Solid tumors are highly heterogeneous and contain many distinct cell types including stromal cells. We hypothesize that only subsets of the tumor cells that harbor particular aberrant signaling pathways will contribute to therapeutic response or resistance. We propose using novel multiplex single cell "omics" to unlock the mechanisms of complete response to ADAPT therapy, an innovative combination therapy designed to target drug-resistant (or dormant) advanced colorectal cancer likely through Wnt-PI3K-CDK axis. In this proposal, we will employ comprehensive single cell genomics, transcriptomics, and proteomics to study in vitro and in vivo the dynamic transition of tumor and stromal cells populations, before and after standard 5-FU based chemotherapy versus ADAPT therapy directly in fresh colorectal cancer biopsies samples. This study will lead to greater insight into the pathways of response and resistance to ADAPT therapy and enable the development of a transformational single cell technology (SPARTA) that simultaneously measures multiple transcripts and proteins to monitor and stratify response/resistance.

Public Health Relevance

We will use novel multiplex single cell omics methods to develop insights into the mechanisms of response and resistance to ADAPT therapy, an innovative combination therapy designed to target drug-resistant (or dormant) advanced colorectal cancer. This study will enable the development of a transformational single cell technology (SPARTA) that simultaneously measures multiple transcripts and proteins to monitor and stratify response/resistance. This strategy may also improve the cure rate of patients with late-stage colon cancer and other malignancies sharing a similar molecular pathway, and is therefore of interest to the broader cancer community.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA190122-01
Application #
8792144
Study Section
Special Emphasis Panel (ZCA1-RPRB-M (A1))
Program Officer
Yovandich, Jason L
Project Start
2014-09-16
Project End
2018-08-31
Budget Start
2014-09-16
Budget End
2015-08-31
Support Year
1
Fiscal Year
2014
Total Cost
$591,830
Indirect Cost
$231,548
Name
Institute for Systems Biology
Department
Type
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98109