RG4733 / Roche - LARVOL DELTA

CLL Cells within the Proliferation Centers of the Patient Lymph Nodes Are Enriched for Notch Signaling, Thus NOTCH a Viable Target for CLL Therapy (ASH 2023) - "Therefore, as a next logical step we treated the MEC-1 and OSU-CLL cells in culture and primary CLL cell from patients with NOTCH inhibitor RO4929097 (RO), a γ-secretase inhibitor for 24, 48 and 72 hours in vitro...This work was partially supported by bridge funding from the American Association of Hematology awarded to Dr. Runqing Lu, who passed away during the pursuit of this study."

Clinical • Chronic Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • BTK • FBXW7 • IRF4 • NEDD4 • NOTCH1 • NOTCH2

Steric Hindrance By APRIL in Binding of BCMA-Directed Bispecific Antibodies: A Novel Refractory Mechanism of BCMA-Directed Immunotherapies in Multiple Myeloma (ASH 2024) - "mBCMA is shed off as soluble BCMA (sBCMA) by γ-secretase; treatment with the γ-secretase inhibitor RO4929097 substantially increased mBCMA levels on MM cells while reducing sBCMA...We further investigated the effects of APRIL on binding of the anti-BCMA/anti-CD3 bispecific Abs, teclistamab and elranatamab to BCMA in MM cells...Therefore, APRIL derived from OCs might cause steric hindrance of BCMA from anti-BCMA Ab binding and alleviate the efficacy of immunotherapies targeting BCMA. Further study is warranted to overcome the resistant mechanisms for BCMA-directed immunotherapies."

IO biomarker • Hematological Malignancies • Multiple Myeloma • Oncology • CXCL12 • CXCR4 • SDC1 • TNFRSF17

Screening of common genomic biomarkers to explore common drugs for the treatment of pancreatic and kidney cancers with type-2 diabetes through bioinformatics analysis. (PubMed, Sci Rep) - "Finally, we identified six top-ranked drug molecules (NVP.BHG712, Irinotecan, Olaparib, Imatinib, RG-4733, and Linsitinib) as potential common treatments for PC, KC and T2D during their co-existence, supported by the literature reviews. Thus, this bioinformatics study provides valuable insights and resources for developing a genome-guided common treatment strategy for PC and/or KC patients who are also suffering from T2D."

Biomarker • Journal • Diabetes • Genito-urinary Cancer • Hepatology • Kidney Cancer • Metabolic Disorders • Oncology • Pancreatic Cancer • Solid Tumor • Type 2 Diabetes Mellitus • BIRC5 • E2F7 • MUC1 • RRM2 • TOP2A

Structural basis of human γ-secretase inhibition by anticancer clinical compounds. (PubMed, Nat Struct Mol Biol) - "Here we report the cryo-electron microscopy structures of human γ-secretase bound individually to five clinically tested GSIs (RO4929097, crenigacestat, BMS906024, nirogacestat and MK-0752) at overall resolutions of 2.4-3.0 Å. The size and shape of the binding pocket are induced by the bound GSI. Analysis of these structural features suggest strategies for modification of the GSI with improved inhibition potency."

Journal • Oncology • NICD

RO4929097 inhibits NICD3 to alleviate pulmonary hypertension via blocking Notch3/HIF-2α/FoxM1 signaling pathway. (PubMed, In Vitro Cell Dev Biol Anim) - "RO4929097 and plasmids including overexpression-NICD3 (oe-NICD3) and NICD3 small interfering RNA (siRNA) were used to alter the expression of NICD3, and HIF-2α inhibitor PT-2385 was used to alter the expression of HIF-2α. Our data suggest that RO4929097 regulates the Notch3/HIF-2α/FoxM1 signaling pathway by inhibiting the expression of NICD3, thereby inhibiting hypoxia-induced proliferation of HPASMCs. In vivo experiments also confirmed that RO4929097 could alleviate PH as a potential therapeutic strategy."

Journal • Cardiovascular • Congestive Heart Failure • Heart Failure • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • EPAS1 • FOXM1 • NOTCH3

RO4929097 and Whole-Brain Radiation Therapy or Stereotactic Radiosurgery in Treating Patients With Brain Metastases From Breast Cancer (clinicaltrials.gov) - P1/2 | N=5 | Terminated | Sponsor: National Cancer Institute (NCI) | Phase classification: P1 ➔ P1/2

Phase classification • Surgery • Breast Cancer • Cutaneous Melanoma • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Negative Breast Cancer • Lung Cancer • Male Breast Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • ER • HER-2

Screening of differential gene expression patterns through survival analysis for diagnosis, prognosis and therapies of clear cell renal cell carcinoma. (PubMed, PLoS One) - "Then we detected 10 repurposable drug molecules (Irinotecan, Imatinib, Telaglenastat, Olaparib, RG-4733, Sorafenib, Sitravatinib, Cabozantinib, Abemaciclib, and Dovitinib.) by molecular docking with KGs-mediated receptor proteins. Their ADME/T analysis and cross-validation with the independent receptors, also supported their potent against ccRCC. Therefore, these outputs might be useful inputs/resources to the wet-lab researchers and clinicians for considering an effective treatment strategy against ccRCC."

Biomarker • Journal • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • CD4 • CD8 • SERPINA5 • SLC2A3

PS1 regulates processing and angiogenic signalling of VEGFR2; effects of FAD mutants. (AAIC 2024) - "This loss of function is comparable to the effect of γ-secretase inhibitor RO4929097... PS1 FAD mutants decrease production of signaling peptide VEGFR2/CTF2 probably due to reduced γ-secretase activity of FAD mutants. Interestingly FAD mutations do not seem to affect the PS1-VEGFR2 association. Our data support that PS1 regulates downstream signaling and angiogenic functions of VEGFR2."

Alzheimer's Disease • CNS Disorders • CEBPZ

The E2F1/MELTF axis fosters the progression of lung adenocarcinoma by regulating the Notch signaling pathway. (PubMed, Mutat Res) - "Together, our outcomes demonstrated that E2F1 fostered LUAD progression by activating MELTF via the Notch signaling activity. Hence, MELTF emerged as a feasible target for treating LUAD."

Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • E2F1 • HES1 • MELTF • MFI2 • NOTCH1

Cdk4 Regulates Glioblastoma Cell Invasion and Stemness and Is Target of a Notch Inhibitor Plus Resveratrol Combined Treatment. (PubMed, Int J Mol Sci) - "In this study, we found that in GBM cells, treatment with low toxicity doses of the γ-secretase inhibitor RO4929097 (GSI), blocking the Notch pathway activity, in combination with resveratrol (RSV) was able to reverse the basal mesenchymal phenotype to an epithelial-like phenotype, affecting invasion and stemness interplay...The exogenous expression of a constitutively active Cdk4 mutant prevented the RSV + GSI inhibitory effects in GBM cell motility/invasion and augmented the expression of stemness-specific markers, as well as the neurosphere sizes/forming abilities in untreated cells. In conclusion, we propose that Cdk4 is an important regulator of GBM stem-like phenotypes and invasive capacity, highlighting how the combined treatment of Notch inhibitors and RSV could be prospectively implemented in the novel therapeutic strategies to target Cdk4 for these aggressive brain tumors."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • CCND1 • CDK4 • VCL

NOTCH pathway inactivation reprograms stem-like oral cancer cells to JAK-STAT dependent state and provides the opportunity of synthetic lethality. (PubMed, Transl Oncol) - "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."

Journal • Synthetic lethality • Head and Neck Cancer • Oncology • Oral Cancer • Solid Tumor • STAT3

Anti-tumor activity of HPN217, a BCMA-targeting tri-specific T cell engager, is enhanced by γ-secretase inhibitors in preclinical models (AACR 2023) - P1 | "To evaluate the effects of GSIs on BCMA expression, MM cell lines MOLP8, KMS-12-BM, and MM.1S were incubated with GSIs LY3039478, PF03084014, or RO4929097overnight. By contrast, the combination of HPN217 and LY3039478 led to a significant increase in survival compared to vehicle or either monotherapy, with a median survival of 43 days. Taken together these results demonstrate the potential utility of GSIs to enhance the anti-tumor activity of HPN217 and supports further investigation of this combinatorial approach in patients."

IO biomarker • Preclinical • Trispecific • Hematological Malignancies • Multiple Myeloma • Oncology

Oscillatory shear stress modulates Notch-mediated endothelial mesenchymal plasticity in cerebral arteriovenous malformations. (PubMed, Cell Mol Biol Lett) - "Our study provides, for the first time, evidence for the role of oscillatory shear stress in mediating the EndMT process and dysregulated expression of cell adhesion molecules, especially multifunctional integrin α9/β1 in human cAVM nidus. Concomitantly, our findings indicate the potential use of small-molecular inhibitors such as RO4929097 in the less-invasive therapeutic management of cAVMs."

Journal • Cardiovascular • Cerebral Hemorrhage • CNS Disorders • Hematological Disorders • Vascular Neurology • CD4 • CDH2 • CDH5 • NOTCH3 • SNAI1

Targeting notch signaling pathway in breast cancer stem cells through drug repurposing approach. (PubMed, Mol Divers) - "In-silico docking potential of Venetoclax was better than the standard γ-secretase inhibitor RO4929097. Venetoclax appeared as the most promising drug of the 1615 FDA-approved drugs. Our in-silico findings suggest that Venetoclax may act as a γ-secretase inhibitor against the Notch signaling pathway in breast cancer stem cells."

Cancer stem cells • Journal • Breast Cancer • Oncology • Solid Tumor

RO4929097, a Selective γ-Secretase Inhibitor, Inhibits Subretinal Fibrosis Via Suppressing Notch and ERK1/2 Signaling in Laser-Induced Mouse Model. (PubMed, Invest Ophthalmol Vis Sci) - "RO exerts its antifibrotic effect by directly inhibiting Notch signaling and indirectly suppressing ERK1/2 signaling. Targeting Notch signaling might provide a therapeutic strategy in prevention and treatment of subretinal fibrosis in neovascular age-related macular degeneration (nAMD)."

Journal • Preclinical • Age-related Macular Degeneration • Fibrosis • Immunology • Macular Degeneration • Ophthalmology • Retinal Disorders • Wet Age-related Macular Degeneration • SMAD2 • TGFB1

Down-regulated NEDD4L facilitates tumor progression through activating Notch signaling in lung adenocarcinoma. (PubMed, PeerJ) - "Consequently, NEDD4L negatively regulated Notch signaling activation in LUAD cells, and RO4929097 (a Notch inhibitor) treatment effectively repressed the effect of NEDD4L knockdown on LUAD cell proliferation. Taken together, these results demonstrate that down-regulated NEDD4L facilitates LUAD progression by activating Notch signaling, and NEDD4L may be a promising target to treat LUAD."

Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • NOTCH2

CAF-TUMOR STC1-NOTCH1 FEEDFORWARD SIGNAL PROMOTES THE STEM CELL CHARACTERISTICS AND THE ACTIVATION OF NOTCH SIGNALING PATHWAY IN HCC. (DDW 2022) - "The role of Notch signaling pathway was verified by inhibiting with γ-secretase inhibitor (RO4929097) or lentivirus...CAF-derived STC1 activated Notch signaling pathway in HCC cells via STC1 directly binding Notch 1 gene, and STC1 was a direct transcriptional target of CSL in HCC cells. In our study, a CAF-Tumor STC1-Notch1 feedforward signal was established that could be a potential therapeutic target for targeted therapy in HCC.Key words: Hepatocellular carcinoma, the stemness characteristics, Cancer associated fibroblasts, Stanniocalcin-1, Notch signaling pathway"

Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • CAFs • NOTCH1 • STC • STC1

Numb-PRRL promotes TGF-β1- and EGF-induced epithelial-to-mesenchymal transition in pancreatic cancer. (PubMed, Cell Death Dis) - "Numb-PRRL overexpression activated TGFβ1-Smad2/3-Snail1 signaling was significantly reversed by the Notch1 inhibitor RO4929097...In vivo, Numb-PRRL overexpression or silencing promoted or inhibited subcutaneous tumor size and distant liver metastases via regulating EMT and Snail signaling, respectively. Numb-PRRL promotes TGF-β1- and EGF-induced EMT in PC by regulating TGF-β1-Smad2/3-Snail and EGF-induced EGFR-ERK/MAPK signaling."

Journal • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CDH1 • NOTCH1 • SNAI1 • SNAI2 • TGFB1 • VIM

PS1 FAD mutant M146V decreases VEGF-induced angiogenesis in brain endothelial cells. (PubMed, Alzheimers Dement) - "Our findings suggest that VEGFR2 is processed by γ-secretase and that γ-secretase promotes VEGF-induced angiogenic functions of brain ECs. Our data also show that PS1 FAD mutant decreases angiogenic functions of pCEC. Importantly the effects of PS1 FAD mutants occur in the absence of amyloid plaques and neurofibrillary tangles indicating that PS1 FAD mutants can affect angiogenesis independent of the neuropathological hallmarks of AD."

Journal • Alzheimer's Disease • CNS Disorders • Dementia • CDH5 • VEGFA

A Phase Ib/II Randomized Study of RO4929097, a Gamma Secretase or Notch Inhibitor with or without Vismodegib, a Hedgehog Inhibitor, in Advanced Sarcoma. (PubMed, Clin Cancer Res) - "The combination of RO4929097 plus vismodegib was generally well tolerated. Although accrual to this study was not completed, vismodegib did not meaningfully enhance the clinical efficacy of RO4929097 in an unplanned analysis. GSIs and GSIs plus vismodegib can inhibit intratumoral Notch and downstream pAkt signaling."

Journal • P1/2 data • Oncology • Sarcoma • Solid Tumor

A Notch inhibitor plus Resveratrol induced blockade of autophagy drives glioblastoma cell death by promoting a switch to apoptosis. (PubMed, Am J Cancer Res) - "We used low doses of the γ-secretase inhibitor RO4929097 (GSI), to block the Notch pathway activity, in combination with Resveratrol (RSV) and we evidenced the mechanisms of autophagy/apoptosis transition in GBM cells...In short, we establish the role of CDK4 in the regulation of autophagy/apoptosis transition induced by RSV and GSI in GBM cells. This new synergistic therapeutic combination, increasing the accumulation of autophagosomes, may have therapeutic value for GBM patients."

Journal • Brain Cancer • Glioblastoma • Glioma • Oncology • Solid Tumor • CASP3 • CASP8 • CASP9 • CDK4 • PARP1

A Phase Ib Dose Escalation Trial of RO4929097 (a γ-secretase inhibitor) in Combination with Exemestane in Patients with ER + Metastatic Breast Cancer (MBC). (PubMed, Clin Breast Cancer) - P1 | "In animal models of endocrine-resistant breast cancer, combinations of tamoxifen and GSIs produce additive or synergistic efficacy, while decreasing the intestinal toxicity of GSIs. Ten patients with evaluable archival tissue showed expression of PKCα, which correlated with expression of Notch4. Mammospheres from a PKCα-expressing, endocrine-resistant T47D cell line were inhibited by a GSI-fulvestrant combination Our data indicate that combinations including endocrine therapy and Notch inhibitors deserve further investigation in endocrine-resistant ERα-positive breast cancer."

Clinical • Combination therapy • Journal • P1 data • Anorexia • Breast Cancer • Diabetes • Estrogen Receptor Positive Breast Cancer • Fatigue • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Renal Disease • Respiratory Diseases • Solid Tumor • ER • NOTCH4

DR-5 and DLL-4 mAb Functionalized SLNs of Gamma-Secretase Inhibitors- An Approach for TNBC Treatment. (PubMed, Adv Pharm Bull) - "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."

Journal • Review • Breast Cancer • Cardiovascular • Fatigue • Heart Failure • Hypertension • Oncology • Pain • Solid Tumor • Triple Negative Breast Cancer • TNFRSF10B

Human umbilical vein endothelial cells derived-exosomes promote osteosarcoma cell stemness by activating Notch signaling pathway. (PubMed, Bioengineered) - "Human osteosarcoma cells (U2OS and 143B) were treated with HUVECs supernatant, HUVECs-exosomes with or without RO4929097 (γ secretase inhibitor, used to block Notch signaling pathway)...In conclusion, this work demonstrated that HUVECs-exosomes promoted cell stemness in osteosarcoma through activating Notch signaling pathway. Thus, our data reveals the mechanism of HUVECs-exosomes in regulating cell stemness of osteosarcoma, and provides a theoretical basis for osteosarcoma treatment by exosomes."

Journal • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • HES1 • KIT • NOTCH1 • POU5F1 • SOX2

Lysine-specific demethylase 1 induced epithelial-mesenchymal transition and promoted renal fibrosis through Jagged-1/Notch signaling pathway. (PubMed, Hum Exp Toxicol) - "Taken together, LSD1 significantly impact on the progression of TGF-β1-mediated EMT and ECM deposition in HK-2 cells, and it may represent novel target for the prevention strategies of renal fibrosis."

Journal • Fibrosis • Immunology • CDH1 • FN1 • KDM1A • NOTCH1 • NOTCH2 • TGFB1 • VIM