Pleiotropic Pathway Modification

The ubiquitin proteasome system plays an essential role in maintaining cellular homeostasis. It regulates the timely degradation of diverse cellular proteins, including cell-cycle regulatory proteins, transcription factors, oncoproteins, and tumor suppressors.1-3 Abnormal regulation of E3 ubiquitin ligases, the largest family of ubiquitin ligases, may contribute to uncontrolled proliferation, genomic instability, and cancer.4,5

Cereblon (CRBN) is a component of an E3 ubiquitin ligase complex (CRL4CRBN) that includes Cul4, DDB1, and Roc1.6-10 CRBN is the protein target of the immunomodulatory agents lenalidomide and pomalidomide as well as the pleiotropic pathway modifier (PPMTM) CC-122.6-12 Binding of immunomodulatory or PPM agents to CRBN is hypothesized to result in altered ubiquitination and degradation of key substrates, including Aiolos and Ikaros, inducing T-cell activation via interleukin-2 upregulation and direct anti-tumor effects through interferon regulatory factor 4 and myc downregulation, as shown in preclinical studies.7-9,13

Proposed Mechanism of Action in Hematologic Malignancies

DDX58, DEAD (Asp-Glu-Ala-Asp) box polypeptide 58; GM-CSF, granulocyte-macrophage colony-stimulating factor; IFIT3, interferon-induced protein with tetratricopeptide repeats 3; IFN, interferon; IL, interleukin; IRF7, interferon regulatory factor 7; NK, natural killer; RANTES, regulated on activation, normal T cell expressed and secreted.

Proposed Mechanism of Action in Solid Tumors

CRBN, cereblon; IFN, interferon; NK, natural killer.

The safety and efficacy of the agents and/or uses under investigation have not been established. There is no guarantee that the agents will receive health authority approval or become commercially available in any country for the uses being investigated.

References

  1. Hershko A, et al. Nat Med. 2000;6:1073-1081.
  2. Pickart CM. Cell. 2004;116:181-190.
  3. Jia L, et al. Curr Cancer Drug Targets. 2011;11:347-356.
  4. Nakayama KI, et al. Nat Rev Cancer. 2006;6:369-381.
  5. Wang Z, et al. Nat Rev Cancer. 2014;14:233-247.
  6. Fecteau JF, et al. Blood. 2014;124:1637-1644.
  7. Gandhi AK, et al. Br J Haematol. 2014;164:811-821.
  8. Krönke J, et al. Science. 2014;343:301-305.
  9. Lu G, et al. Science. 2014;343:305-309.
  10. Zhang LH, et al. Br J Haematol. 2013;160:487-502.
  11. Gandhi AK, et al. Clin Lymphoma Myeloma Leuk. 2013;13:S179 [abstract P-287].
  12. Gandhi AK, et al. Blood. 2012;120 [abstract 2963].
  13. Bjorklund CC, et al. Blood. 2014;124 [abstract 4700].