CC-486 (DNA Methyltransferase Inhibitor)

Proposed Mechanism of Action

The epigenetic modifier CC-486 (an oral formulation of azacitidine)1 is a cytidine nucleoside analogue that is incorporated into newly synthesized DNA as well as RNA.2-4 Once incorporated, CC-486 may deplete DNA methyltransferase 1 (DNMT1), induce DNA damage, and promote hypomethylation of DNA.2,5 The antineoplastic effects of CC-486 are hypothesized to result from this DNA hypomethylation and the ultimate unsilencing of genes involved in cell cycle regulation.2,5

CC-486 Hypothesized Mechanism of Action

CC-486 is an epigenetic modifier hypothesized to induce malignant cell death through the inhibition of protein synthesis or the activation of DNA damage response pathways in hematologic malignancies and solid tumors.

Rationale for Investigation of CC-486 in Hematologic Malignancies

It is hypothesized that prolonged exposure to CC-486 may maximize DNA hypomethylation in hematologic malignancies, such as acute myeloid leukemia, lymphoma, and myelodysplastic syndromes.

Rationale for Investigation of CC-486 in Solid Tumors

Hypothesized re-expression of epigenetically silenced tumor suppressor genes by CC-486 may reverse resistance to chemotherapy and prime solid tumors, such as breast and lung cancer, for subsequent cancer therapies.

CC-486 by Disease State

CC-486 in Acute Myeloid Leukemia

  • Phase 3 Acute Myeloid Leukemia Post-induction AML maintenance
  • View Trials Investigating CC-486 in Acute Myeloid Leukemia.

    CC-486 in AML

Rationale for Clinical Development

Preclinical studies suggest that the antileukemic effects of CC-486 include direct cytotoxicity due to inhibition of protein synthesis and DNA damage and the re-expression of aberrantly silenced tumor suppressor genes due to DNA hypomethylation.2,5-7 In vitro studies have shown that serial cycles of DNA replication are required to induce hypomethylation, and extensive demethylation requires prolonged exposure.2,3,8 Extended dosing with CC-486 may prolong drug exposure, which is hypothesized to allow more opportunity for incorporation into cycling malignant cells.2

Most patients with acute myeloid leukemia (AML) will relapse following achievement of remission with intensive chemotherapy, and it has been shown that duration of remission is predictive of long-term outcomes.8 Stem cell transplant is associated with the lowest rates of relapse.9 However, not all patients are candidates for stem cell transplant, and relapse remains a significant problem even for patients who do receive a transplant.10-12 There is an unmet need to prolong duration of remission following intensive chemotherapy with or without stem cell transplant.

CC-486 in Breast Cancer

  • Phase 2 Breast Cancer Metastatic

Rationale for Clinical Development

Based on preclinical evidence, azacitidine is hypothesized to exert antineoplastic effects through hypomethylation of DNA and induction of DNA damage.2 Furthermore, in vitro studies demonstrated that through incorporation into RNA, azacitidine may lead to inhibition of protein synthesis.2

It is estimated that hormone receptor (HR)–positive disease accounts for approximately 75% to 85% of breast cancer in the Western world.9 For HR-positive patients treated with hormonal therapies, treatment options are limited once the disease progresses with sequential endocrine therapy.10 CC-486 may allow for extended dosing and prolonged drug exposure, which is hypothesized to provide more opportunity for incorporation into cycling malignant cells.11 Preclinical studies suggest that epigenetic-modifying agents, such as CC-486, may have possible functions in reversing resistance to hormonal therapy.12,13

CC-486 in Lymphoma

  • Phase 1 Lymphoma Diffuse large B-cell lymphoma

Rationale for Clinical Development

Preclinical studies suggest that CC-486 has antitumor effects that include direct cytotoxicity due to activation of DNA damage response pathways, inhibition of protein synthesis, and re-expression of aberrantly silenced tumor suppressor genes due to DNA hypomethylation.2,5-7 One study in lymphoma cell lines has suggested that this hypomethylation may lead to re-expression of antitumor genes that are commonly silenced in non-Hodgkin lymphoma.14

CC-486 in Lung Cancer

  • Phase 2 Lung Cancer Non-small cell lung: Advanced

Rationale for Clinical Development

DNA hypermethylation occurs in many solid tumor types and can result in the silencing of tumor suppressor genes.6,15-18 This silencing may support tumor development by promoting survival and clonal expansion of tumor stem cells.19 CC-486 reduces DNA methylation, as demonstrated in correlative studies.1,3,6 Both in vitro and in correlative studies, DNA demethylating agents have been shown to unsilence tumor suppressor genes, potentially allowing tumor cells to become more sensitive to anti-cancer therapies; this process is known as epigenetic priming.7,20-26

CC-486 in Myelodysplastic Syndromes

  • Phase 3 Myelodysplastic Syndromes Lower-risk
  • Phase 2 Myelodysplastic Syndromes Post hypomethylating agent (HMA) failure
  • View Trials Investigating CC-486 in Myelodysplastic Syndromes.

    CC-486 in MDS

Rationale for Clinical Development

Similar to the effects described in AML, CC-486 has exhibited antileukemic effects in preclinical studies.2,5-7 Additionally, prolonged exposure to CC-486 may allow more opportunity for incorporation into cycling malignant cells.2,3,8

Approximately two-thirds of patients with myelodysplastic syndromes (MDS) present with lower-risk disease that is generally viewed as having a favorable prognosis27 and is often treated with only supportive care.1 However, many patients with lower-risk disease have poor prognostic features and could benefit from early active treatment.1The only potential cure for most patients with MDS remains stem cell transplant, which is generally reserved for younger patients with higher-risk disease.28,29 However, even patients who receive a transplant often relapse.28 There is an unmet need for additional treatment options in the post-transplant setting to improve disease-free survival.


  1. Garcia-Manero G, et al. Leukemia. 2008;22:1680-1684. PMID: 18548103
  2. Hollenbach PW, et al. PLoS One. 2010;5:e9001. PMID: 20126405
  3. Garcia-Manero G, et al. J Clin Oncol. 2011;29:2521-2527. PMID: 21576646
  4. Santi DV, et al. Proc Natl Acad Sci. 1984;91:6993-6997. PMID: 6209710
  5. Palii SS, et al. Mol Cell Biol. 2008;28:752-771. PMID: 17991895
  6. Herman JG, et al. Proc Natl Acad Sci. 1994;91:9700-9704. PMID: 7937876
  7. Li H, et al. Am J Obstet Gynecol. 2009;177.
  8. Lu LJ, Randerath K. Mol Pharmacol. 1984;26:594-603. PMID: 6208475
  9. Glück S. Clin Breast Cancer. 2014;14:75-84. PMID: 24355138
  10. NCCN Clinical Practice Guidelines in Oncology. Breast Cancer. V2.2015. PMID: 25870381
  11. Laille E, et al. J Clin Pharmacol. 2014;54:630-639. PMID: 24374798
  12. Di Cello F, et al. PLoS One. 2013;8:e68630. PMID: 23844228
  13. Pitta CA, et al. Cancer Lett. 2013;337:167-176. PMID: 23752064
  14. Wang W, et al. Int J Mol Med. 2015;36:698-704. PMID: 26133246
  15. Ibanez de Caceres I, et al. Cancer Res. 2004;64:6476-6481. PMID: 15374957
  16. Merlo A, et al. Nat Med. 1995;1:686-692. PMID: 7585152
  17. Burbee DG, et al. J Natl Cancer Inst. 2001;93:691-699. PMID: 11333291
  18. Sakai E, et al. World J Gasteroenterol. 2014;20:978-987. PMID: 24574770
  19. Jones PA, Baylin SB. Cell. 2007;128:683-692. PMID: 17320506
  20. Li H, et al. Oncotarget. 2014;5:587-598. PMID: 24583822
  21. Matei D, et al. Cancer Res. 2012;72:2197-2205. PMID: 22549947
  22. Juergens RA, et al. Cancer Disc. 2011;1:598-607. PMID: 22586682
  23. Gordian E, et al. Anticancer Res. 2009;29:3207-3210. PMID: 19661336
  24. Juergens RA, Rudin CM. Am Soc Clin Oncol Educ Book. 2013. doi: 10.1200/EdBook_AM.2013.33.e295. PMID: 23714528
  25. LoRusso P, et al. Mol Cancer Ther. 2013; 12(suppl) [abstract A120].
  26. Laille E, et al. Mol Cancer Ther. 2013; 12(suppl) [abstract B217].
  27. Greenberg P, et al. Blood. 1997;89:2079-2088. PMID: 9058730
  28. Garcia-Manero G, et al. Am J Hematol. 2014;89:97-108. PMID: 24464505
  29. NCCN Clinical Practice Guidelines in Oncology. Myelodysplastic Syndromes. V2.2015.