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
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.
|Lisova, Ksenia; Sergeev, Maxim; Evans-Axelsson, Susan et al. (2018) Microscale radiosynthesis, preclinical imaging and dosimetry study of [18F]AMBF3-TATE: A potential PET tracer for clinical imaging of somatostatin receptors. Nucl Med Biol 61:36-44|
|Turner, Kristen M; Deshpande, Viraj; Beyter, Doruk et al. (2017) Extrachromosomal oncogene amplification drives tumour evolution and genetic heterogeneity. Nature 543:122-125|
|Ghosh, Dhimankrishna; Funk, Cory C; Caballero, Juan et al. (2017) A Cell-Surface Membrane Protein Signature for Glioblastoma. Cell Syst 4:516-529.e7|
|Su, Yapeng; Shi, Qihui; Wei, Wei (2017) Single cell proteomics in biomedicine: High-dimensional data acquisition, visualization, and analysis. Proteomics 17:|
|Collins, Jeffrey; Waldmann, Christopher M; Drake, Christopher et al. (2017) Production of diverse PET probes with limited resources: 24 18F-labeled compounds prepared with a single radiosynthesizer. Proc Natl Acad Sci U S A 114:11309-11314|
|Hong, Candice Sun; Graham, Nicholas A; Gu, Wen et al. (2016) MCT1 Modulates Cancer Cell Pyruvate Export and Growth of Tumors that Co-express MCT1 and MCT4. Cell Rep 14:1590-1601|
|Henning, Ryan K; Varghese, Joseph O; Das, Samir et al. (2016) Degradation of Akt using protein-catalyzed capture agents. J Pept Sci 22:196-200|
|Poovathingal, Suresh Kumar; Kravchenko-Balasha, Nataly; Shin, Young Shik et al. (2016) Critical Points in Tumorigenesis: A Carcinogen-Initiated Phase Transition Analyzed via Single-Cell Proteomics. Small 12:1425-31|
|Wei, Wei; Shin, Young Shik; Xue, Min et al. (2016) Single-Cell Phosphoproteomics Resolves Adaptive Signaling Dynamics and Informs Targeted Combination Therapy in Glioblastoma. Cancer Cell 29:563-573|
|Ghosh, Dhiman; Ulasov, Ilya V; Chen, LiPing et al. (2016) TGF?-Responsive HMOX1 Expression Is Associated with Stemness and Invasion in Glioblastoma Multiforme. Stem Cells 34:2276-89|
Showing the most recent 10 out of 55 publications