Page 32 - Read Online

Sabol et al. J Cancer Metastasis Treat 2021;7:20 https://dx.doi.org/10.20517/2394-4722.2021.35 Page 9 of 15

The contribution of Notch signals to the protracted suppression of bone formation in MM is unclear.
Osteoblast precursors isolated from MM patients exhibit increased Notch signaling and decreased
osteogenic capacity compared to precursors derived from healthy subjects [101,102] . Interestingly, treatment
with GSI restored Runx2 expression and the osteogenic capacity in osteoblasts precursors from MM
patients in vitro, suggesting a potential role of Notch signaling in the suppression of new bone formation
induced by MM cells [101,102] . Yet, studies manipulating Notch components in osteoblastic cells are required to
establish the specific contribution of Notch signaling in MM-induced suppression of osteoblastogenesis. It
is also possible that MM cells suppress osteoblasts indirectly, by acting on other cells in the marrow
microenvironment. In this regard, our group has reported that MM cells deeply alter osteocyte biology in
[43]
bones infiltrated with MM tumors . For instance, MM cells increase the expression in osteocytes of critical
regulators of bone remodeling, such as Sclerostin or Dkk-1. Genetic and pharmacologic inhibition of
Sclerostin dramatically improves bone health in animal models of established disease, with no effects on
tumor growth [15-17] . Although it has been shown that genetic manipulation of Notch components in bone
cells can result in changes in Sclerostin production , whether the increase in osteocyte-derived Sclerostin
[103]
induced by MM cells is secondary to Notch activation remains to be determined. Importantly,
pharmacologic inhibition of this pathway in animal models of MM results in decreased bone resorption and
mitigation of the osteolytic disease, with no significant effects on bone formation [49,54,101,104,105] .

Collectively, these findings suggest that Notch signals contribute to the development of bone disease in
MM, primarily through the generation of a microenvironment conducive to bone resorption and
destruction. Further studies are needed to clarify the potential role of Notch signaling in osteoblasts
suppression.

NOTCH COMPONENTS AS THERAPEUTIC TARGETS
Several strategies have been tested to inhibit Notch [106-108] . However, due to the role of Notch signaling in the
development and homeostasis of multiple tissues, the majority of approaches developed so far have led to
undesirable, dose-limiting toxicities. For a detailed review of the existing clinical trials testing Notch
[106]
inhibitors in cancer patients, refer to the recent manuscript by Moore et al. . The most traditional and
common approach to inhibit Notch is to prevent the proteolytic cleavage of the Notch receptors by blocking
the γ-secretase complex with GSIs [109,110] . GSIs are attractive due to their ability to unselectively inhibit Notch
signaling regardless of the ligand-Notch receptor involved. However, GSIs can lead to severe unwanted
side-effects on tissues endogenously regulated by Notch, particularly the gut, where Notch inhibition causes
secretory goblet cell metaplasia [110,111] . So far, the FDA has only approved, via Orphan Drug Designation and
Fast Track Designation, the use of the GSIs Nirogacestat and AL101, for the treatment of desmoid tumors
and Notch-mutant adenoid cystic carcinoma respectively, an important breakthrough in this field of
research [106,107] . A more targeted approach to inhibit Notch is the use of monoclonal antibodies or soluble
decoys against individual Notch components to disrupt specific ligand-receptor interactions. Several
antibodies against Dll 4 (Demcizumab) and Notch receptors 1, 2, and 3 (Brontictuzumab and Tarextumab)
have been tested in clinical trials [106,107] . Unfortunately, lack of clinic benefit over standard of care or
intolerable toxicities have precluded the approval of these agents in the clinic. Moreover, these strategies are
limited to particular Notch ligand-receptor interactions and thus, might not have a widespread application
for the treatment of cancer patients. Another approach is the use of small-molecule inhibitors to target the
Notch transcription complex (i.e., SAHM1, RIN1, and CB-103) [106,107] . Promising results have been obtained
in preclinical models with these agents, particularly with CB-103, which exhibited a safe profile with no gut
toxicity . Ongoing clinical trials are evaluating CB-103’s anti-tumor efficacy in solid and hematological
[112]
malignancies (NTC034226790).