bmn-673 and Glioblastoma

Exploration of novel strategies to extend the benefit of PARP inhibitors beyond. Selective sensitivity to the PARP inhibitor talazoparib was screened and validated in two sets [test set (

Topics: Animals; Brain Neoplasms; Cell Line, Tumor; DNA Damage; ErbB Receptors; Gene Amplification; Glioblastoma; Humans; Male; Mice; Mice, Nude; Oxidative Stress; Phthalazines; Poly(ADP-ribose) Polymerase Inhibitors; Spheroids, Cellular; Xenograft Model Antitumor Assays

With increasing uses of poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) for cancer therapy, understanding their resistance is becoming urgent. However, acquired PARPi resistance in the phosphatase and tensin homolog (PTEN)-deficient background is poorly understood. We generated 3 PARPi-resistant PTEN-deficient glioblastoma U251 variants separately with olaparib (U251/OP), talazoparib (U251/TP) and simmiparib (U251/SP). These variants displayed consistent resistance (2.46-71.78-fold) to all 5 PARPi, including niraparib and rucaparib, and showed higher degrees of resistance to the PARPi to which the parental cells were more sensitive. The resistance was characteristic of fast emergence and high stability. However, the resistance acquirement did not cause an increasingly aggressive phenotype. The resistance was not correlated to various factors, including PTEN mutations. The PARPi-treated variants produced less γH2AX and G2/M arrest. Consistently, loss of 53BP1 occurred in all variants and its compensation enhanced their sensitivity to PARPi by approximately 76%. The variants revealed slightly different cross-resistance profiles to 13 non-PARPi anticancer drugs. All were resistant to Ara-C (6-8-fold) but showed differential resistance to 5-fluorouracil, gemcitabine and paclitaxel. Almost no resistance was observed to the rest drugs, including cisplatin. SAMHD1 was overexpressed in all the variants and its knockout completely restored their sensitivity to Ara-C but did not affect their PARPi sensitivity. The present study demonstrates a consistent resistance profile to PARPi and a unique cross-resistance profile to non-PARPi drugs in different PARPi-resistant U251 cells and reveals 53BP1 loss and SAMHD1 overexpression as the primary mechanisms responsible for their resistance to PARPi and Ara-C, respectively. These effects probably result from heritable gene change(s) caused by persistent PARPi exposure.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cytarabine; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Glioblastoma; Humans; Phthalazines; Piperazines; Poly(ADP-ribose) Polymerase Inhibitors; PTEN Phosphohydrolase; SAM Domain and HD Domain-Containing Protein 1; Tumor Suppressor p53-Binding Protein 1

Despite continuous improvements in treatment of glioblastoma, tumor recurrence and therapy resistance still occur in a high proportion of patients. One underlying reason for this radioresistance might be the presence of glioblastoma cancer stem cells (GSCs), which feature high DNA repair capability. PARP protein plays an important cellular role by detecting the presence of damaged DNA and then activating signaling pathways that promote appropriate cellular responses. Thus, PARP inhibitors (PARPi) have recently emerged as potential radiosensitizing agents. In this study, we investigated the preclinical efficacy of talazoparib, a new PARPi, in association with low and high linear energy transfer (LET) irradiation in two GSC cell lines. Reduction of GSC fraction, impact on cell proliferation, and cell cycle arrest were evaluated for each condition. All combinations were compared with a reference schedule: photonic irradiation combined with temozolomide. The use of PARPi combined with photon beam and even more carbon beam irradiation drastically reduced the GSC frequency of GBM cell lines in vitro. Furthermore, talazoparib combined with irradiation induced a marked and prolonged G2/M block, and decreased proliferation. These results show that talazoparib is a new candidate that effects radiosensitization in radioresistant GSCs, and its combination with high LET irradiation, is promising.

Topics: Cell Cycle; Cell Line, Tumor; Cell Proliferation; Glioblastoma; Humans; Linear Energy Transfer; Neoplastic Stem Cells; Phthalazines; Poly(ADP-ribose) Polymerase Inhibitors; Radiation-Sensitizing Agents; Signal Transduction

BMN 673 is a potent inhibitor of poly-ADP ribose polymerase (PARP) that is in clinical testing with a primary focus on BRCA-mutated cancers. BMN 673 is active both through inhibiting PARP catalytic activity and by tightly trapping PARP to DNA at sites of single strand breaks.. BMN 673 was tested in vitro at concentrations ranging from 0.1 nM to 1 μM and in vivo at a daily dose of 0.33 mg/kg administered orally twice daily (Mon-Fri) and once daily on weekends (solid tumors) for 28 days.. The median relative IC50 (rIC50 ) concentration against the PPTP cell lines was 25.8 nM. The median rIC50 for the Ewing cell lines was lower than for the remaining cell lines (6.4 vs. 31.1 nM, respectively). In vivo BMN 673 induced statistically significant differences in EFS distribution in 17/43 (39.5%) xenograft models. Three objective regressions were observed: a complete response (CR) in a medulloblastoma line (BT-45), a maintained CR in a Wilms tumor line (KT-10), and a maintained CR in an ependymoma line (BT-41). BMN 673 maintained its high level of activity against KT-10 with a threefold reduction in dose. KT-10 possesses a truncating mutation in PALB2 analogous to PALB2 mutations associated with hereditary breast and ovarian cancer that abrogate homologous recombination (HR) repair.. The PPTP results suggest that single agent BMN 673 may have limited clinical activity against pediatric cancers. Single agent activity is more likely for patients whose tumors have defects in HR repair.

Topics: Animals; Bone Neoplasms; Drug Evaluation, Preclinical; Enzyme Inhibitors; Fanconi Anemia Complementation Group N Protein; Female; Glioblastoma; Humans; Mice; Mutation; Neuroblastoma; Nuclear Proteins; Phthalazines; Poly(ADP-ribose) Polymerase Inhibitors; Rhabdomyosarcoma; Sarcoma, Ewing; Tumor Suppressor Proteins