Journal: The Journal of Clinical Investigation

Article Title: WWP1 inactivation enhances efficacy of PI3K inhibitors while suppressing their toxicities in breast cancer models

doi: 10.1172/JCI140436

Figure Lengend Snippet: ( A ) Evaluation of subcellular localization of PTEN upon BKM120 treatment. Membrane fractions and whole-cell lysate (WCL) were extracted from MDA-MB-231 cells treated with BKM120 over time and subsequently analyzed by WB. EGFR served as a membrane marker and HSP90 as the internal control. ( B ) Longitudinal subcellular localization of PTEN in MCF7 cells upon treatment with BYL719. LRP6 served as a membrane marker. Blots are from duplicate gels run in parallel. ( C ) Analysis of PTEN membrane fraction upon treatment with various PI3K inhibitors. MDA-MB-231 cells were treated with the indicated drugs for 48 hours, and membrane and cytosol fractions were extracted. The following doses were used: BKM120 (1.0 μM); BAY80-6946 (1.0 μM); BYL719 (5.0 μM); GDC-0032 (1.0 μM); TGX-221 (5.0 μM). The negative loading control for each fraction is shown in Supplemental Figure 1A as a technical replicate. ( D ) Analysis of endogenous PTEN ubiquitination over time after BKM120 treatment. Whole lysate was extracted from MDA-MB-231 cells treated with BKM120 for the indicated durations and immunoprecipitated with anti-PTEN beads. Arrow indicates the band with the mouse anti-IgG heavy-chain antibody. Numbers below the blot lanes represent the relative intensities of the PTEN band normalized to the respective loading control. PTEN-Ub(n)/PTEN, relative intensity of polyubiquitinated PTEN normalized to precipitated total PTEN.

Article Snippet: BAY80-6946, BYL719, GDC-0032, and TGX-221 were purchased from MedChem Express.

Techniques: Clinical Proteomics, Membrane, Marker, Control, Ubiquitin Proteomics, Immunoprecipitation

Journal: International Journal of Molecular Sciences

Article Title: PI3K Inhibitors in Cancer: Clinical Implications and Adverse Effects

doi: 10.3390/ijms22073464

Figure Lengend Snippet: Summary of trials, outcomes and adverse events associated with isoform-specific PI3K inhibitors in various phases of clinical studies.

Article Snippet: Taselisib in combination with anti-androgen therapy, Enzalutamide (Enz) in AR+ metastatic TNBC patients [ ] , Active, not recruiting , Vanderbilt-Ingram Cancer Center in collaboration with NCI, Translational Breast Cancer Research Consortium, Conquer Cancer Foundation and Genentech, Inc. , I/II, NCT02457910 , Arm A: Patients received Taselisib (4 mg) orally once daily on days 1 to 28 and Enz (160 mg) PO QD on days 9 to 28 of cycle 1 and days 1 to 28 of subsequent cycles. Arm B: Patients received 160 mg Enz PO QD on days 1 to 28. Cycles were repeated after 28 days. The combination was safe, well tolerated and increased the CBR in these patients ( n = 30). The CBR was 35.7% including 4 patients with SD and 1 patient with PR. The median PFS was 3.4 months with median PFS for ER+ patients (7.2 months) being substantially higher than that for TNBC patients (2.1 months). There was no difference in PFS across groups receiving drug combinations or Enz only. There was no difference in PFS or CBR with the PIK3CA status. However, better CBR was reported in TNBC patients with LAR subtype tumors versus other subtypes (75% vs. 12.5%; p = 0.06) along with better median PFS of 4.6 months vs. other subtypes (PFS = 2 months). LAR subtype tumors demonstrated a decrease in proliferation and AR target gene expression post-treatment with combination. Mutational landscape assessment of tumors suggested that LAR tumors were enriched GATA3 and FOXA1 genes. TP53 mutations were frequent across all subtypes. In contrast, non-LAR tumors were enriched in RB1 , S82X , R467X (deleterious mutations in cell-cycle) as well as ESCO1,BRCA1 , BRACA2 , BAP1 and FANCE (DNA repair genes) along with activating mutations in MAPK pathway and growth factor receptors. Two potential oncogenic gene fusions FGFR2-TACC2 and FGFR2-TAOK1 were identified which represent a mechanism by which LAR tumors activated the PI3K pathway. Pathways associated with complement and innate immunity were augmented post-treatment. Treatment with Taselisib and Enz specifically increased T-cell and NK cell markers. AR splice variants might contribute to Enz resistance. The MTD was not reached and the trial was terminated early. The RP2D was achieved at 4 mg daily dose of Taselisib with 160 mg Enz/day. 13 patients were enrolled in the phase I and 17 patients (Enz; n = 5 and Enz + Taselisib; n = 12) in phase II trial. , Hyperglycemia, rash, increased AST/ALT, anemia, neutropenia, fever, fatigue, nausea, vomiting and pruritus..

Techniques: Mutagenesis, Activity Assay, Amplification, Expressing, Incubation, Staining, Inhibition, Transformation Assay, Infection, Modification, Concentration Assay, Marker

Journal: Cancer discovery

Article Title: Phase I Dose Escalation Study of Taselisib (GDC-0032), an Oral PI3K Inhibitor, in Patients with Advanced Solid Tumors

doi: 10.1158/2159-8290.CD-16-1080

Figure Lengend Snippet: In vivo efficacy of taselisib in the KPL-4 PIK3CA-mutant breast cancer xenograft model. Taselisib was dosed orally and daily at the doses indicated for 21 days as indicated by treatment period (Rx). Control tumor bearing mice were treated with 0.5% methylcellulose/0.2% Tween-80 (vehicle). Tumor volumes were measured and calculated as described in Materials and Methods.

Article Snippet: Taselisib (Genentech, Inc.) was taken on an empty stomach as a single dose (powder-in-capsule formulation) at the same time of day +/- 2 hours ( 33 ).

Techniques: In Vivo, Mutagenesis, Control

Journal: Cancer discovery

Article Title: Phase I Dose Escalation Study of Taselisib (GDC-0032), an Oral PI3K Inhibitor, in Patients with Advanced Solid Tumors

doi: 10.1158/2159-8290.CD-16-1080

Figure Lengend Snippet: Pharmacokinetic Parameters of Taselisib (GDC-0032)

Article Snippet: Taselisib (Genentech, Inc.) was taken on an empty stomach as a single dose (powder-in-capsule formulation) at the same time of day +/- 2 hours ( 33 ).

Techniques:

Journal: Cancer discovery

Article Title: Phase I Dose Escalation Study of Taselisib (GDC-0032), an Oral PI3K Inhibitor, in Patients with Advanced Solid Tumors

doi: 10.1158/2159-8290.CD-16-1080

Figure Lengend Snippet: Pharmacodynamic modulation of the PI3K pathway. Needle core tumor biopsies obtained from patients at baseline and at steady state (cycle 1, between days 15-21) were fixed and evaluated by reverse phase protein array for PI3K-Akt pathway markers. Decreases of > 60% in pAkt and pS6, and up-phosphorylation of BIM (pro-apoptopic protein) were demonstrated in comparison to baseline for (A) patient 1 on 3 mg QD taselisib with paired biopsies from right endobronchial mass and (B) patient 2 on 16 mg QD taselisib with paired biopsies from right upper anterior thigh mass.

Article Snippet: Taselisib (Genentech, Inc.) was taken on an empty stomach as a single dose (powder-in-capsule formulation) at the same time of day +/- 2 hours ( 33 ).

Techniques: Protein Array, Phospho-proteomics, Comparison