uprosertib (LAE003) / Novartis, Laekna Therap - LARVOL DELTA

CD52 PROMOTER METHYLATION PREDICTS RESPONSE TO AKT-TARGETING DRUGS IN ACUTE MYELOID LEUKEMIA (EHA 2025) - "Sensitivity to Akt inhibitors (Uprosertib/Afuresertib) was tested in ten wild-type (WT) cell lines and SET-2 shRNA model via MTT. CD52, an indicator of poor prognosis in AML, is associated with Akt expression in cell lines and patients. This seems to contribute to an aggressive phenotype characterized by enhanced cell proliferation and viability, resulting in a reduced survival rate in AML patients. This finding underlines the potential of targeting Akt in AML depending on the CD52 methylation profile, based on the favorable results obtained in vitro."

Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • CD52

SWOG-S1221: Uprosertib, Dabrafenib, and Trametinib in Treating Patients With Stage IIIC-IV Cancer (clinicaltrials.gov) - P1/2 | N=27 | Completed | Sponsor: National Cancer Institute (NCI) | Active, not recruiting ➔ Completed

Trial completion • Cutaneous Melanoma • Hematological Malignancies • Melanoma • Oncology • Solid Tumor

Phase II study of MEK inhibitor trametinib alone and in combination with AKT inhibitor GSK2141795/uprosertib in patients with metastatic triple negative breast cancer. (PubMed, Breast Cancer Res Treat) - "In patients with mTNBC, Trametinib monotherapy demonstrated limited efficacy and addition of Uprosertib was associated with numerically greater objective responses but no difference in PFS. Translational analyses suggest ctDNA clearance as a potential early biomarker of response."

Clinical • Combination therapy • Journal • Metastases • P2 data • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

SWOG-S1221: Uprosertib, Dabrafenib, and Trametinib in Treating Patients With Stage IIIC-IV Cancer (clinicaltrials.gov) - P1/2 | N=27 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Oct 2024 ➔ Oct 2025

Combination therapy • Trial completion date • Cutaneous Melanoma • Hematological Malignancies • Melanoma • Oncology • Solid Tumor

Phase II study of trametinib alone and in combination with uprosertib in patients with metastatic triple negative breast cancer previously treated with chemotherapy: OSU 13317 (AACR 2024) - "Trametinib alone and in combination with uprosertib demonstrates anti-tumor activity in a subset of TNBC patients with kinome evidence of target engagment. ctDNA clearance at C2D1 may be useful as an early biomarker to identify patients most likely to respond. Understanding biomarkers of response and resistance may guide future opportunities for MEK/AKT inhibition in TNBC."

Clinical • Combination therapy • Metastases • P2 data • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • MAP2K2

A phase 1 study of triple-targeted therapy with BRAF, MEK, and AKT inhibitors for patients with BRAF-mutated cancers. (PubMed, Cancer) - P1/2 | "Concomitant inhibition of both the MAPK and PI3K-AKT pathways for the treatment of BRAF-mutated cancers was well tolerated, leading to objective responses, but higher level drug-drug interactions affected exposure to dabrafenib and its metabolites."

Journal • P1 data • Endocrine Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thyroid Gland Carcinoma • Thyroid Gland Papillary Carcinoma

SWOG-S1221: Uprosertib, Dabrafenib, and Trametinib in Treating Patients With Stage IIIC-IV Cancer (clinicaltrials.gov) - P1/2 | N=27 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Oct 2023 ➔ Oct 2024

Combination therapy • Trial completion date • Cutaneous Melanoma • Hematological Malignancies • Melanoma • Oncology • Solid Tumor

Comprehensive analysis of angiogenesis pattern and related immune landscape for individual treatment in osteosarcoma. (PubMed, NPJ Precis Oncol) - "OS patients with high ANGscore might be resistant to uprosertib, and be sensitive to VE821, AZD6738 and BMS.345541. In conclusion, we established a novel ANGscore system by comprehensively analysing the expression pattern of angiogenesis genes, which can accurately differentiate the prognosis and immune characteristics of OS populations. Additionally, the ANGscore can be used for patient stratification during immunotherapy, and guide individualized treatment strategies."

IO biomarker • Journal • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • IFNG

Suxiao Jiuxin Pill attenuates acute myocardial ischemia via regulation of coronary artery tone. (PubMed, Front Pharmacol) - "Vasodilation caused by senkyunolide A and scopoletin was inhibited by uprosertib (Akt inhibitor) and eNOS/sGC/PKG axis inhibitors...The K channel inhibitor 4-AP, K inhibitor TEA, and K inhibitor BaCl significantly inhibited the vasorelaxant effect of borneol in the coronary artery. In conclusion, the results show that Suxiao Jiuxin Pill protects the heart against acute myocardial infarction."

Journal • Cardiovascular • Heart Failure • Myocardial Infarction • Myocardial Ischemia • NOS3 • PACERR • PTGS2

Phase I/II Study of the Safety and Efficacy of the AKT Inhibitor GSK2141795 in Combination with the BRAF Inhibitor Dabrafenib and Trametinib in Patients with BRAF Mutant Cancer (SWOG-Fall 2022) - No abstract available

Clinical • Combination therapy • P1/2 data • Oncology

[VIRTUAL] Antitumor activity of tipifarnib and PI3K pathway inhibitors in HRAS-associated head and neck squamous cell carcinoma (AACR-NCI-EORTC 2020) - P2 | "In this study we explored the activity of tipifarnib in cellular models and six HRAS-mutant and twelve HRAS WT HNSCC patient-derived xenograft models alone and in combination with clinical stage inhibitors of PI3K-a (alpelisib), AKT (uprosertib) and mTORC1/2 (sapanisertib). Regressions with the FTI-PI3K-a inhibitor doublet were observed both in tumors that were WT or with PIK3CAmutations or amplification and in HRAS mutants that carried or lacked PIK3CA mutations, suggesting concomitant blockade of both targets may have broad and potent anti-tumor activity in HNSCC. Additional biomarkers associated with sensitivity or resistance and alterations in gene expression (by RNAseq) and oncogenic signaling following treatment either as a monotherapy or in combinations will be reported."

Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CASP8 • HRAS • PIK3CA • TP53

[VIRTUAL] Antitumor activity of tipifarnib and PI3K pathway inhibitors in HRAS-associated head and neck squamous cell carcinoma (AACR-NCI-EORTC 2020) - P2 | "In this study we explored the activity of tipifarnib in cellular models and six HRAS-mutant and twelve HRAS WT HNSCC patient-derived xenograft models alone and in combination with clinical stage inhibitors of PI3K-a (alpelisib), AKT (uprosertib) and mTORC1/2 (sapanisertib). Regressions with the FTI-PI3K-a inhibitor doublet were observed both in tumors that were WT or with PIK3CAmutations or amplification and in HRAS mutants that carried or lacked PIK3CA mutations, suggesting concomitant blockade of both targets may have broad and potent anti-tumor activity in HNSCC. Additional biomarkers associated with sensitivity or resistance and alterations in gene expression (by RNAseq) and oncogenic signaling following treatment either as a monotherapy or in combinations will be reported."

Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CASP8 • HRAS • PIK3CA • TP53

SWOG-S1221: Uprosertib, Dabrafenib, and Trametinib in Treating Patients With Stage IIIC-IV Cancer (clinicaltrials.gov) - P1/2 | N=27 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Dec 2022 ➔ Oct 2023

Combination therapy • Trial completion date • Cutaneous Melanoma • Hematological Malignancies • Melanoma • Oncology • Solid Tumor

FOXO1 Alleviates Liver Ischemia-reperfusion Injury by Regulating the Th17/Treg Ratio through the AKT/Stat3/FOXO1 Pathway. (PubMed, J Clin Transl Hepatol) - "The AKT/Stat3/FOXO1 pathway was verified by targeting AKT with GSK2141795...Liver IRI induced Th17/Treg imbalance. Upregulation of FOXO1 reversed the imbalance and alleviated liver inflammation."

Journal • Cardiovascular • Hepatology • Immunology • Inflammation • Liver Failure • Reperfusion Injury • FOXO1

SWOG S1221: A phase 1 dose escalation study co-targeting MAPK-dependent and MAPK-independent BRAF inhibitor resistance in BRAF mutant advanced solid tumors with dabrafenib, trametinib, and GSK2141795 (ClinicalTrials.gov NCT01902173). (ASCO 2017) - P1/2; "Inhibition of both MAPK and PI3K/AKT pathways was well tolerated, leading to durable objective responses in pts with metastatic melanoma, thyroid cancer, and lung cancer. Further study of dual pathway inhibition is warranted."

Clinical • P1 data • Biosimilar • Lung Cancer • Melanoma • Thyroid Gland Carcinoma

A single arm, single stage phase II trial of trametinib (GSK1120212) and GSK2141795 in persistent or recurrent cervical cancer (AACR 2017) - "Abstract embargoed at this time."

Clinical • P2 data • Biosimilar • Cervical Cancer • Oncology

Targeting Akt/PKB in Pediatric Tumors: A Review From Preclinical to Clinical Trials. (PubMed, Pharmacol Res) - "This review summarizes recent available evidence of Akt inhibitors in pediatric cancers, from both preclinical and clinical studies. In short, we demonstrate the impact that Akt inhibition provides in tumorigenesis, and we suggest targeting the PI3K/Akt/mTOR signaling pathway, alone or in combination with other inhibitors, is a feasible tool to achieve better outcomes in pediatric tumors."

Journal • Preclinical • Review • Oncology • Pediatrics

An effective AKT inhibitor-PARP inhibitor combination therapy for recurrent ovarian cancer. (PubMed, Cancer Chemother Pharmacol) - "Collectively, our results suggest that the combination of AKT inhibitor and PARP inhibitor could be a viable approach for clinical testing in recurrent ovarian cancer patients."

Combination therapy • Journal • Oncology • Ovarian Cancer • Solid Tumor

[VIRTUAL] “Phase I/II Study of the Safety and E!cacy of the AKT Inhibitor GSK2141795 in Combination with the BRAF Inhibitor Dabrafenib and Trametinib in Patients with BRAF Mutant Cancer.” (SWOG-Fall 2021) - No abstract available

Clinical • Combination therapy • P1/2 data • Oncology

Trametinib and Akt Inhibitor GSK2141795 in Treating Patients With Relapsed or Refractory Multiple Myeloma (clinicaltrials.gov) - P2 | N=25 | Completed | Sponsor: National Cancer Institute (NCI) | Active, not recruiting ➔ Completed

Trial completion • Hematological Malignancies • Multiple Myeloma • Oncology • BRAF

Targeting AKT and DNA-PK as a therapeutic strategy in platinum resistant high-grade serous ovarian cancer (ESGO 2021) - "Result(s)* Following treatment with cisplatin in combination with AKT or DNA-PK inhibitors, different levels of synergy were observed in platinum resistant HGSOC cell lines; strong synergy was noted for AKT inhibitors Afurosertib, Uprosertib, and Triciribine. Proteomic analysis confirmed targeting of the PI3K/AKT/mTOR pathway. With the aim of resensitising a resistant patient to their platinum-based chemotherapy a synergistic effect between the resensitising compound and chemotherapy agent is essential; this data suggests targeting of the PI3K/AKT/mTOR pathway in platinum-resistant HGSOC patients with AKT or DNAPK inhibition is a potentially useful therapeutic strategy."

Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor

[VIRTUAL] Antitumor activity of tipifarnib and PI3K pathway inhibitors in HRAS-associated HNSCC. (ASCO 2020) - P2 | "In this study we explored the activity of tipifarnib in cellular models and six HRAS-mutant and twelve HRAS WT HNSCC patient-derived xenograft (PDX) models alone and in combination with inhibitors of PI3K-a (BYL-719), AKT (GSK2141795) and mTORC1/2 (INK128). Concomitant blockade of both targets may have surprisingly broad and potent anti-tumor activity in HNSCC. Additional biomarkers associated with sensitivity or resistance and alterations in gene expression (by RNAseq) and oncogenic signaling following treatment either as a monotherapy or in combinations will also be described. Research Funding: Kura Oncology"

Head and Neck Cancer • Oncology • Squamous Cell Carcinoma of Head and Neck • CASP8 • HRAS • PIK3CA • TP53

Clusterin inhibits Cr(VI)-induced apoptosis via enhancing mitochondrial biogenesis through AKT-associated STAT3 activation in L02 hepatocytes. (PubMed, Ecotoxicol Environ Saf) - "We used the STAT3 inhibitor C188-9 and the AKT inhibitor Uprosertib to eliminate the anti-apoptotic effect of CLU, and found that CLU inhibited Cr(VI)-induced apoptosis by up-regulating AKT/STAT3 signal. Based on the fact that both AKT and STAT3 are closely related to mitochondrial biogenesis and mitochondrial pathway-associated apoptosis, this study is the first time to link CLU, STAT3, AKT and mitochondrial biogenesis function after Cr(VI) exposure, to further enrich the experimental basis of Cr(VI)-induced hepatotoxicity, clarify the molecular mechanism of CLU helping cells to escape apoptosis, and also suggest that new ways can be sought to prevent and treat Cr(VI)-induced hepatotoxicity by regulating mitochondrial biosynthesis."

Journal • Hepatology • CLU • STAT3

RNF43 and PWWP2B inhibit cancer cell proliferation and are predictive or prognostic biomarker for FDA-approved drugs in patients with advanced gastric cancer. (PubMed, J Cancer) - "Our data demonstrated that RNF43 and PWWP2B are a biomarker that predict recurrence of gastric cancer. Our findings suggest that docetaxel trihydrate, uprosertib and pelitinib could be used as novel therapeutic agents for the prevention and treatment of gastric cancer with a decrease in RNF43 and PWWP2B expression."

Biomarker • Clinical • FDA event • Journal • Chronic Myeloid Leukemia • Gastric Cancer • Gastrointestinal Cancer • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • RNF43

Uprosertib, Dabrafenib, and Trametinib in Treating Patients With Stage IIIC-IV Cancer (clinicaltrials.gov) - P1/2; N=27; Active, not recruiting; Sponsor: National Cancer Institute (NCI); Trial completion date: Dec 2021 ➔ Dec 2022

Trial completion date • Cutaneous Melanoma • Hematological Malignancies • Melanoma • Neutropenia • Oncology • Solid Tumor