sf-1126 and Neoplasms

SF1126 is a peptidic pro-drug inhibitor of pan-PI3K/mTORC. A first-in-human study evaluated safety, dose limiting toxicities (DLT), maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of SF1126, in patients with advanced solid and B-cell malignancies.. SF1126 was administered IV days 1 and 4, weekly in 28day-cycles. Dose escalation utilised modified Fibonacci 3+3. Samples to monitor PK and PD were obtained.. Forty four patients were treated at 9 dose levels (90-1110 mg/m(2)/day). Most toxicity was grade 1 and 2 with a single DLT at180 mg/m(2) (diarrhoea). Exposure measured by peak concentration (C(max)) and area under the time-concentration curve (AUC(0-)(t)) was dose proportional. Stable disease (SD) was the best response in 19 of 33 (58%) evaluable patients. MTD was not reached but the maximum administered dose (MAD) was 1110 mg/m(2). The protocol was amended to enrol patients with CD20+ B-cell malignancies at 1110 mg/m(2). A CLL patient who progressed on rituximab [R] achieved SD after 2 months on SF1126 alone but in combination with R achieved a 55% decrease in absolute lymphocyte count and a lymph node response. PD studies of CLL cells demonstrated SF1126 reduced p-AKT and increased apoptosis indicating inhibition of activated PI3K signalling.. SF1126 is well tolerated with SD as the best response in patients with advanced malignancies.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Chromones; Dose-Response Relationship, Drug; Female; Gastrointestinal Diseases; Hematologic Diseases; Humans; Hypokalemia; Infusions, Intravenous; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Large B-Cell, Diffuse; Male; Maximum Tolerated Dose; Mechanistic Target of Rapamycin Complex 1; Middle Aged; Molecular Targeted Therapy; Multiprotein Complexes; Neoplasm Proteins; Neoplasms; Oligopeptides; Phosphoinositide-3 Kinase Inhibitors; Prodrugs; Protein Kinase Inhibitors; Proteins; Salvage Therapy; TOR Serine-Threonine Kinases; Young Adult

Tumor growth, progression, and response to the hypoxic tumor microenvironment involve the action of hypoxia-inducible transcription factors, HIF1 and HIF2. HIF is a heterodimeric transcription factor containing an inducible HIFα subunit and a constitutively expressed HIFβ subunit. The signaling pathways operational in macrophages regulating hypoxia-induced HIFα stabilization remain the subject of intense investigation. Here, it was discovered that the PTEN/PI3K/AKT signaling axis controls hypoxia-induced HIF1α (HIF1A) and HIF2α (EPAS1) stability in macrophages. Using genetic mouse models and pan-PI3K as well as isoform-specific inhibitors, inhibition of the PI3K/AKT pathway blocked the accumulation of HIFα protein and its primary transcriptional target VEGF in response to hypoxia. Moreover, blocking the PI3K/AKT signaling axis promoted the hypoxic degradation of HIFα via the 26S proteasome. Mechanistically, a macrophage-dominant PI3K isoform (p110γ) directed tumor growth, angiogenesis, metastasis, and the HIFα/VEGF axis. Moreover, a pan-PI3K inhibitor (SF1126) blocked tumor-induced angiogenesis and inhibited VEGF and other proangiogenic factors secreted by macrophages. These data define a novel molecular mechanism by which PTEN/PI3K/AKT regulates the proteasome-dependent stability of HIFα under hypoxic conditions, a signaling pathway in macrophages that controls tumor-induced angiogenesis and metastasis.. This study indicates that PI3K inhibitors are excellent candidates for the treatment of cancers where macrophages promote tumor progression.

Topics: Animals; Basic Helix-Loop-Helix Transcription Factors; Cell Hypoxia; Cell Proliferation; Chromones; Gene Deletion; Gene Expression Regulation, Neoplastic; Hypoxia-Inducible Factor 1, alpha Subunit; Isoenzymes; Macrophages; Mice; Models, Biological; Neoplasm Metastasis; Neoplasms; Neovascularization, Pathologic; Oligopeptides; Phosphatidylinositol 3-Kinases; Proteasome Endopeptidase Complex; Protein Kinase Inhibitors; Protein Stability; Proteolysis; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; RNA, Messenger; Signal Transduction; Transcription, Genetic; Vascular Endothelial Growth Factor A

PTEN and the pan phosphoinositide 3-kinase (PI3K) inhibitor 2-(4-morpholinyl)-8-phenyl-4H-1 benzopyran-4-one (LY294002) exert significant control over tumor-induced angiogenesis and tumor growth in vivo. The LY294002 compound is not a viable drug candidate due to poor pharmacologic variables of insolubility and short half-life. Herein, we describe the development and antitumor activity of a novel RGDS-conjugated LY294002 prodrug, termed SF1126, which is designed to exhibit increased solubility and bind to specific integrins within the tumor compartment, resulting in enhanced delivery of the active compound to the tumor vasculature and tumor. SF1126 is water soluble, has favorable pharmacokinetics, and is well tolerated in murine systems. The capacity of SF1126 to inhibit U87MG and PC3 tumor growth was enhanced by the RGDS integrin (alpha v beta 3/alpha 5 beta 1) binding component, exhibiting increased activity compared with a false RADS-targeted prodrug, SF1326. Antitumor activity of SF1126 was associated with the pharmacokinetic accumulation of SF1126 in tumor tissue and the pharmacodynamic knockdown of phosphorylated AKT in vivo. Furthermore, SF1126 seems to exhibit both antitumor and antiangiogenic activity. The results support SF1126 as a viable pan PI3K inhibitor for phase I clinical trials in cancer and provide support for a new paradigm, the application of pan PI3K inhibitory prodrugs for the treatment of cancer.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Chromones; Enzyme Inhibitors; Humans; Mice; Mice, Inbred Strains; Neoplasms; Neovascularization, Pathologic; Oligopeptides; Phosphoinositide-3 Kinase Inhibitors; Prodrugs; Xenograft Model Antitumor Assays