Patricia Hamilton

Publications (2)35.81 Total impact

• Article: Anti-VEGF antibody therapy does not promote metastasis in genetically engineered mouse tumour models.

  Mallika Singh, Suzana S Couto, William F Forrest, Anthony Lima, Jason H Cheng, Rafael Molina, Jason E Long, Patricia Hamilton, Angela McNutt, Ian Kasman, [......], 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
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  ABSTRACT: 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.
  The Journal of Pathology 05/2012; 227(4):417-30. · 6.32 Impact Factor
• Article: Assessing therapeutic responses in Kras mutant cancers using genetically engineered mouse models.

  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 A Nannini, Germaine Fuh, Richard A D Carano, Hartmut Koeppen, Ron X Yu, William F Forrest, Gregory D Plowman, Leisa Johnson
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  ABSTRACT: 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.
  Nature Biotechnology 06/2010; 28(6):585-93. · 29.50 Impact Factor