In this application we seek to develop better vectors and reagents that will improve the therapy of pancreatic cancer. Pancreatic cancer is the fifth leading cause of cancer death in the US and accounts for approximately 29,000 deaths per year in the United States and 50,000 deaths per year in Europe (excluding the former USSR). Median survival is six months or less, and only four percent of patients are alive five years after diagnosis. Thus, incidence and death rates are virtually identical. One approach to the treatment of this devastating disease is gene therapy. However, it is widely believed that gene therapy will not succeed until vectors are endowed with the ability to target tumor cells. As will be described in the application, Sindbis viral vectors can systemically target and specifically infect tumor cells in vivo. However, they require further study to enhance these capabilities. To do so we seek to accomplish the following:
(Aim 1) To use multiple imaging modalities, including IVlS, MRI, microCT, microSPECT, and microPET to monitor in vivo, in two different mouse models of pancreatic cancer, the extent and specificity of targeting and antitumor efficacy of various Sindbis vectors (generated in Aim 2).
(Aim 2) To generate rationally designed Sindbis vectors that can be tested in the two animals models of Aim 1, with the goal of maximizing vector targeting and efficacy. The goal of Aim 2 is to design and develop Sindbis vectors that can induce complete remission in pancreatic cancers and their metastases through a combination of (a) the vector's known apoptosis-inducing potential, (b) the therapeutic payload they encode, and (c) their customizable targeting capabilities. In vivo monitoring of the targeting and efficacy of the new vectors, as discussed in Aim 1, will be critical to achieving this goal.
(Aim 3) To examine the effects of the immune system on Sindbis-vector mediated therapy in an immunocompetent mouse model. Such studies will play a role in the design, generation and selection of Sindbis vectors created in Aim 2.
(Aim 4) To perform pharmacokinetic studies with the Sindbis vectors to be used for vector-mediated therapy in immunocompetent mice. Such studies will help guide the design, generation and selection of Sindbis vectors created in Aim 2.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA100687-02
Application #
6908073
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Arya, Suresh
Project Start
2004-07-01
Project End
2009-04-30
Budget Start
2005-07-01
Budget End
2006-04-30
Support Year
2
Fiscal Year
2005
Total Cost
$302,318
Indirect Cost
Name
New York University
Department
Pathology
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
DiGiacomo, Vincent; Meruelo, Daniel (2016) Looking into laminin receptor: critical discussion regarding the non-integrin 37/67-kDa laminin receptor/RPSA protein. Biol Rev Camb Philos Soc 91:288-310
Digiacomo, Vincent; Gando, Ivan A; Venticinque, Lisa et al. (2015) The Transition of the 37-Kda Laminin Receptor (Rpsa) to Higher Molecular Weight Species: Sumoylation or Artifact? Cell Mol Biol Lett 20:571-85
Pampeno, Christine; Derkatch, Irina L; Meruelo, Daniel (2014) Interaction of human laminin receptor with Sup35, the [PSI?] prion-forming protein from S. cerevisiae: a yeast model for studies of LamR interactions with amyloidogenic proteins. PLoS One 9:e86013
Granot, Tomer; Yamanashi, Yoshihide; Meruelo, Daniel (2014) Sindbis viral vectors transiently deliver tumor-associated antigens to lymph nodes and elicit diversified antitumor CD8+ T-cell immunity. Mol Ther 22:112-22
Pampeno, Christine; Hurtado, Alicia; Meruelo, Daniel (2012) ATM kinase is activated by sindbis viral vector infection. Virus Res 166:97-102
Venticinque, Lisa; Meruelo, Daniel (2012) Comprehensive proteomic analysis of nonintegrin laminin receptor interacting proteins. J Proteome Res 11:4863-72
Granot, T; Meruelo, D (2012) The role of natural killer cells in combinatorial anti-cancer therapy using Sindbis viral vectors and irinotecan. Cancer Gene Ther 19:588-91
Jamieson, Kelly V; Hubbard, Stevan R; Meruelo, Daniel (2011) Structure-guided identification of a laminin binding site on the laminin receptor precursor. J Mol Biol 405:24-32
Venticinque, Lisa; Jamieson, Kelly V; Meruelo, Daniel (2011) Interactions between laminin receptor and the cytoskeleton during translation and cell motility. PLoS One 6:e15895
Granot, Tomer; Venticinque, Lisa; Tseng, Jen-Chieh et al. (2011) Activation of cytotoxic and regulatory functions of NK cells by Sindbis viral vectors. PLoS One 6:e20598

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