Nanobiopolymer for Direct Targeting and Inhibition of EGFR Expression in Triple Negative Breast Cancer

Treatment options for triple negative breast cancer (TNBC) are generally limited to cytotoxic chemotherapy. Recently, anti-epidermal growth factor receptor (EGFR) therapy has been introduced for TNBC patients. We engineered a novel nanobioconjugate based on a poly(β-L-malic acid) (PMLA) nanoplatform for TNBC treatment. The nanobioconjugate carries anti-tumor nucleosome-specific monoclonal antibody (mAb) 2C5 to target breast cancer cells, anti-mouse transferrin receptor (TfR) antibody for drug delivery through the host endothelial system, and Morpholino antisense oligonucleotide (AON) to inhibit EGFR synthesis. The nanobioconjugates variants were: (1) P (BioPolymer) with AON, 2C5 and anti-TfR for tumor endothelial and cancer cell targeting, and EGFR suppression (P/AON/2C5/TfR), and (2) P with AON and 2C5 (P/AON/2C5). Controls included (3) P with 2C5 but without AON (P/2C5), (4) PBS, and (5) P with PEG and leucine ester (LOEt) for endosomal escape (P/mPEG/LOEt). Drugs were injected intravenously to MDA-MB-468 TNBC bearing mice. Tissue accumulation of injected nanobioconjugates labeled with Alexa Fluor 680 was examined by Xenogen IVIS 200 (live imaging) and confocal microscopy of tissue sections. Levels of EGFR, phosphorylated and total Akt in tumor samples were detected by western blotting

Loss of PTEN Is Not Associated with Poor Survival in Newly Diagnosed Glioblastoma Patients of the Temozolomide Era

Introduction: Pre-temozolomide studies demonstrated that loss of the tumor suppressor gene PTEN held independent prognostic significance in GBM patients. We investigated whether loss of PTEN predicted shorter survival in the temozolomide era. The role of PTEN in the PI3K/Akt pathway is also reviewed. Methods: Patients with histologically proven newly diagnosed GBM were identified from a retrospective database between 2007 and 2010. Cox proportional hazards analysis was used to calculate the independent effects of PTEN expression, age

Role of PTEN in the PI3K-AKT signaling pathway.

<p>Role of PTEN in the PI3K-AKT signaling pathway.</p

Multivariate analysis of Overall Survival: Adjusted hazards ratio (HR) of mortality, 95% Confidence Intervals (CI), and p values.

<p>Multivariate analysis of Overall Survival: Adjusted hazards ratio (HR) of mortality, 95% Confidence Intervals (CI), and p values.</p

Patient and tumor characteristics stratified by PTEN expression (retained vs. loss).

*<p>Near-gross/gross-total-resection high resection; biopsy/partial low resection.</p>**<p>Standard treatment: radiotherapy+temolozolomide.</p

Median overall survival by patient and tumor characteristics.

*<p>Near-gross/gross-total-resection high resection; biopsy/partial low resection.</p>**<p>Standard treatment: radiotherapy+ temolozolomide.</p

Immunohistochemical analysis, example of a patient with PTEN loss.

<p>Immunohistochemical analysis, example of a patient with PTEN loss.</p

Kaplan-Meir overall 260 survival functions for newly diagnosed glioblastoma patients according to PTEN expression (dashed: PTEN loss, solid: PTEN retained).

<p>Kaplan-Meir overall 260 survival functions for newly diagnosed glioblastoma patients according to PTEN expression (dashed: PTEN loss, solid: PTEN retained).</p

Immunohistochemical analysis, example of a patient with PTEN retained.

<p>Immunohistochemical analysis, example of a patient with PTEN retained.</p

Significant accumulation of P/2C5 in MDA-MB-468 breast tumor <i>in vivo</i>.

<p>(3a), An MDA-MB-468 subcutaneous tumor-bearing mouse was administered with P/2C5 intravenously. 24 hours later, the animal showed drug distribution mostly in the tumor, as well as in kidney and liver (drug clearing organs). (3b), Other than in kidney and liver, the drug was seen exclusively in the tumor.</p