Notch Signaling

The Notch signaling pathway plays a central role in the development of stem cells by regulating cell-fate decisions, such as proliferation, apoptosis, and differentiation.1,2 Aberrant Notch signaling has been associated with tumorigenesis and chemoresistance in a variety of cancers.2,3

The Notch signaling pathway consists of 4 Notch receptors and at least 5 ligands, including Delta-like ligands (DLLs) 1, 3, and 4.2 Preclinical studies suggest that blocking DLL4 results in anti-tumor activity via multiple mechanisms, including reducing cancer stem cell frequency, promoting cell differentiation, deregulating angiogenesis, and augmenting anti-tumor immune responses.4-7

In a preclinical study, the combination of anti-DLL4 plus anti-VEGF with an anti–PD-1 checkpoint inhibitor demonstrated heightened anti-tumor and immune-cell memory responses.8 A phase Ib clinical trial is evaluating the combination of demcizumab and pembrolizumab in solid tumors.9

CSC, cancer stem cell; DC, dendritic cell; DLL4, Delta-like ligand 4; IL, interleukin; i-NOS, inducible nitric oxide synthase; MDSC, myeloid-derived suppressor cell; Th17, T helper 17.

Celgene has partnered with OncoMed Pharmaceuticals in developing demcizumab (anti-DLL4) for the treatment of non-small cell lung and pancreatic cancers. Celgene has also partnered with OncoMed in developing OMP-305B83, a bispecific antibody targeting DLL4 and VEGF.

Demcizumab and OMP-305B83 are currently owned by OncoMed Pharmaceuticals.

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. Hori K, et al. J Cell Sci. 2013;126:2135-2140.
  2. Ntziachristos P, et al. Cancer Cell. 2014;25:318-334.
  3. Güngör C, et al. Br J Pharmacol. 2014;171:849-858.
  4. Yan M, Plowman GD. Clin Cancer Res. 2007;13:7243-7246.
  5. Fischer M, et al. Cancer Res. 2011;71:1520-1525.
  6. Hoey T, et al. Cell Stem Cell. 2009;5:168-177.
  7. Srivastava M, et al. AACR 2015 [abstract 225].
  8. Srivastava M, et al. J Immunother Cancer. 2015;3(suppl2):P373.
  9. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02722954. Accessed June 30, 2016.