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// Lingfei Wang 1, 2, * , Xiaojie Yu 2, * , Chao Wang 2, * , Shujun Pan 3, * , Beibei Liang 1 , Yajun Zhang 2 , Xiaodan Chong 2 , Yanchun Meng 4 , Jian Dong 5 , Yirong Zhao 2 , Yang Yang 2 , Huajing Wang 2 , Jie Gao 6 , Huafeng Wei 1, 2 , Jian Zhao 1, 2 , Hao Wang 2 , Chaohua Hu 7 , Wenze Xiao 8 and Bohua Li 1, 2 1 Shanghai Key Laboratory for Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai 201318, China 2 International Joint Cancer Institute, Second Military Medical University, Shanghai 200433, China 3 Hangzhou Sanatorium of People’s Liberation Army, Hangzhou 310007, China 4 Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai Medical College of Fudan University, Shanghai 200032, China 5 Department of Vascular Surgery, Changhai Hospital, Second Military Medical University, Shanghai, 200433, China 6 Department of Pharmaceutical Sciences, Second Military Medical University, Shanghai 200433, China 7 Department of General Surgery, Xiaogan Central Hospital Affiliated to Wuhan University of Science and Technology, Wuhan 432000, China 8 Department of Rheumatology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai 201399, China * These authors contributed equally to this work Correspondence to: Chaohua Hu, email: huchaohua2006@126.com Wenze Xiao, email: wenzexiao@yahoo.com Bohua Li, email: bohuali1020@163.com Keywords: trastuzumab resistance, GDC-0941, anti-ErbB2 antibody, programmed cell death, breast cancer Received: March 07, 2017 Accepted: May 05, 2017 Published: May 16, 2017 ABSTRACT Trastuzumab, an anti-ErbB2 humanized antibody, brings benefit to patients with ErbB2-amplified metastatic breast cancers. However, the resistance to trastuzumab is common. Our previously reported H2-18, an anti-ErbB2 antibody, potently induced programmed cell death in trastuzumab-resistant breast cancer cells. Here, we aim to investigate the antitumor efficacy of H2-18 in combination with the pan-PI3K inhibitor GDC-0941 in trastuzumab-resistant breast cancer cell lines. The results showed that H2-18 and GDC-0941 synergistically inhibited the in vitro proliferation of BT-474, SKBR-3, HCC-1954 and HCC-1419 breast cancer cells. H2-18 plus GDC-0941 showed significantly enhanced programmed cell death-inducing activity compared with each drug used alone. The combination of H2-18 and GDC-0941 did not increase the effect of single agent on ROS production, cell cycle and ErbB2 signaling. Importantly, the in vivo antitumor efficacy of H2-18 plus GDC-0941 was superior to that of single agent. Thus, the enhanced in vivo antitumor efficacy of H2-18 plus GDC-0941 may mainly be attributable to its increased programmed cell death-inducing activity. Collectively, H2-18 plus GDC-0941 could effectively inhibit tumor growth, suggesting the potential to be translated into clinic as an efficient strategy for ErbB2-overexpressing breast cancers.

// Rogerio B. Craveiro 1, * , Michael Ehrhardt 1, * , Julia Velz 1 , Martin Olschewski 1 , Barbara Goetz 1 , Torsten Pietsch 2 and Dagmar Dilloo 1 1 Department of Pediatric Hematology and Oncology, Center for Pediatrics, University of Bonn Medical Center, D-53113 Bonn, Germany 2 Department of Neuropathology, University of Bonn, D-53105 Bonn, Germany * These authors have contributed equally to this work Correspondence to: Rogerio B. Craveiro, email: Rogerio.craveiro@ukb.uni-bonn.de Keywords: medulloblastoma, Vandetanib, GDC-0941, targeted therapy, multi-kinase inhibitor (MKI) Received: July 27, 2016 Accepted: December 26, 2016 Published: January 31, 2017 ABSTRACT Medulloblastoma is comprised of at least four molecular subgroups with distinct clinical outcome (WHO classification 2016). SHH-TP53-mutated as well as MYC-amplified Non-WNT/Non-SHH medulloblastoma show the worst prognosis. Here we present evidence that single application of the multi-kinase inhibitor Vandetanib displays anti-neoplastic efficacy against cell lines derived from high-risk SHH-TP53-mutated and MYC-amplified Non-WNT/Non-SHH medulloblastoma. The narrow target spectrum of Vandetanib along with a favourable toxicity profile renders this drug ideal for multimodal treatment approaches. In this context our investigation documents that Vandetanib in combination with the clinically available PI3K inhibitor GDC-0941 leads to enhanced cytotoxicity against MYC-amplified and SHH-TP53-mutated medulloblastoma. In line with these findings we show for MYC-amplified medulloblastoma a profound reduction in activity of the oncogenes STAT3 and AKT. Furthermore, we document that Vandetanib and the standard chemotherapeutic Etoposide display additive anti-neoplastic efficacy in the investigated medulloblastoma cell lines that could be further enhanced by PI3K inhibition. Of note, the combination of Vandetanib, GDC-0941 and Etoposide results in MYC-amplified and SHH-TP53-mutated cell lines in complete loss of cell viability. Our findings therefore provide a rational to further evaluate Vandetanib in combination with PI3K inhibitors as well as standard chemotherapeutics in vivo for the treatment of most aggressive medulloblastoma variants.

// Wani Arjumand 1, 2, 4 , Cole D. Merry 1, 2 , Chen Wang 1, 2 , Elias Saba 1, 2 , John B. McIntyre 3 , Shujuan Fang 1, 2 , Elizabeth Kornaga 3 , Prafull Ghatage 4 , Corinne M. Doll 2, 4 , Susan P. Lees-Miller 1, 2, 4 1 Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada 2 Robson DNA Science Centre, Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Alberta, Canada 3 Translational Laboratory, Tom Baker Cancer Centre, Calgary, Alberta, Canada 4 Department of Oncology, University of Calgary, Calgary, Alberta, Canada Correspondence to: Susan P. Lees-Miller, email: leesmill@ucalgary.ca Corinne Doll, email: Corinne.Doll@albertahealthservices.ca Keywords: PI3K pathway, PIK3CA-E545K, Akt, GDC-0941, cisplatin Received: February 11, 2016 Accepted: July 18, 2016 Published: July 30, 2016 ABSTRACT The phosphatidylinositol-3 kinase (PI3K)/Akt/mTOR signaling pathway is activated in many human cancers. Previously, we reported that patients with early stage cervical cancer whose tumours harbour PIK3CA exon 9 or 20 mutations have worse overall survival in response to treatment with radiation and cisplatin than patients with wild-type PIK3CA . The purpose of this study was to determine whether PIK3CA-E545K mutation renders cervical cancer cells more resistant to cisplatin and/or radiation, and whether PI3K inhibition reverses the phenotype. We found that CaSki cells that are heterozygous for the PIK3CA -E545K mutation are more resistant to cisplatin or cisplatin plus radiation than either HeLa or SiHa cells that express only wild-type PIK3CA . Similarly, HeLa cells engineered to stably express PIK3CA -E545K were more resistant to cisplatin or cisplatin plus radiation than cells expressing only wild-type PIK3CA or with PIK3CA depleted. Cells expressing the PIK3CA -E545K mutation also had constitutive PI3K pathway activation and increased cellular migration and each of these phenotypes was reversed by treatment with the PI3K inhibitor GDC-0941/Pictilisib. Our results suggests that cervical cancer patients whose tumours are positive for the PIK3CA -E545K mutation may benefit from PI3K inhibitor therapy in concert with standard cisplatin and radiation therapy.

Deregulation of the Phosphoinositide 3-kinase (PI3K)/AKT signalling network is a hallmark of oncogenesis. Also medulloblastoma, the most common malignant brain tumor in children, is characterized by high levels of AKT phosphorylation and activated PI3K signalling in medulloblastoma is associated with enhanced cellular motility, survival and chemoresistency underscoring its role of as a potential therapeutic target. Here we demonstrate that GDC-0941, a highly specific PI3K inhibitor with good clinical tolerability and promising anti-neoplastic activity in adult cancer, also displays anti-proliferative and pro-apoptotic effects in pediatric human medulloblastoma cell lines. Loss in cell viability is accompanied by reduced phosphorylation of AKT, a downstream target of PI3K. Furthermore, we show that GDC-0941 attenuates the migratory capacity of medulloblastoma cells and targets subpopulations expressing the stem cell marker CD133. GDC-0941 also synergizes with the standard medulloblastoma chemotherapeutic etoposide. In an orthotopic xenograft model of the most aggressive human medulloblastoma variant we document that oral adminstration of GDC-0941 impairs tumor growth and significantly prolongs survival. These findings provide a rational to further investigate GDC-0941 alone and in combination with standard chemotherapeutics for medulloblastoma treatment.

// Aparna Lakshmanan 1, 2 , Daniel Scarberry 1, 2 , Jill A. Green 3 , Xiaoli Zhang 4 , Samia Selmi-Ruby 5 , Sissy M. Jhiang 1, 2, 3 1 Department of Physiology and Cell Biology, The Ohio State University, Columbus, OH-43210, USA 2 Molecular, Cellular and Developmental Biology Graduate Program, The Ohio State University, Columbus, OH-43210, USA 3 Comprehensive Cancer Center, The Ohio State University, Columbus, OH-43210, USA 4 Center for Biostatistics, The Ohio State University, Columbus, OH-43210, USA 5 Centre de Recherche en Cancerologie de Lyon – UMR 1052- INSERM (Institut National de la Sante et de la Recherche Medicale, INSERM, Faculte de Medecine RTH Laennec, F-69372 Lyon, France Correspondence to: Sissy M. Jhiang, e-mail: jhiang.1@osu.edu Keywords: thyroid cancer, NIS, TGF-β, apigenin, GDC-0941 Received: June 02, 2015 Accepted: August 27, 2015 Published: September 09, 2015 ABSTRACT Targeted radioiodine therapy for thyroid cancer is based on selective stimulation of Na + /I - Symporter (NIS)-mediated radioactive iodide uptake (RAIU) in thyroid cells by thyrotropin. Patients with advanced thyroid cancer do not benefit from radioiodine therapy due to reduced or absent NIS expression. To identify inhibitors that can be readily translated into clinical care, we examined oncological pipeline inhibitors targeting Akt, MEK, PI3K, Hsp90 or BRAF in their ability to increase RAIU in thyroid cells expressing BRAF V600E or RET/PTC3 oncogene. Our data showed that (1) PI3K inhibitor GDC-0941 outperformed other inhibitors in RAIU increase mainly by decreasing iodide efflux rate to a great extent; (2) RAIU increase by all inhibitors was extensively reduced by TGF-β, a cytokine secreted in the invasive fronts of thyroid cancers; (3) RAIU reduction by TGF-β was mainly mediated by NIS reduction and could be reversed by Apigenin, a plant-derived flavonoid; and (4) In the presence of TGF-β, GDC-0941 with Apigenin co-treatment had the highest RAIU level in both BRAF V600E expressing cells and RET/PTC3 expressing cells. Taken together, Apigenin may serve as a dietary supplement along with small molecule inhibitors to improve radioiodine therapeutic efficacy on invasive tumor margins thereby minimizing future metastatic events.