MK-0752 / Cancer Research UK, Merck (MSD) - LARVOL DELTA

Daxx is a novel predictive biomarker of response to anti-notch plus endocrine therapy to target cancer stem cells in ER-positive breast cancer (SABCS 2025) - "This research in both cell lines and xenografts uniquely demonstrated that GSI-induced DAXX was necessary for the anti-CSC and anti-tumor efficacy of the GSI. DAXX is a potent CSC inhibitor and possible predictive biomarker of response to ET or ET plus the GSI MK-0752. In summary, ET plus a GSI modulated Notch and other CSC genes, in particular DAXX, a potential predictive biomarker of ET plus GSI efficacy in ER+ BC."

Biomarker • Cancer stem • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ALDH1A1 • CDH1 • DAXX • ER • FOXA1 • GATA3 • KLF4 • NANOG • NOTCH1 • NOTCH4 • SOX2

Implication of an exosome-based gene signature for estimating clinical outcomes of triple-negative breast cancer and assisting in individualized therapy. (PubMed, Sci Rep) - "High-risk tumors owned shorter overall survival time, but were suitable for treatment with docetaxel and several small-molecule agents (MK-0752, BRD-K33199242, IC-87114, fumonisin B1, ilomastat, GW-788388, afobazole, and batimastat). Experimentally, inhibition of FAM129B effectively attenuated proliferative and aggressive phenotypes of TNBC cells. Collectively, our findings proposed the exosome-based gene signature for accurate estimation of clinical outcomes and assisting in individually tailoring therapies in TNBC as well as discovered FAM129B as a potential therapeutic target."

Biomarker • Clinical data • Gene Signature • IO biomarker • Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CD276 • KRT6A • NRP1 • PGK1 • SERPINE1 • THY1 • TNFRSF4 • TNFSF4

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

A novel platelets-related gene signature for predicting prognosis, immune features and drug sensitivity in gastric cancer. (PubMed, Front Immunol) - "Furthermore, High-risk patients tended to be more sensitive to thalidomide, MK-0752, and BRD-K17060750. The novel platelets-related genes signature we identified could be used for prognosis and treatment prediction in GC."

Biomarker • Gene Signature • Journal • Gastric Cancer • Oncology • Solid Tumor • ANXA5 • APOA1 • SERPINE1

Molecular analysis of BRCA1 and BRCA2 genes in La Rioja (Spain): five new variants. (PubMed, Hered Cancer Clin Pract) - "The spectrum of pathogenic variants in the BRCA1/2 genes in La Rioja is similar to that in other Spanish regions, with some unique characteristics. The pathogenic c.6024dupG variant in the BRCA2 gene was detected in a large number of families and could have a founding effect in the Ebro riverside areas in the regions of La Rioja and Navarra."

Biomarker • Journal • Oncology • Ovarian Cancer • Solid Tumor • BRCA1 • BRCA2

Combined Treatment of Uterine Leiomyosarcoma with Gamma Secretase Inhibitor MK-0752 and Chemotherapeutic Agents Decreases Cellular Invasion and Increases Apoptosis. (PubMed, Cancers (Basel)) - "In conclusion, the combinations of MK-0752 with either doxorubicin, docetaxel, or gemcitabine plus docetaxel are potential novel therapeutic approaches for uLMS. (* p < 0.05, ** p < 0.01)."

Journal • Leiomyosarcoma • Oncology • Sarcoma • Solid Tumor • Uterine Corpus Leiomyosarcoma

Combined Treatment of Uterine Leiomyosarcoma with Gamma Secretase Inhibitor MK-0752 and Chemotherapeutic Agents Decreases Cellular Invasion and Increases Apoptosis (Multidisciplinary Digital Publishing Institute) - "Cell cycle analysis demonstrated increases in the apoptotic sub-G1 population with MK-0752 alone in SK-UT-1B (1.4-fold) and SK-LMS-1 (2.7-fold), along with increases with all combinations in both cell lines. The combination treatments had limited effects on proliferation, while MK-0752 alone decreased proliferation in SK-LMS-1 (0.63-fold). Both MK-0752 alone and in combination altered gene expression and KEGG pathways."

Preclinical • Uterine Corpus Leiomyosarcoma

Clinical research progress of ridaforolimus (AP23573, MK8668) over the past decade: a systemic review. (PubMed, Front Pharmacol) - "Rapamycin, an established mTOR inhibitor in clinical practice, is widely recognized for its therapeutic efficacy...These trials employed diverse drug combinations, incorporating agents such as ponatinib, bicalutamide, dalotuzumab, MK-2206, MK-0752, and taxanes...Our review encompassed analyses of signaling pathways, ridaforolimus as a single therapeutic agent, its compatibility in combination with other drugs, and an assessment of adverse events (AEs). We conclude by recommending further research to advance our understanding of ridaforolimus's clinical applications."

Journal • Review • Breast Cancer • Endometrial Cancer • Genito-urinary Cancer • Oncology • Ovarian Cancer • Prostate Cancer • Renal Cell Carcinoma • Solid Tumor

Gamma secretase inhibitors, in combination with cytotoxic agents, decrease migration and invasion of uterine leiomyosarcoma (SGO 2024) - "In clinical practice, commonly used chemotherapeutic agents, including gemcitabine (Gem) with docetaxel (Doce) or single doxorubicin (Doxo), have limited efficacy and toxicity in primary and recurrent uLMS... SK-LMS-1 and SK-UT-1B cells were exposed to GSI, MK-0752 (M, used in clinical trials) and Gem, Doce, and Doxo, either individually or in combination for 72 hours... Combined treatment of SK-LMS-1 and SK-UT-1B with MK- 0752 and standard chemotherapeutics for uLMS had a synergistic reduction in cell viability and decreased cell migration and invasion. Our data suggests these drug combinations are promising and need to be further confirmed in 3D cell culture models or in vivo to determine the most efficacious combinations. These studies will help develop the foundation for clinical trials using GSIs combined with cytotoxic agents in uLMS."

Combination therapy • Colorectal Cancer • Gynecologic Cancers • Leiomyosarcoma • Oncology • Sarcoma • Solid Tumor • Uterine Corpus Leiomyosarcoma • Vaginal Cancer

Notch inhibition with γ-secretase inhibitor increases apoptosis of uterine leiomyosarcoma cells (SGO 2024) - "Combining MK0752 and chemotherapies including doxorubicin, docetaxel or gemcitabine decreases uLMS cell migration and invasion. Notch inhibition with GSI MK0752 greatly increased apoptosis in both SKUT1B and SKLMS1 uLMS cells. Our data reveals synergism with combination therapy using low, tolerable doses of both MK0752 and chemotherapeutic agents. Determining the efficacy of MK0752 and Notch inhibition in combination with common chemotherapeutic agents for uterine leiomyosarcoma deserves further investigation."

Leiomyosarcoma • Oncology • Sarcoma • Solid Tumor • Uterine Corpus Leiomyosarcoma • Vaginal Cancer

Increasing DAXX as a Novel Approach to Inhibit Breast Cancer Stem Cells and Estrogen Receptor-positive Tumor Recurrence (SABCS 2023) - "Background: Resistance to endocrine therapy (ET; tamoxifen, aromatase inhibitors, AI, or fulvestrant) in ER+ breast cancer (BC) could be due to survival of breast cancer stem cells (BCSCs)...We discovered a novel and potent anti-BCSC gene, Death Associated Protein 6 (DAXX) through a pre-surgical biomarker window study combining ET plus a Notch inhibitor [MK-0752, a g-secretase inhibitor (GSI)]...ER+ cells were treated with kinase inhibitors for AURKA (alisertib), AURKB (barasertib), CK1 (CK-IN-1), or CK2 (CX-4945) and DAXX protein was detected by western blotting... ET decreased DAXX protein levels in ER+ PDX and human tumors. Downregulation of the DAXX protein by ET was through activation of AURKB and hyper-phosphorylation of DAXX which resulted in protein degradation and enhanced survival of BCSCs. Therefore, Inhibition of AURKB using barasertib partially restored DAXX expression, inhibited BCSCs, and delayed tumor recurrence."

Cancer stem • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • AURKA • AURKB • DAXX • ER • NOTCH4

In vitro antineoplastic effects of MK0752 in HPV-positive head and neck squamous cell carcinoma. (PubMed, J Cancer Res Clin Oncol) - "Our novel findings indicate a therapeutic potential of MK0752 in HPV-positive HNSCC. Indeed, further investigation is needed for validation of our results and for the assessment of the mechanistic background."

Journal • Preclinical • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CASP3 • CASP7

Effect of Notch Signal Pathway on Steroid Synthesis Enzymes in TM3 Cells. (PubMed, Endocr Metab Immune Disord Drug Targets) - "We found the level of P450Scc, 3β-HSD, StAR and SF1 to be decreased after treatment with MK-0752, while overexpression of Notch1 up-regulated the expression of 3β-HSD, P450Scc, StAR and SF1. MK-0752 and overexpression of different Notch members had no influence on the expression of GATA4 and GATA6. In conclusion, Notch1 signaling may contribute to the steroid synthesis in Leydig cells through regulating SF1 and downstream steroidogenic enzymes (3β-HSD, StAR and P450Scc)."

Journal • GATA6 • NOTCH1

NEPHROPROTECTIVE EFFECT OF GAMMA-SECRETASE INHIBITOR ON SEPSIS- INDUCED RENAL INJURY IN MOUSE MODEL OF CLP. (PubMed, Wiad Lek) - " Taken together, these results suggest that MK0752 could be protective against the renal injury induced by sepsis through its ameliorative impact on renal architecture and modulating cytokines and Notch1 singling pathway. Further studies regarding the role of Notch signaling pathways would be worthwhile."

Journal • Preclinical • Infectious Disease • Renal Disease • Septic Shock • IL10 • IL6 • NOTCH1 • TNFA • TNFRSF1A

Increasing DAXX expression in ER+ breast cancer cells to overcome endocrine therapy resistance (SABCS 2022) - "Background: New treatment paradigms are needed to overcome resistance to endocrine therapy (ET; tamoxifen or aromatase inhibitors, AI) in ER+ breast cancer (BC)...In order to identify Notch specific biomarkers for the purpose of patient selection for anti-Notch therapy, we conducted a pre-surgical biomarker window study combining ET plus MK-0752, a -secretase inhibitor (GSI)... Expressing high DAXX levels is a potent method to inhibit ET-resistant BC cell proliferation and BCSC survival. The mechanism by which DAXX inhibits ET-resistant BC is through activation of JNK signaling, regulation of pro-apoptotic genes, and induction of apoptosis. The translational impact of this research is to identify novel agents that can increase DAXX expression and test them pre-clinically and in clinical trials for patients with ET-resistant breast cancer."

IO biomarker • Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • ANXA5 • BAX • BCL2 • BCL2L1 • BCL2L11 • CASP8 • DAXX • ER • NOTCH1

Gamma Secretase Inhibitors as Potential Therapeutic Targets for Notch Signaling in Uterine Leiomyosarcoma. (PubMed, Int J Mol Sci) - "Exposure of SK-UT-1B and SK-LMS-1 to DAPT and MK-0752 decreased expression of HES1 and decreased uLMS cell viability in a dose- and time-dependent manner that was unique to each GSI. Our findings suggest that GSIs are potential therapeutics for uLMS, albeit with limited efficacy."

Journal • Leiomyosarcoma • Oncology • Sarcoma • Solid Tumor • Uterine Cancer • Uterine Corpus Leiomyosarcoma • Uterine Leiomyoma • HES1 • NOTCH3 • NOTCH4

Resistance to MK-0752 alters Notch activity and expression of stemness markers in uterine leiomyosarcoma cell lines (AACR 2022) - "Cellular morphology, Notch signaling activity and expression of stemness markers differs in GSI resistant SK-LMS-1 compared to GSI resistant SK-UT-1B cells. The subpopulation of MK-0752 resistant SK-LMS-1 cells have reduced Notch activity and reduced expression of stemness marker, c-MYC, while the resistant SK-UT-1B cells have increased Notch activity. Further studies are required to identify additional factors associated with uLMS resistance to GSIs and the importance of this heterogeneity of uLMS in vivo."

Preclinical • Leiomyosarcoma • Oncology • Sarcoma • Solid Tumor • Uterine Corpus Leiomyosarcoma • CD133 • HES1 • MYC • SOX2

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

PLK1 and NOTCH Positively Correlate in Melanoma and their Combined Inhibition Results in Synergistic Modulations of Key Melanoma Pathways. (PubMed, Mol Cancer Ther) - "Next, utilizing small-molecule inhibitors of PLK1 and NOTCH (BI 6727 and MK-0752, respectively), we found a synergistic anti-proliferative response of combined treatment in multiple human melanoma cells. We identified the modulations of several key genes relevant to melanoma progression/metastasis, including MAPK, PI3K, and RAS, as well as some new genes such as Apobec3G, BTK and FCER1G which have not been well-studied in melanoma. In conclusion, our study demonstrated a synergistic anti-proliferative response of a concomitant targeting of PLK1 and NOTCH in melanoma, unraveling a potential novel therapeutic approach for detailed preclinical/clinical evaluation."

Journal • Genetic Disorders • Melanoma • Oncology • Skin Cancer • Solid Tumor • NOTCH1

Function and mechanism exploration of zinc finger protein 64 in lung adenocarcinoma cell growth and metastasis. (PubMed, J Recept Signal Transduct Res) - "However, Notch inhibitor MK-0752 inhibited the effects of overexpressed ZFP64 on H1975 cell viability, cell cycle, migration, EMT progress, and Notch pathway activation. Overexpressed ZFP64 promoted the development of lung adenocarcinoma cells by activating Notch pathway."

Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CDH1 • HES1 • PCR • VIM

Long-term response to Olaparib in carcinomatous meningitis of a n BRCA2n mutated ovarian cancer: A case report. (PubMed, Mol Clin Oncol) - "After Paclitaxel and Carboplatin treatment, followed by a debulking surgery and several lines of chemotherapy due to progression, the patient's disease evolved into carcinomatous meningitis within 6 months after the end of treatment...Following bioinformatics alignment and variant annotation, a pathogenic BRCA2 mutation, c.7617+1G>T, was observed, and this was already detected in her family...Due to the presence of a pathogenic mutation and a loss of wild-type BRCA2 allele, a maintenance treatment by Olaparib was initiated after radiotherapy and Cisplatin monotherapy. The patient received olaparib treatment for 14 months with a very good disease control and an excellent tolerance. Despite long control, the patient succumbed to meningeal and peritoneal progression."

Clinical • Journal • Gynecologic Cancers • Immunology • Infectious Disease • Oncology • Ovarian Cancer • Solid Tumor

[VIRTUAL] RNA-seq analysis of differential gene expression in melanoma cells after combined inhibition of Plk1 and Notch (AACR-II 2020) - "In this study, to determine the possible mechanisms behind this observed synergism, we used RNA-seq technology to obtain the differential gene expression following treatment of SK-MEL-2 human metastatic melanoma cells with Plk1 inhibitor volasertib (BI6727, 20 nM) and Notch1 inhibitor MK-0752 (100 μM) for 48 h. After data pre-processing by RSEM algorithm, the DESeq2 package was implemented to identify differentially expressed genes (DEGs,;log2-fold change| >= 1, false positive rate <= 0.05) when comparing the individual and combined treatments to vehicle (DMSO), as well as the interaction between volasertib:MK-0752. Overall, our data demonstrated that not only does targeting both Plk1 and Notch1 signaling pathways alters multiple melanoma progression pathways, but it may also potentially result in an increased sensitivity to other therapeutic targets, such as immune checkpoint blockade. However, these mechanistic findings need to be validated further in other..."

Melanoma • Oncology • Solid Tumor • NOTCH1

Safety and tolerability of different dose combinations of ridaforolimus with MK-2206 or MK-0752 for participants with advanced cancer (MK-8669-049 AM1) (clinicaltrials.gov) - P1, N=124; Sponsor: Merck; Recruiting -> Active, not recruiting.

Enrollment closed • Non-Hodgkin’s Lymphoma • Oncology

MK0752 and gemcitabine hydrochloride in treating patients with stage III and IV pancreatic cancer that cannot be removed by surgery (clinicaltrials.gov) - P1, N=60; Recruiting; Primary completion date: Dec 2014 -> Jun 2015.

Trial primary completion date • Oncology • Pancreatic Cancer

Safety and Tolerability of Different Dose Combinations of Ridaforolimus With MK-2206 or MK-0752 for Participants With Advanced Cancer (MK-8669-049) (clinicaltrials.gov) - P1; N=65; Completed; Sponsor: Merck Sharp & Dohme Corp.; Active, not recruiting ➔ Completed; N=124 ➔ 65

Enrollment change • Trial completion • Biosimilar