Hani Bou Reslan
Genentech
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Publication
Featured researches published by Hani Bou Reslan.
Cancer Cell | 2008
Maresa Caunt; Judy Mak; Wei-Ching Liang; Scott Stawicki; Qi Pan; Raymond K. Tong; Joe Kowalski; Calvin Ho; Hani Bou Reslan; Jed Ross; Leanne Berry; Ian Kasman; Constance Zlot; Zhiyong Cheng; Jennifer Le Couter; Ellen Filvaroff; Greg Plowman; Franklin Peale; Dorothy French; Richard A. D. Carano; Alexander W. Koch; Yan Wu; Ryan J. Watts; Marc Tessier-Lavigne; Anil Bagri
Metastasis, which commonly uses lymphatics, accounts for much of the mortality associated with cancer. The vascular endothelial growth factor (VEGF)-C coreceptor, neuropilin-2 (Nrp2), modulates but is not necessary for developmental lymphangiogenesis, and its significance for metastasis is unknown. An antibody to Nrp2 that blocks VEGFC binding disrupts VEGFC-induced lymphatic endothelial cell migration, but not proliferation, in part independently of VEGF receptor activation. It does not affect established lymphatics in normal adult mice but reduces tumoral lymphangiogenesis and, importantly, functional lymphatics associated with tumors. It also reduces metastasis to sentinel lymph nodes and distant organs, apparently by delaying the departure of tumor cells from the primary tumor. Our results demonstrate that Nrp2, which was originally identified as an axon-guidance receptor, is an attractive target for modulating metastasis.
Nature Biotechnology | 2010
Mallika Singh; Anthony Lima; Rafael Molina; Patricia Hamilton; Anne C Clermont; Vidusha Devasthali; Jennifer D. Thompson; Jason H. Cheng; Hani Bou Reslan; Calvin C K Ho; Timothy C Cao; Chingwei V. Lee; Michelle Nannini; Germaine Fuh; Richard A. D. Carano; Hartmut Koeppen; Ron Yu; William F. Forrest; Gregory D. Plowman; Leisa Johnson
The low rate of approval of novel anti-cancer agents underscores the need for better preclinical models of therapeutic response as neither xenografts nor early-generation genetically engineered mouse models (GEMMs) reliably predict human clinical outcomes. Whereas recent, sporadic GEMMs emulate many aspects of their human disease counterpart more closely, their ability to predict clinical therapeutic responses has never been tested systematically. We evaluated the utility of two state-of-the-art, mutant Kras-driven GEMMs—one of non-small-cell lung carcinoma and another of pancreatic adenocarcinoma—by assessing responses to existing standard-of-care chemotherapeutics, and subsequently in combination with EGFR and VEGF inhibitors. Standard clinical endpoints were modeled to evaluate efficacy, including overall survival and progression-free survival using noninvasive imaging modalities. Comparisons with corresponding clinical trials indicate that these GEMMs model human responses well, and lay the foundation for the use of validated GEMMs in predicting outcome and interrogating mechanisms of therapeutic response and resistance.
Cell | 2010
Carlos Bais; Xiumin Wu; Jenny Yao; Suya Yang; Yongping Crawford; Krista McCutcheon; Christine Tan; Ganesh Kolumam; Jean-Michel Vernes; Jeffrey Eastham-Anderson; Peter Haughney; Marcin Kowanetz; Thijs J. Hagenbeek; Ian Kasman; Hani Bou Reslan; Jed Ross; Nick van Bruggen; Richard A. D. Carano; Yu-Ju Gloria Meng; Jo-Anne Hongo; Jean Philippe Stephan; Masabumi Shibuya; Napoleone Ferrara
It has been recently reported that treatment with an anti-placenta growth factor (PlGF) antibody inhibits metastasis and primary tumor growth. Here we show that, although anti-PlGF treatment inhibited wound healing, extravasation of B16F10 cells, and growth of a tumor engineered to overexpress the PlGF receptor (VEGFR-1), neutralization of PlGF using four novel blocking antibodies had no significant effect on tumor angiogenesis in 15 models. Also, genetic ablation of the tyrosine kinase domain of VEGFR-1 in the host did not result in growth inhibition of the anti-VEGF-A sensitive or resistant tumors tested. Furthermore, combination of anti-PlGF with anti-VEGF-A antibodies did not result in greater antitumor efficacy than anti-VEGF-A monotherapy. In conclusion, our data argue against an important role of PlGF during primary tumor growth in most models and suggest that clinical evaluation of anti-PlGF antibodies may be challenging.
Clinical Cancer Research | 2009
James P B O'Connor; Richard A. D. Carano; Andrew R Clamp; Jed Ross; Calvin C K Ho; Alan Jackson; Geoff J.M. Parker; Christopher Rose; Franklin Peale; Michel Friesenhahn; Claire Mitchell; Yvonne Watson; Caleb Roberts; Lynn Hope; Susan Cheung; Hani Bou Reslan; Mary Ann T Go; Glenn Pacheco; Xiumin Wu; Tim C. Cao; Sarajane Ross; Giovanni A. Buonaccorsi; Karen Davies; Jurjees Hasan; Paula Thornton; Olivia del Puerto; Napoleone Ferrara; Nicholas van Bruggen; Gordon C Jayson
Purpose: Little is known concerning the onset, duration, and magnitude of direct therapeutic effects of anti–vascular endothelial growth factor (VEGF) therapies. Such knowledge would help guide the rational development of targeted therapeutics from bench to bedside and optimize use of imaging technologies that quantify tumor function in early-phase clinical trials. Experimental Design: Preclinical studies were done using ex vivo microcomputed tomography and in vivo ultrasound imaging to characterize tumor vasculature in a human HM-7 colorectal xenograft model treated with the anti-VEGF antibody G6-31. Clinical evaluation was by quantitative magnetic resonance imaging in 10 patients with metastatic colorectal cancer treated with bevacizumab. Results: Microcomputed tomography experiments showed reduction in perfused vessels within 24 to 48 h of G6-31 drug administration (P ≤ 0.005). Ultrasound imaging confirmed reduced tumor blood volume within the same time frame (P = 0.048). Consistent with the preclinical results, reductions in enhancing fraction and fractional plasma volume were detected in patient colorectal cancer metastases within 48 h after a single dose of bevacizumab that persisted throughout one cycle of therapy. These effects were followed by resolution of edema (P = 0.0023) and tumor shrinkage in 9 of 26 tumors at day 12. Conclusion: These data suggest that VEGF-specific inhibition induces rapid structural and functional effects with downstream significant antitumor activity within one cycle of therapy. This finding has important implications for the design of early-phase clinical trials that incorporate physiologic imaging. The study shows how animal data help interpret clinical imaging data, an important step toward the validation of image biomarkers of tumor structure and function. (Clin Cancer Res 2009;15(21):6674–82)Purpose Little is known concerning the onset, duration and magnitude of direct therapeutic effects of anti-VEGF therapies. Such knowledge would help guide the rational development of targeted therapeutics from bench to bedside and optimize use of imaging technologies that quantify tumor function in early phase clinical trials.
The Journal of Pathology | 2012
Mallika Singh; Suzana S. Couto; William F. Forrest; Anthony Lima; Jason H. Cheng; Rafael Molina; Jason E. Long; Patricia Hamilton; Angela McNutt; Ian Kasman; Michelle Nannini; Hani Bou Reslan; Tim C. Cao; Calvin C K Ho; Kai H. Barck; Richard A. D. Carano; Oded Foreman; Jeffrey Eastham-Anderson; Adrian M. Jubb; Napoleone Ferrara; Leisa Johnson
Resistance to anti‐angiogenic therapy can occur via several potential mechanisms. Unexpectedly, recent studies showed that short‐term inhibition of either VEGF or VEGFR enhanced tumour invasiveness and metastatic spread in preclinical models. In an effort to evaluate the translational relevance of these findings, we examined the consequences of long‐term anti‐VEGF monoclonal antibody therapy in several well‐validated genetically engineered mouse tumour models of either neuroendocrine or epithelial origin. Anti‐VEGF therapy decreased tumour burden and increased overall survival, either as a single agent or in combination with chemotherapy, in all four models examined. Importantly, neither short‐ nor long‐term exposure to anti‐VEGF therapy altered the incidence of metastasis in any of these autochthonous models, consistent with retrospective analyses of clinical trials. In contrast, we observed that sunitinib treatment recapitulated previously reported effects on tumour invasiveness and metastasis in a pancreatic neuroendocrine tumour (PNET) model. Consistent with these results, sunitinib treatment resulted in an up‐regulation of the hypoxia marker GLUT1 in PNETs, whereas anti‐VEGF did not. These results indicate that anti‐VEGF mediates anti‐tumour effects and therapeutic benefits without a paradoxical increase in metastasis. Moreover, these data underscore the concept that drugs targeting VEGF ligands and receptors may affect tumour metastasis in a context‐dependent manner and are mechanistically distinct from one another. Copyright
Clinical Cancer Research | 2012
Laurent Salphati; Timothy P. Heffron; Bruno Alicke; Merry Nishimura; Kai H. Barck; Richard A. D. Carano; Jonathan Cheong; Kyle A. Edgar; Joan M. Greve; Samir Kharbanda; Hartmut Koeppen; Shari Lau; Leslie Lee; Jodie Pang; Emile Plise; Jenny L. Pokorny; Hani Bou Reslan; Jann N. Sarkaria; Jeffrey Wallin; Xiaolin Zhang; Stephen E. Gould; Alan G. Olivero; Heidi S. Phillips
Purpose: Glioblastoma (GBM), the most common primary brain tumor in adults, presents a high frequency of alteration in the PI3K pathway. Our objectives were to identify a dual PI3K/mTOR inhibitor optimized to cross the blood–brain barrier (BBB) and characterize its brain penetration, pathway modulation in the brain and efficacy in orthotopic xenograft models of GBM. Experimental Design: Physicochemical properties of PI3K inhibitors were optimized using in silico tools, leading to the identification of GNE-317. This compound was tested in cells overexpressing P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP). Following administration to mice, GNE-317 plasma and brain concentrations were determined, and phosphorylated biomarkers (pAkt, p4EBP1, and pS6) were measured to assess PI3K pathway suppression in the brain. GNE-317 efficacy was evaluated in the U87, GS2, and GBM10 orthotopic models of GBM. Results: GNE-317 was identified as having physicochemical properties predictive of low efflux by P-gp and BCRP. Studies in transfected MDCK cells showed that GNE-317 was not a substrate of either transporter. GNE-317 markedly inhibited the PI3K pathway in mouse brain, causing 40% to 90% suppression of the pAkt and pS6 signals up to 6-hour postdose. GNE-317 was efficacious in the U87, GS2, and GBM10 orthotopic models, achieving tumor growth inhibition of 90% and 50%, and survival benefit, respectively. Conclusions: These results indicated that specific optimization of PI3K inhibitors to cross the BBB led to potent suppression of the PI3K pathway in healthy brain. The efficacy of GNE-317 in 3 intracranial models of GBM suggested that this compound could be effective in the treatment of GBM. Clin Cancer Res; 18(22); 6239–48. ©2012 AACR.
Clinical Cancer Research | 1909
James P B O'Connor; Richard A. D. Carano; Andrew R Clamp; Jed Ross; Calvin C K Ho; Alan Jackson; Geoff J.M. Parker; Chris Rose; Franklin Peale; Michel Friesenhahn; Claire Mitchell; Yvonne Watson; Caleb Roberts; Lynn Hope; Susan Cheung; Hani Bou Reslan; Mary Ann T Go; Glenn Pacheco; Xiumin Wu; Tim C. Cao; Sarajane Ross; Giovanni A. Buonaccorsi; Karen Davies; Jurjees Hasan; Paula Thornton; Olivia del Puerto; Napoleone Ferrara; Nicholas van Bruggen; Gordon C Jayson
Purpose: Little is known concerning the onset, duration, and magnitude of direct therapeutic effects of anti–vascular endothelial growth factor (VEGF) therapies. Such knowledge would help guide the rational development of targeted therapeutics from bench to bedside and optimize use of imaging technologies that quantify tumor function in early-phase clinical trials. Experimental Design: Preclinical studies were done using ex vivo microcomputed tomography and in vivo ultrasound imaging to characterize tumor vasculature in a human HM-7 colorectal xenograft model treated with the anti-VEGF antibody G6-31. Clinical evaluation was by quantitative magnetic resonance imaging in 10 patients with metastatic colorectal cancer treated with bevacizumab. Results: Microcomputed tomography experiments showed reduction in perfused vessels within 24 to 48 h of G6-31 drug administration (P ≤ 0.005). Ultrasound imaging confirmed reduced tumor blood volume within the same time frame (P = 0.048). Consistent with the preclinical results, reductions in enhancing fraction and fractional plasma volume were detected in patient colorectal cancer metastases within 48 h after a single dose of bevacizumab that persisted throughout one cycle of therapy. These effects were followed by resolution of edema (P = 0.0023) and tumor shrinkage in 9 of 26 tumors at day 12. Conclusion: These data suggest that VEGF-specific inhibition induces rapid structural and functional effects with downstream significant antitumor activity within one cycle of therapy. This finding has important implications for the design of early-phase clinical trials that incorporate physiologic imaging. The study shows how animal data help interpret clinical imaging data, an important step toward the validation of image biomarkers of tumor structure and function. (Clin Cancer Res 2009;15(21):6674–82)Purpose Little is known concerning the onset, duration and magnitude of direct therapeutic effects of anti-VEGF therapies. Such knowledge would help guide the rational development of targeted therapeutics from bench to bedside and optimize use of imaging technologies that quantify tumor function in early phase clinical trials.
Clinical Cancer Research | 2009
James O’Connor; Richard A. D. Carano; Andrew R Clamp; Jed Ross; Calvin C K Ho; Alan Jackson; Geoff J.M. Parker; Chris Rose; Franklin Peale; Michel Friesenhahn; Claire Mitchell; Yvonne Watson; Caleb Roberts; Lynn Hope; Susan Cheung; Hani Bou Reslan; Mary Ann T Go; Glenn Pacheco; Xiumin Wu; Tim C. Cao; Sarajane Ross; Giovanni A. Buonaccorsi; Karen Davies; Jurjees Hasan; Paula Thornton; Olivia del Puerto; Napoleone Ferrara; Nicholas van Bruggen; Gordon C Jayson
Purpose: Little is known concerning the onset, duration, and magnitude of direct therapeutic effects of anti–vascular endothelial growth factor (VEGF) therapies. Such knowledge would help guide the rational development of targeted therapeutics from bench to bedside and optimize use of imaging technologies that quantify tumor function in early-phase clinical trials. Experimental Design: Preclinical studies were done using ex vivo microcomputed tomography and in vivo ultrasound imaging to characterize tumor vasculature in a human HM-7 colorectal xenograft model treated with the anti-VEGF antibody G6-31. Clinical evaluation was by quantitative magnetic resonance imaging in 10 patients with metastatic colorectal cancer treated with bevacizumab. Results: Microcomputed tomography experiments showed reduction in perfused vessels within 24 to 48 h of G6-31 drug administration (P ≤ 0.005). Ultrasound imaging confirmed reduced tumor blood volume within the same time frame (P = 0.048). Consistent with the preclinical results, reductions in enhancing fraction and fractional plasma volume were detected in patient colorectal cancer metastases within 48 h after a single dose of bevacizumab that persisted throughout one cycle of therapy. These effects were followed by resolution of edema (P = 0.0023) and tumor shrinkage in 9 of 26 tumors at day 12. Conclusion: These data suggest that VEGF-specific inhibition induces rapid structural and functional effects with downstream significant antitumor activity within one cycle of therapy. This finding has important implications for the design of early-phase clinical trials that incorporate physiologic imaging. The study shows how animal data help interpret clinical imaging data, an important step toward the validation of image biomarkers of tumor structure and function. (Clin Cancer Res 2009;15(21):6674–82)Purpose Little is known concerning the onset, duration and magnitude of direct therapeutic effects of anti-VEGF therapies. Such knowledge would help guide the rational development of targeted therapeutics from bench to bedside and optimize use of imaging technologies that quantify tumor function in early phase clinical trials.
Neoplasia | 2013
Deepak Sampath; Jason Oeh; Shelby K. Wyatt; Tim C. Cao; Hartmut Koeppen; Jeffrey Eastham-Anderson; Liliane Robillard; Calvin C K Ho; Jed Ross; Guanglei Zhuang; Hani Bou Reslan; Philip Vitorino; Kai H. Barck; Sharon E. Ungersma; Jean Michel Vernes; Maresa Caunt; Nick van Bruggen; Weilan Ye; Ulka Vijapurkar; Yu-Ju Gloria Meng; Napoleone Ferrara; Lori S. Friedman; Richard A. D. Carano
Clinical Cancer Research | 2009
James O’Connor; Richard A. D. Carano; Andrew R Clamp; Jeremy A. Ross; Chung Kuang Hou; Andrew Jackson; Geoffrey J. M. Parker; Chris Rose; Franklin Peale; Michel Friesenhahn; Claire Mitchell; Yvonne Watson; Chris Roberts; Lynn Hope; Susan Cheung; Hani Bou Reslan; Masahiro J. Go; Glenn Pacheco; Xiumin Wu; Tingting Cao; Sarajane Ross; Giovanni A. Buonaccorsi; G Davies; J. Hasan; Paula Thornton; Olivia del Puerto; Nicola Ferrara; Nicholas van Bruggen; Gordon C Jayson