxicity of Esters of Caffeic and Dihydrocaffeic Acids”, Bioorganic & Medicinal Chemistry (2001), 9:199-209. [cited by applicant]
Sanderson, J.T. et al. “Antiproliferative, antiandrogenic and cytotoxic effects of novel caffeic acid derivatives in LNCaP human androgen-dependent prostate cancer cells”, Bioorganic & Medicinal Chemistry (2013), 21:718… [cited by applicant]
Beauregard, A-P. et al. “CAPE Analogs Induce Growth Arrest and Apoptosis in Breast Cancer Cells”, Molecules (2015), 20:12576-12589. [cited by applicant]
International Search Report and the Written Opinion of the International Searching Authority for PCT/CA2018/000198, Feb. 15, 2019. [cited by applicant]
Koru, O. et al. “Cytotoxic effects of caffeic acid phenethyl ester (CAPE) on the human multiple myeloma cell line”, Turk J. Med Sci (2009), 39:863-870. [cited by applicant]
International Search Report of the International Searching Authority for PCT/CA2021/050339, Apr. 15, 2021. [cited by applicant]
Written Opinion of the International Searching Authority for PCT/CA2021/050339, Apr. 15, 2021. [cited by applicant]
Akyol et al., “In Vivo and In Vitro Antineopastic Actions of Caffeic Acid Phenethyl Ester (CAPE): Therapeutic Perspectives”, Nutrition and Cancer, 2013, vol. 65, No. 4, pp. 515-526, ISSN 0163-5581. [cited by applicant]
Omene et al., “Propolis and its Active Component, Caffeic Acid Phenethyl Ester (CAPE), Modulate Breast Cancer Therapeutic Targets via an Epigenetically Mediated Mechanism of Action”, J. of Cancer Sci Ther, 2013, vol. 5,… [cited by applicant]
Chen Hui-Zhen et al., “Synthesis and antitumor activity of feruloyl and caffeoyl derivatives”, Bioorganic & Medical Chemistry Letters, vol. 24. No. 18, Sep. 1, 2014, pp. 4367-4371. [cited by applicant]
Nagaoka T et al., “Selective antiproliferative activity of caffeic acid phenethyl ester analogues on highly liver-Metastatic murine colon 26-L5 carcinoma cell line”, Bioorganic & Medical Chemistry, Elsevier, Amsterdam, … [cited by applicant]
Jeremie A. Doiron et al: “Structure-activity relationship of caffeic acid phenethyl ester analogs as new 5-lipoxygenase inhibitors”, Chemical Biology & Drug Design, vol. 89, No. 4, Nov. 15, 2016, pp. 514-528. [cited by applicant]
Elizabeth Hernandez Marin et al: “Anti-Cancer Effect of Fluorinated Caffeic Acid Phenethyl Ester on Multiple Myeloma Cells—marin—2017—The FASEB Journal—Wiley Online Library”, The Faseb Journal, Oct. 3, 2018, p. 1b533. [cited by applicant]
My Lien Jackson et al: “inhibitory effects of caffeic acid phenethyl ester (CAPE) derivatives on multiple myeloma cell growth—Jackson—2019—The FASEB Journal—Wiley Online Library”, The Faseb Journal, Apr. 1, 2019, p. 816… [cited by applicant]
Chen J-H et al.: “Inhibitory effect of caffeic acid phenethyle ester on human leukemia HL-60 cells”, Cancer Letters, New York, NY, US, vol. 108, No. 2, Jan. 1, 1996, pp. 211-214. [cited by applicant]
Kurata a et al: “Enzymatic synthesis of caffeic acid phenethyl ester analogues in ionic liquid”, Journal of Biotechnology, Elsevier, Amsterdam NL, vol. 148, No. 2-3. [cited by applicant]
European Search Report dated Dec. 21, 2022 for EP Application No. 20791750, national phase of on PCT/CA2020050523. [cited by applicant]
Qian, Yiping et al: “Structure-activity relationship for anti-haemolysis and cytotoxicity against HL-60 cells of caffeic acid phenethyl ester derivatives”, Shengwu Wuli Xuebao (2010), 26(4), 294-300. [cited by applicant]
Verma R.P. et al. “An approach towards the quantitative structure-activity relationships of caffeic acid and its derivatives”, Chembiochem (2004), 5(9), 1188-1195. [cited by applicant]
International Search Report of the International Searching Authority for PCT/CA2020/050523, Jun. 18, 2020. [cited by applicant]
Abdi J, Chen G, Chang H. (2013) Drug resistance in multiple myeloma: latest findings and new concepts on molecular mechanisms. Oncotarget: 4: 2186-2207. [cited by applicant]
Armutcu, F., Akyol, S., Ustunsoy, S., & Turan, F. F. (2015). Therapeutic potential of caffeic acid phenethyl ester and its anti-inflammatory and immunomodulatory effects (Review). Experimental and Therapeutic Medicine, … [cited by applicant]
Bai B, Wu S, Wang R, Xu J, and Chen L, Bone marrow IRF4 level in multiple myeloma: an indicator of peripheral blood Th17 and disease. Oncotarget, 2017, vol. 8, (49), pp. 85392-85400. [cited by applicant]
Bertrand E, Jouy N, Manier S, Fouquet G, Guidez S, Boyle E, Noel S, Tomowiak C, Herbaux C, Schraen S, Preudhomme C, Quesnel B, Poulain S and Leleu X, Role of IRF4 in resistance to immunomodulatory (IMid) compounds in Wa… [cited by applicant]
Bjorklund CC, Ma W, Wang ZQ, Davis RE, Kuhn DJ, Kornblau SM, et al. Evidence of a role for activation of Wnt/beta-catenin signaling in the resistance of plasma cells to lenalidomide. J Biol Chem. 2011; 286: 11009-11020. [cited by applicant]
Boddicker, R. L., Kip, N. S., Xing, X., Zeng, Y., Yang, Z.-Z., Lee, J.-H., . . . Feldman, A. L. (2015). The oncogenic transcription factor IRF4 is regulated by a novel CD30/NF-κB positive feedback loop in peripheral T-c… [cited by applicant]
Chesi, M., et al., The t(4;14) translocation in myeloma dysregulates both FGFR3 and a novel gene, MMSET, resulting in IgH/MMSET hybrid transcripts. Blood, 1998a. 92(9): p. 3025-34. [cited by applicant]
Chesi, M., et al., Dysregulation of cyclin D1 by translocation into an IgH gamma switch region in two multiple myeloma cell lines. Blood, 1996. 88(2): p. 674-81. [cited by applicant]
Chesi, M., et al., Frequent dysregulation of the c-maf proto-oncogene at 16q23 by translocation to an Ig locus in multiple myeloma. Blood, 1998b. 91(12): p. 4457-63. [cited by applicant]
Do, T. N., Ucisik-Akkaya, E., Davis, C. F., Morrison, B. A., & Dorak, M. T. (2010). An intronic polymorphism of IRF4 gene influences gene transcription in vitro and shows a risk association with childhood acute lymphobl… [cited by applicant]
Fesen, M. R., Pommier, Y., Leteurtre, F., Hiroguchi, S., Yung, J., & Kohn, K. W. (1994). Inhibition of HIV-1 integrase by flavones, caffeic acid phenethyl ester (CAPE) and related compounds. Biochemical Pharmacology, 48… [cited by applicant]
Greenberg, A., Walters, D., Kumar, S., Rajkumar V., Jelinek, D., Responsiveness of cytogenetically discrete human myeloma cell lines to lenalidomide: Lack of correlation with cereblon and interferon regulatory factor 4 … [cited by applicant]
Lopez-Girona A, Mendy D, Ito T, Miller K, Gandhi AK, Kang J. (2012). Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide. Leukemia, 26: 2326-2335. [cited by applicant]
Hans, C. P., Weisenburger, D. D., Greiner, T. C., Gascoyne, R. D., Delabie, J., Ott, G., . . . Chan, W. C. (2004). Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry us… [cited by applicant]
Hengeveld, P. J., & Kersten, M. J. (2015). B-cell activating factor in the pathophysiology of multiple myeloma: a target for therapy? Blood Cancer Journal, 5, e282. http://doi.org/10.1038/bcj.2015.3. [cited by applicant]
Iida, S., Rao, P. H., Butler, M., Corradini, P., Boccadoro, M., Klein, B., . . . Dalla-Favera, R. (1997). Deregulation of MUM1/IRF4 by chromosomal translocation in multiple myeloma. Nature Genetics, 17(2), 226-30. http:… [cited by applicant]
Ito T, Ando H, Suzuki T, Ogura T, Hotta K . . . Handa H. (2010) dentification of a primary target of thalidomide teratogenicity. Science. Mar. 12;327(5971):1345 50. [cited by applicant]
Jost, P. J., & Ruland, J. (2007). Aberrant NF-kappaB signaling in lymphoma: mechanisms, consequences, and therapeutic implications. Blood, 109(7), 2700-7. http://doi.org/10.1182/blood-2006-07-025809. [cited by applicant]
Klein, U., Casola, S., Cattoretti, G., Shen, Q., Lia, M., Mo, T., . . . Dalla-Favera, R. (2006). Transcription factor IRF4 controls plasma cell differentiation and class-switch recombination. Nature Immunology, 7(7), 77… [cited by applicant]
Kyle, RA, Gertz, MA, Witzig, TE, et al. Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clinic Proceedings 2003;78(1):21-33. [cited by applicant]
Larki-Harchegani, A., Hemmati, A. A., Arzi, A., Ghafurian-Boroojerdnia, M., Shabib, S., Zadkarami, M. R., & Esmaeilzadeh, S. (2013). Evaluation of the Effects of Caffeic Acid Phenethyl Ester on Prostaglandin E2 and Two … [cited by applicant]
Marriott JB, Muller G, Stirling D, Dalgleish AG. (2001) Immunotherapeutic and antitumour potential of thalidomide analogues. Expert Opin Biol Ther., Jul;1(4):675-82. [cited by applicant]
Matsui W, Wang Q, Barber JP, Brennan S, Smith BD, Borrello I, et al. Clonogenic multiple myeloma progenitors, stem cell properties, and drug resistance. Cancer Res. 2008; 68: 190-197. [cited by applicant]
Morgan GJ, Walker BA, Davies FE. (2012). The genetic architecture of multiple myeloma. Nat Rev Cancer, 12: 335-348. [cited by applicant]
Natarajan, K., Singh, S., Burke, T. R., Grunberger, D., & Aggarwal, B. B. (1996). Caffeic acid phenethyl ester is a potent and specific inhibitor of activation of nuclear transcription factor NF-kappa B. Proceedings of … [cited by applicant]
Nishida, K., et al., The Ig heavy chain gene is frequently involved in chromosomal translocations in multiple myeloma and plasma cell leukemia as detected by in situ hybridization. Blood, 1997. 90(2): p. 526-34. [cited by applicant]
Odqvist, L., Sánchez-Beato, M., Montes-Moreno, S., Martín-Sánchez, E., Pajares, R., Sánchez-Verde, L., . . . Piris, M. A. (2013). NIK controls classical and alternative NF-κB activation and is necessary for the survival… [cited by applicant]
Okutan, H., Ozcelik, N., Yilmaz, H. R., & Uz, E. (2005). Effects of caffeic acid phenethyl ester on lipid peroxidation and antioxidant enzymes in diabetic rat heart. Clinical Biochemistry, 38(2), 191-6. http://doi.org/1… [cited by applicant]
Onori, P.; DeMorrow, S.; Gaudio, E.; Franchitto, A.; Mancinelli, R.; Venter, J.; Kopriva, S.; Ueno, Y.; Alvaro, D.; Savage, J.; et al. Caffeic acid phenethyl ester decreases cholangiocarcinoma growth by inhibition of NF… [cited by applicant]
Patel, S. (2016). Emerging Adjuvant Therapy for Cancer: Propolis and its Constituents. Journal of Dietary Supplements, 13(3), 245-68. http://doi.org/10.3109/19390211.2015.1008614. [cited by applicant]
Rajkumar SV. Multiple myeloma: 2014 update on diagnosis, risk-stratification, and management. Am J Hematol 2014;89(10):998-1009. [cited by applicant]
Rajkumar SV, Hayman SR, Lacy MQ, Dispenzieri A Gertz MA. (2005) Blood. Combination therapy with lenalidomide plus dexamethasone (Rev/Dex) for newly diagnosed myeloma. Blood, Dec. 15;106(13):4050-3. Epub Aug. 23, 2005. [cited by applicant]
Ryu, D., Kim, H. J., Joung, J.-G., Lee, H.-O., Bae, J. S., Kim, S. J., . . . Kim, K. (2014). Comprehensive genomic profiling of IgM multiple myeloma identifies IRF4 as a prognostic marker. Oncotarget, 7(30). http://doi.… [cited by applicant]
Saito, M., Gao, J., Basso, K., Kitagawa, Y., Smith, P. M., Bhagat, G., . . . Dalla-Favera, R. (2007). A signaling pathway mediating downregulation of BCL6 in germinal center B cells is blocked by BCL6 gene alterations i… [cited by applicant]
Sanderson, J. T., Clabault, H., Patton, C., Lassalle-Claux, G., Jean-François, J., Paré, A. F., . . . Touaibia, M. (2013). Antiproliferative, antiandrogenic and cytotoxic effects of novel caffeic acid derivatives in LNC… [cited by applicant]
Shaffer, A. L., Emre, N. C. T., Lamy, L., Ngo, V. N., Wright, G., Xiao, W., . . . Staudt, L. M. (2008). IRF4 addiction in multiple myeloma. Nature, 454(7201), 226-31. http://doi.org/10.1038/nature07064. [cited by applicant]
Shaughnessy, J., Jr., et al., Cyclin D3 at 6p21 is dysregulated by recurrent chromosomal translocations to immunoglobulin loci in multiple myeloma. Blood, 2001. 98(1): p. 217-23. [cited by applicant]
Shen, H., Yamashita, A., Nakakoshi, M., Yokoe, H., Sudo, M., Kasai, H., . . . Moriishi, K. (2013). Inhibitory effects of caffeic acid phenethyl ester derivatives on replication of hepatitis C virus. PloS One, 8(12), e82… [cited by applicant]
Singhal S, Mehta J, Desikan R, Ayers D, Roberson P Barlogie B. (1999) Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med. Nov. 18;341(21):1565-71. [cited by applicant]
Sy, L. B., Yang, L.-K., Chiu, C.-J., & Wu, W.-M. (2011). The immunoregulatory effects of caffeic acid phenethyl ester on the cytokine secretion of peripheral blood mononuclear cells from asthmatic children. Pediatrics a… [cited by applicant]
Szliszka, E., Czuba, Z. P., Bronikowska, J., Mertas, A., Paradysz, A., & Krol, W. (2011). Ethanolic Extract of Propolis Augments TRAIL-Induced Apoptotic Death in Prostate Cancer Cells. Evidence-Based Complementary and A… [cited by applicant]
Toman I, Loree J, Klimowicz AC, Bahlis N, Lai R, Belch A, Pilarski L, Reiman T. (2011). Expression and prognostic significance of Oct2 and Bob1 in multiple myeloma: implications for targeted therapeutics. Leuk Lymphoma … [cited by applicant]
Turesson, I., et al., Patterns of improved survival in patients with multiple myeloma in the twenty-first century: a population-based study. Journal of clinical oncology : official journal of the American Society of Cli… [cited by applicant]
Wang, L., Chu, K., Liang, Y., Lin, Y., & Chiang, B. (2010). Caffeic acid phenethyl ester inhibits nuclear factor-kappaB and protein kinase B signalling pathways and induces caspase-3 expression in primary human CD4+ T c… [cited by applicant]
Wang L, Yao ZQ, Moorman JP, Xu Y, Ning S (2014) Gene Expression Profiling Identifies IRF4-Associated Molecular Signatures in Hematological Malignancies. PLoS One 9(9): e106788. doi:10.1371/journal.pone.0106788. [cited by applicant]
Wang L, Toomey NL, Diaz LA, Walker G, Ramos JC, et al. (2011) Oncogenic IRFs provide a survival advantage for EBV- or HTLV1-transformed cells through induction of BIC expression. J Virol 85: 8328-8337. [cited by applicant]
Watabe, M., Hishikawa, K., Takayanagi, A., Shimizu, N., & Nakaki, T. (2004). Caffeic acid phenethyl ester induces apoptosis by inhibition of NFkappaB and activation of Fas in human breast cancer MCF-7 cells. The Journal… [cited by applicant]
Xu D, Zhao L, Del Valle L, Miklossy J, Zhang L (2008) Interferon regulatory factors 4 is involved in Epstein-Barr virus-mediated transformation of human B lymphocytes. J Virol 82: 6251-6258. [cited by applicant]
Yang Y, Shi J, Tolomelli G, Xu H, Xia J, Wang H. (2013). RARα2 expression confers myeloma stem cell features. Blood, 122: 1437-1447. [cited by applicant]
Zheng, W., Liu, D., Fan, X., Powers, L., Goswami, M., Hu, Y., . . . Wang, S. A. (2013). Potential therapeutic biomarkers in plasma cell myeloma: a flow cytometry study. Cytometry. Part B, Clinical Cytometry, 84(4), 222-… [cited by applicant]
Cited By (1)
US 12,605,352