Rapid translation from validated molecular targets in cancer to treatments that benefit patients has been hampered by difficulties in rapidly developing effective, targeted therapeutics, as many targets are not druggable by traditional medicinal chemistry approaches. We propose here to invesfigate a new methodology to accelerate the translation of understandings of molecular events in cancer cell biology into new therapies by using RNA interference-based therapeutics (targeted nanoparticle based systems are used here) combined with multi-time point blood/serum-based miRNA profiling. This strategy will be demonstrated using a previously undruggable target, the oncogenic N-Ras mutation in melanoma. We propose to evaluate the hypothesis that the integration of targeted delivery of RNA interference-based therapeutics that allow quick translation from concept to clinic with multi-time point blood/serum monitoring of cancer-specific miRNA biomarkers can rapidly lead to mechanistically verified cancer treatments with blood/serum biomarkers that can provide minimally invasive proof of function in patients.
Specific Aims : 1. Demonstrate tumor targeting, N-Ras knock-down, and anti-tumor effects with systemically delivered nanoparticles carrying siRNA. 2. Demonstrate that minimally invasive, multi-time point blood/serum miRNA measurements correlate with multi-time point miRNA profiles in tumors after initiation of RNAi that inhibits the N-Ras gene product. 3. Demonstrate that systemically delivered nanoparticles carrying anti-N-Ras siRNA can provide antitumor effects and that the time course of the N-Ras gene inhibition can be monitored via blood/serum miRNA profiles

Public Health Relevance

The approach of integrating multi-time point blood miRMA profiling to provide pharmacodynamic monitoring matched with the specific deliverable gene knockdown has applications to any gene target in any cancer type. A secondary hypothesis implied here is that the short-time-dependent response of the profiled biomarkers can provide significant new and specific information related to therapeutic efficacy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54CA151819-04
Application #
8545712
Study Section
Special Emphasis Panel (ZCA1-GRB-S)
Project Start
Project End
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
4
Fiscal Year
2013
Total Cost
$161,922
Indirect Cost
Name
California Institute of Technology
Department
Type
DUNS #
009584210
City
Pasadena
State
CA
Country
United States
Zip Code
91125
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