Autophagy inhibition augments the anticancer effects of epirubicin treatment in anthracycline-sensitive and -resistant triple-negative breast cancer.

Purpose: Triple-negative breast cancers (TNBC) are defined by a lack of expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (ERBB2/HER2). Although initially responsive to chemotherapy, most recurrent TNBCs develop resistance, resulting in disease progression. Autophagy is a lysosome-mediated degradation and recycling process that can function as an adaptive survival response during chemotherapy and contribute to chemoresistance.

Induction of autophagy is an early response to gefitinib and a potential therapeutic target in breast cancer.

Gefitinib (Iressa(®), ZD1839) is a small molecule inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase. We report on an early cellular response to gefitinib that involves induction of functional autophagic flux in phenotypically diverse breast cancer cells that were sensitive (BT474 and SKBR3) or insensitive (MCF7-GFPLC3 and JIMT-1) to gefitinib. Our data show that elevation of autophagy in gefitinib-treated breast cancer cells correlated with downregulation of AKT and ERK1/2 signaling early in the course of treatment.

Combined RNAi-mediated suppression of Rictor and EGFR resulted in complete tumor regression in an orthotopic glioblastoma tumor model.

The PI3K/AKT/mTOR pathway is commonly over activated in glioblastoma (GBM), and Rictor was shown to be an important regulator downstream of this pathway. EGFR overexpression is also frequently found in GBM tumors, and both EGFR and Rictor are associated with increased proliferation, invasion, metastasis and poor prognosis. This research evaluated in vitro and in vivo whether the combined silencing of EGFR and Rictor would result in therapeutic benefits.

The combination of gefitinib and RAD001 inhibits growth of HER2 overexpressing breast cancer cells and tumors irrespective of trastuzumab sensitivity.

Background: HER2-positive breast cancers exhibit high rates of innate and acquired resistance to trastuzumab (TZ), a HER2-directed antibody used as a first line treatment for this disease. TZ resistance may in part be mediated by frequent co-expression of EGFR and by sustained activation of the mammalian target of rapamycin (mTOR) pathway. Here, we assessed feasibility of combining the EGFR inhibitor gefitinib and the mTOR inhibitor everolimus (RAD001) for treating HER2 overexpressing breast cancers with different sensitivity to TZ.

Neuroendocrine carcinoma in a patient with Birt-Hogg-Dubé syndrome.

Background: A patient with Birt-Hogg-Dubé syndrome (BHD) presented with gross hematuria of 6 months' duration. Imaging revealed the presence of a mass in the left prostatic lobe, in addition to a previously observed renal mass. Prostate biopsy and imaging findings indicated an inflammatory etiology, and the patient was discharged.

Inhibition of 4E-BP1 sensitizes U87 glioblastoma xenograft tumors to irradiation by decreasing hypoxia tolerance.

Purpose: Eukaryotic initiation factor 4E (eIF4E) is an essential rate-limiting factor for cap-dependent translation in eukaryotic cells. Elevated eIF4E activity is common in many human tumors and is associated with disease progression. The growth-promoting effects of eIF4E are in turn negatively regulated by 4E-BP1.

Development and evaluation of a cetuximab-based imaging probe to target EGFR and EGFRvIII.

Background And Purpose: The epidermal growth factor receptor (EGFR) is overexpressed in a significant percentage of human malignancies and its expression is associated with tumour aggressiveness and treatment resistance. The monoclonal antibody cetuximab (IMC-C225) blocks the ligand-binding domain of EGFR with high affinity, preventing downstream signalling resulting in tumour growth inhibition. We developed and characterized a novel imaging probe using Oregon Green 488 labelled cetuximab to evaluate its usage as an imaging agent to target EGFR.

Expression of EGFR variant vIII promotes both radiation resistance and hypoxia tolerance.

Background And Purpose: EGFRvIII has been described to function as an oncoprotein with constitutive activation promoting neoplastic transformation and tumorigenicity. The present study was undertaken to test whether EGFRvIII also contributes to hypoxia tolerance.

Material And Methods: The human glioma cell line U373 was genetically modified to stably express EGFRvIII.

Response of U87 glioma xenografts treated with concurrent rapamycin and fractionated radiotherapy: possible role for thrombosis.

Background And Purpose: Rapamycin, a highly specific mTOR inhibitor, has shown anti-proliferative and anti-angiogenic properties, as well as an enhancement in tumour growth delay when used in combination with radiation in mouse xenograft models. Our goal was to determine if rapamycin can also have a positive effect on the local tumour control achieved by radiotherapy.

Materials And Methods: Nude mice bearing U87 glioblastoma xenografts were treated with concomitant rapamycin and radiotherapy over a 5 day fractionation schedule.

Gene expression during acute and prolonged hypoxia is regulated by distinct mechanisms of translational control.

Hypoxia has recently been shown to activate the endoplasmic reticulum kinase PERK, leading to phosphorylation of eIF2alpha and inhibition of mRNA translation initiation. Using a quantitative assay, we show that this inhibition exhibits a biphasic response mediated through two distinct pathways. The first occurs rapidly, reaching a maximum at 1-2 h and is due to phosphorylation of eIF2alpha.