This program project grant is in response to RFA-CA-08-020 entitled "Tumor Stem Cells in Cancer Biology, Prevention, and Therapy". Recent evidence suggests that cancers have a cellular hierarchy in which a minority population of cancer cells, called cancer stem cells, drives the growth and spread of a tumor. The ability to prospectively identify tumorigenic cancer cells will facilitate the identification of pathways that regulate their growth, metastasis and survival in patients. Targeting the pathways involved in essential processes such as self renewal may lead to more effective therapies. This proposal is an interlocking set of projects designed to identify new cancer stem cell therapeutic targets against breast cancer and leukemia stem cells and to test drugs against some of these targets in a preclinical cancer stem cell model. The three projects of our Program are listed below. Project 1: Identification of self-renewal pathways in breast cancer stem cells and development of therapeutic pharmacological interventions. PI Mike Clarke, Stanford University. Project 2: Therapeutic targeting of CD47 on human leukemia and other cancer stem cells PI, Irv Weissman, Stanford University. Project 3: Microfluidic techniques for the molecular and functional analysis of gene expression, chromatin structure and in vitro culturing of cancer stem cells. PI Steve Quake, Stanford University. These projects are highly interconnected and reliant on each other for the success of the individual project as well as the success of this program. Each project will be supported by 4 cores: an administrative core, a bioinformatics core, an animal model core, and a flow cytometry core.
The focus of this application is to identify new therapeutic targets and drugs against breast and leukemia cancer stem cells. Success of this project would lead to more effective cancer therapeutics. This has obvious immense relevance to public health.
|Krampitz, Geoffrey Wayne; George, Benson M; Willingham, Stephen B et al. (2016) Identification of tumorigenic cells and therapeutic targets in pancreatic neuroendocrine tumors. Proc Natl Acad Sci U S A 113:4464-9|
|Weiskopf, Kipp; Schnorr, Peter J; Pang, Wendy W et al. (2016) Myeloid Cell Origins, Differentiation, and Clinical Implications. Microbiol Spectr 4:|
|Dalerba, Piero; Sahoo, Debashis; Paik, Soonmyung et al. (2016) CDX2 as a Prognostic Biomarker in Stage II and Stage III Colon Cancer. N Engl J Med 374:211-22|
|Weiskopf, Kipp; Jahchan, Nadine S; Schnorr, Peter J et al. (2016) CD47-blocking immunotherapies stimulate macrophage-mediated destruction of small-cell lung cancer. J Clin Invest 126:2610-20|
|Feng, Mingye; Chen, James Y; Weissman-Tsukamoto, Rachel et al. (2015) Macrophages eat cancer cells using their own calreticulin as a guide: roles of TLR and Btk. Proc Natl Acad Sci U S A 112:2145-50|
|Jeong, Youngtae; Swami, Srilatha; Krishnan, Aruna V et al. (2015) Inhibition of Mouse Breast Tumor-Initiating Cells by Calcitriol and Dietary Vitamin D. Mol Cancer Ther 14:1951-61|
|McCracken, Melissa N; Cha, Adriel C; Weissman, Irving L (2015) Molecular Pathways: Activating T Cells after Cancer Cell Phagocytosis from Blockade of CD47 "Don't Eat Me" Signals. Clin Cancer Res 21:3597-601|
|Cheah, Ming T; Chen, James Y; Sahoo, Debashis et al. (2015) CD14-expressing cancer cells establish the inflammatory and proliferative tumor microenvironment in bladder cancer. Proc Natl Acad Sci U S A 112:4725-30|
|Feng, Weiguo; Gentles, Andrew; Nair, Ramesh V et al. (2014) Targeting unique metabolic properties of breast tumor initiating cells. Stem Cells 32:1734-45|
|Wang, Jianbin; Quake, Stephen R (2014) RNA-guided endonuclease provides a therapeutic strategy to cure latent herpesviridae infection. Proc Natl Acad Sci U S A 111:13157-62|
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