ABSTRACT
Samuraciclib is a selective oral CDK7-inhibitor. A multi-modular, open-label Phase I study to evaluate safety and tolerability of samuraciclib in patients with advanced malignancies was designed (ClinicalTrials.gov: NCT03363893). Here we report results from dose escalation and 2 expansion cohorts: Module 1A dose escalation with paired biopsy cohort in advanced solid tumor patients, Module 1B-1 triple negative breast cancer (TNBC) monotherapy expansion, and Module 2A fulvestrant combination in HR+/HER2- breast cancer patients post-CDK4/6-inhibitor. Core study primary endpoints are safety and tolerability, and secondary endpoints are pharmacokinetics (PK), pharmacodynamic (PD) activity, and anti-tumor activity. Common adverse events are low grade nausea, vomiting, and diarrhea. Maximum tolerated dose is 360 mg once daily. PK demonstrates dose proportionality (120 mg-480 mg), a half-life of approximately 75 hours, and no fulvestrant interaction. In dose escalation, one partial response (PR) is identified with disease control rate of 53% (19/36) and reduction of phosphorylated RNA polymerase II, a substrate of CDK7, in circulating lymphocytes and tumor tissue. In TNBC expansion, one PR (duration 337 days) and clinical benefit rate at 24 weeks (CBR) of 20.0% (4/20) is achieved. In combination with fulvestrant, 3 patients achieve PR with CBR 36.0% (9/25); in patients without detectable TP53-mutation CBR is 47.4% (9/19). In this study, samuraciclib exhibits tolerable safety and PK is supportive of once-daily oral administration. Clinical activity in TNBC and HR+/HER2-breast cancer post-CDK4/6-inhibitor settings warrants further evaluation.
Subject(s)
Triple Negative Breast Neoplasms , Humans , Fulvestrant , Administration, Oral , Biopsy , Cyclin-Dependent Kinase Inhibitor Proteins , Cyclin-Dependent Kinases , Enzyme InhibitorsABSTRACT
Mammalian target of rapamycin (mTOR) is essential in controlling several cellular functions. This pathway is dysregulated in keloid disease (KD). KD is a common fibroproliferative dermal lesion with an ill-defined treatment strategy. KD demonstrates excessive matrix deposition, angiogenesis, and inflammatory cell infiltration. In KD, both total and phosphorylated forms of mTOR and p70(S6K)(Thr421/Ser424) are upregulated. Therefore, the aim of this study was to investigate adenosine triphosphate-competitive inhibitors of mTOR kinase previously unreported in keloid and their comparative efficacy with Rapamycin. Here, we present two mTOR kinase inhibitors, KU-0063794 and KU-0068650, that target both mTORC1 and mTORC2 signaling. Treatment with either KU-0063794 or KU-0068650 resulted in complete suppression of Akt, mTORC1, and mTORC2, and inhibition of keloid cell spreading, proliferation, migration, and invasive properties at a very low concentration (2.5 µmol l(-1)). Both KU-0063794 and KU-0068650 significantly (P<0.05) inhibited cell cycle regulation and HIF1-α expression compared with that achieved with Rapamycin alone. In addition, both compounds induced shrinkage and growth arrest in KD, associated with the inhibition of angiogenesis, induction of apoptosis, and reduction in keloid phenotype-associated markers. In contrast, Rapamycin induced minimal antitumor activity. In conclusion, potent dual mTORC1 and mTORC2 inhibitors display therapeutic potential for the treatment of KD.
Subject(s)
Enzyme Inhibitors/therapeutic use , Keloid/drug therapy , Keloid/pathology , Morpholines/therapeutic use , Multiprotein Complexes/antagonists & inhibitors , Pyrimidines/therapeutic use , TOR Serine-Threonine Kinases/antagonists & inhibitors , Adolescent , Adult , Aged , Cell Movement/drug effects , Cell Proliferation/drug effects , Cells, Cultured , Dose-Response Relationship, Drug , Enzyme Inhibitors/pharmacology , Female , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Immunosuppressive Agents/pharmacology , Immunosuppressive Agents/therapeutic use , In Vitro Techniques , Keloid/metabolism , Male , Mechanistic Target of Rapamycin Complex 1 , Mechanistic Target of Rapamycin Complex 2 , Middle Aged , Morpholines/pharmacology , Multiprotein Complexes/drug effects , Multiprotein Complexes/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Pyrimidines/pharmacology , Signal Transduction/drug effects , Sirolimus/pharmacology , Sirolimus/therapeutic use , TOR Serine-Threonine Kinases/drug effects , TOR Serine-Threonine Kinases/metabolism , Young AdultABSTRACT
Triggering innate immune responses through TLRs is expected to be a novel therapeutic strategy for the treatment of allergic diseases. TLR agonists are able to modulate Th2 immune responses through undefined mechanisms. We investigated the mechanism of action of the suppression of Th2 immune responses with a novel antedrug TLR7 agonist. The antedrug is rapidly metabolized by plasma esterases to an acid with reduced activity to limit systemic responses. Topical administration of this compound inhibited features of the allergic airway inflammatory response in rat and murine allergic airways model. Type I IFN played a role in the suppression of Th2 cytokines produced from murine splenocytes. Inhibition of Th2 immune responses with the antedrug TLR7 agonist was shown to be via a type I IFN-dependent mechanism following short-term exposure to the compound, although there might be type I IFN-independent mechanisms following long-term exposure. We have demonstrated that local type I IFN signaling and plasmacytoid dendritic cells, but not Th1 immune responses, are required for in vivo efficacy against murine airway Th2-driven eosinophilia. Furthermore, migration of dendritic cell subsets into the lung was related to efficacy and is dependent on type I IFN signaling. Thus, the mechanism of action at the cytokine and cellular level involved in the suppression of Th2 allergic responses has been characterized, providing a potential new approach to the treatment of allergic disease.