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.
|Cai, Shang; Kalisky, Tomer; Sahoo, Debashis et al. (2017) A Quiescent Bcl11b High Stem Cell Population Is Required for Maintenance of the Mammary Gland. Cell Stem Cell 20:247-260.e5|
|Jeong, Youngtae; Hoang, Ngoc T; Lovejoy, Alexander et al. (2017) Role of KEAP1/NRF2 and TP53 Mutations in Lung Squamous Cell Carcinoma Development and Radiation Resistance. Cancer Discov 7:86-101|
|Betancur, Paola A; Abraham, Brian J; Yiu, Ying Y et al. (2017) A CD47-associated super-enhancer links pro-inflammatory signalling to CD47 upregulation in breast cancer. Nat Commun 8:14802|
|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:|
|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|
|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; Anderson, Katie L; Ito, Daisuke et al. (2016) Eradication of Canine Diffuse Large B-Cell Lymphoma in a Murine Xenograft Model with CD47 Blockade and Anti-CD20. Cancer Immunol Res 4:1072-1087|
|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, 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|
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