LY-411575

Our findings strongly indicate that c-Fos plays a crucial role in the promotion of cell proliferation through Notch1 signaling in KSHV-infected cells. Furthermore, our results suggest that the inhibition of expression of key viral pathogenic proteins is likely involved in this process.

Therefore, we have focused on combination therapy using a γ-secretase inhibitor LY411575 that would enhance the efficacy of SAHA by blocking the canonical Notch pathway mediated via its intracellular domain. Besides, it also mediates autophagy-independent cell death and diminishes the expression of inflammatory cytokines, along with the downregulation in the expression of the Notch downstream genes and mesenchymal markers. Altogether, our study provides a mechanistic basis for combating EMT potentiated by SAHA, which could be utilized as a rational strategy for the treatment of solid tumors, especially triple-negative breast cancer.

Study revealed for the first time that NOTCH pathway-inactive state exhibit activation of JAK-STAT pathways, as synthetic lethal pair. Therefore, co-inhibition of these pathway may serve as novel therapeutic strategy against aggressive oral cancer.

LY411575 is most effective, showing ~2-log greater potency than DAPT in all tested MM cell lines and patient MM cells regardless of baseline BCMA expression and statuses of disease and drug resistance...Moreover, a single treatment with GSI at ~ 2-log lower drug concentration than used to induce anti-cancer activity maximizes mBCMA density without harming normal cells. Rationally incorporating GSI into all BCMA-targeting immunotherapy therefore represents a promising novel combination approach to further improve patient outcome in MM.

GSIs, i.e., 2 nM LY-411575 or 1 μM DAPT, robustly increased mBCMA densities on CD138 but not CD3 patient cells, concomitantly with minimum soluble/shed BCMA (sBCMA) in 1 day-culture supernatants...Importantly, LY41157 rapidly cleared sBCMA from circulation of MM-bearing NSG mice reconstituted with human T cells and significantly enhanced anti-MM efficacy of PL33 with prolonged host survival. Taken together, these results further support ongoing combination BCMA-targeting immunotherapies with GSI clinical studies to improve patient outcome.

Furthermore, overexpression of the MAEL gene enhanced drug resistance against LY411575. Conclusively, MAEL promotes LY411575 resistance in T-ALL cells increasing the expression of MRP and LRP genes.

Further, the GSIs (DAPT, LY-411575, RO4929097, MK0752, etc.) suffer from poor bioavailability and off-target side effects such as diarrhea, suppression of lymphopoiesis, headache, hypertension, fatigue, and ventricular dysfunctions. The delivery system is designed to deliver the drug cargo precisely to TNBCs through its DR-5 receptors and hence expected to reduce the off-target side effects of GSIs. Further, DLL4 mAb and GSIs are expected to act synergistically to block the Notch signal mediated BCSCs proliferation, differentiation, and metastasis.

Therefore, in IRB and IACUC approved studies, we investigated mBCMA and sBCMA in AL patient marrow and blood specimens, modulated mBCMA on CD138-selected AL plasma cells with the γ-secretase inhibitor (GSI) LY-411575, and studied sBCMA in the blood of smoldering multiple myeloma patients (SMM) and in a mouse xenograft model with the λ light-chain secreting ALMC-1 AL cell line... mBCMA expression is present on AL plasma cells and sBCMA is present in all AL patients and correlates with iFLC. mBCMA can be significantly up-regulated on AL patient plasma cells with GSI. sBCMA may be useful as a marker of disease activity in patients with low iFLC.

Such therapeutic resistance could be overcome through combined treatments with LY-411575 and phenformin. Overall, we uncover a previously unappreciated plasticity of LKB1-deficient tumors and identify the Nanog-Notch axis in regulating gastric differentiation, which holds important therapeutic implication for the treatment of mucinous lung cancer.