gdc-0152 and Neoplasms

A liquid chromatography-tandem mass spectrometric (LC-MS/MS) method was developed and validated for the determination of GDC-0152 in human plasma to support clinical development. The method consisted of a solid-phase extraction for sample preparation and LC-MS/MS analysis in the positive ion mode using TurboIonSpray(TM) for analysis. d(7) -GDC-0152 was used as the internal standard. A linear regression (weighted 1/concentration(2) ) was used to fit calibration curves over the concentration range of 0.02-10.0 ng/mL for GDC-0152. There were no endogenous interference components in the blank human plasma tested. The accuracy at the lower limit of quantitation was 99.3% with a precision (%CV) of 13.9%. For quality control samples at 0.0600, 2.00 and 8.00 ng/mL, the between-run %CV was ≤8.64. Between-run percentage accuracy ranged from 98.2 to 99.6%. GDC-0152 was stable in human plasma for 363 days at -20°C and for 659 days at -70°C storage. GDC-0152 was stable in human plasma at room temperature for up to 25 h and through three freeze-thaw cycles. In whole blood, GDC-0152 was stable for 12 h at 4°C and at ambient temperature. This validated LC-MS/MS method for determination of GDC-0152 was used to support clinical studies.

Topics: Chromatography, Liquid; Cyclohexanes; Dose-Response Relationship, Drug; Drug Stability; Humans; Linear Models; Neoplasms; Pyrroles; Reproducibility of Results; Sensitivity and Specificity; Solid Phase Extraction; Tandem Mass Spectrometry

Current therapies fail to cure over a third of osteosarcoma patients and around three quarters of those with metastatic disease. "Smac mimetics" (also known as "IAP antagonists") are a new class of anti-cancer agents. Previous work revealed that cells from murine osteosarcomas were efficiently sensitized by physiologically achievable concentrations of some Smac mimetics (including GDC-0152 and LCL161) to killing by the inflammatory cytokine TNFα in vitro, but survived exposure to Smac mimetics as sole agents.. Nude mice were subcutaneously or intramuscularly implanted with luciferase-expressing murine 1029H or human KRIB osteosarcoma cells. The impacts of treatment with GDC-0152, LCL161 and/or doxorubicin were assessed by caliper measurements, bioluminescence,. Treatment with GDC-0152 or LCL161 suppressed the growth of subcutaneously or intramuscularly implanted osteosarcomas. In both models, co-treatment with doxorubicin and Smac mimetics impeded average osteosarcoma growth to a greater extent than either drug alone, although these differences were not statistically significant. Co-treatments were also more toxic. Co-treatment with LCL161 and doxorubicin was particularly effective in the KRIB intramuscular model, impeding primary tumor growth and delaying or preventing metastasis. Although the Smac mimetics were effective in vivo, in vitro they only efficiently killed osteosarcoma cells when TNFα was supplied. Implanted tumors contained high levels of TNFα, produced by infiltrating immune cells. Spontaneous osteosarcomas that arose in genetically-engineered immunocompetent mice also contained abundant TNFα.. These data imply that Smac mimetics can cooperate with TNFα secreted by tumor-associated immune cells to kill osteosarcoma cells in vivo. Smac mimetics may therefore benefit osteosarcoma patients whose tumors contain Smac mimetic-responsive cancer cells and TNFα-producing infiltrating cells.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cyclohexanes; Disease Models, Animal; Humans; Magnetic Resonance Imaging; Mice; Neoplasms; Positron-Emission Tomography; Pyrroles; Thiazoles; Xenograft Model Antitumor Assays

DNA damaging therapies can spur the formation of therapy-related cancers, due to mis-repair of lesions they create in non-cancerous cells. This risk may be amplified in patients with impaired DNA damage responses. We disabled key DNA damage response pathways using genetic and pharmacological approaches, and assessed the impact of these deficiencies on the mutagenicity of chemotherapy drugs or the "Smac mimetic" GDC-0152, which kills tumor cells by targeting XIAP, cIAP1 and 2. Doxorubicin and cisplatin provoked mutations in more surviving cells deficient in ATM, p53 or the homologous recombination effector RAD51 than in wild type cells, but suppressing non-homologous end joining (NHEJ) by disabling DNA-PKcs prevented chemotherapy-induced mutagenesis. Vincristine-induced mutagenesis required p53 and DNA-PKcs but was not affected by ATM status, consistent with it provoking ATM-independent p53-mediated activation of caspases and CAD, which creates DNA lesions in surviving cells that could be mis-repaired by NHEJ. Encouragingly, GDC-0152 failed to stimulate mutations in cells with proficient or defective DNA damage response pathways. This study highlights the elevated oncogenic risk associated with treating DNA repair-deficient patients with genotoxic anti-cancer therapies, and suggests a potential advantage for Smac mimetic drugs over traditional therapies: a reduced risk of therapy-related cancers.

Topics: Apoptosis Regulatory Proteins; Biomimetic Materials; Cell Line, Tumor; Cyclohexanes; DNA Damage; DNA End-Joining Repair; Drug Delivery Systems; HEK293 Cells; Humans; Intracellular Signaling Peptides and Proteins; Mitochondrial Proteins; Mutagenesis; Neoplasm Proteins; Neoplasms; Pyrroles