Though most advanced solid tumors initially respond to genotoxic chemotherapy and/or radiation, the development of resistance is common and portends a poor outcome. This proposal will test the hypothesis that DNA damage in the tissue microenvironment, induced by cancer therapeutics, promotes detrimental tumor cell phenotypes (therapy resistance) through cell non-autonomous mechanisms dictated by non-neoplastic resident cell types. We further hypothesize that inhibiting specific components of this DNA damage secretory program (DDSP) will attenuate therapy resistance and enhance tumor responses. We propose to test this hypothesis through three specific aims.
Aim 1 will determine the ability of specific paracrine-acting DNA-damage Secretory Program (DDSP) proteins to modulate adverse tumor cell behaviors (e.g. therapy resistance) and determine the mechanism(s) by which they do so.
Aim 2 will determine the intracellular signal transduction programs that differentially modulate subsets of effector proteins comprising DDSP.
Aim 3 will determine the consistency of the DDSP across different tumor types and establish the temporal and cell type-specific variability of damage response programs. The successful completion of these aims will alter current concepts of treatment resistance, both to genotoxic and to pathway directed (e.g. EGFR) therapeutics, by shifting the emphasis from intrinsic tumor cell alterations (rare, clonally-selected events) to a context-dependent (genotoxic damage) microenvironment influence on tumor cell phenotypes. Determining the mechanisms by which the DDSP promotes therapy resistance will provide rationale for co-targeting specific DDSP components and/or their regulatory nodes to mitigate microenvironment signals that promote both intrinsic tumor cell programs of resistance (e.g. EMT) and collective effects such as enhanced tumor cell repopulation kinetics.

Public Health Relevance

The tumor microenvironment (TME) is increasingly recognized as a major contributor to the development and progression of malignant neoplasms. We propose to evaluate the original concept that conventional cancer therapeutics, such as ionizing radiation and alkylating drugs, which exert anti-tumor effects through DNA damage, modify the TME to enhance resistance to subsequent treatments, and consequently promote adverse cancer phenotypes.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Forry, Suzanne L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Fred Hutchinson Cancer Research Center
United States
Zip Code
Levesque, Christine; Nelson, Peter S (2018) Cellular Constituents of the Prostate Stroma: Key Contributors to Prostate Cancer Progression and Therapy Resistance. Cold Spring Harb Perspect Med 8:
Feng, Shu; Shao, Longjiang; Castro, Patricia et al. (2017) Combination treatment of prostate cancer with FGF receptor and AKT kinase inhibitors. Oncotarget 8:6179-6192
Gomez-Sarosi, Luis; Sun, Yu; Coleman, Ilsa et al. (2017) DNA Damage Induces a Secretory Program in the Quiescent TME that Fosters Adverse Cancer Phenotypes. Mol Cancer Res 15:842-851
Nguyen, Holly M; Vessella, Robert L; Morrissey, Colm et al. (2017) LuCaP Prostate Cancer Patient-Derived Xenografts Reflect the Molecular Heterogeneity of Advanced Disease an--d Serve as Models for Evaluating Cancer Therapeutics. Prostate 77:654-671
Hernandez, Michael X; Jiang, Shan; Cole, Tracy A et al. (2017) Prevention of C5aR1 signaling delays microglial inflammatory polarization, favors clearance pathways and suppresses cognitive loss. Mol Neurodegener 12:66
Don-Doncow, Nicholas; Marginean, Felicia; Coleman, Ilsa et al. (2017) Expression of STAT3 in Prostate Cancer Metastases. Eur Urol 71:313-316
Valta, Maija P; Zhao, Hongjuan; Saar, Matthias et al. (2016) Spheroid culture of LuCaP 136 patient-derived xenograft enables versatile preclinical models of prostate cancer. Clin Exp Metastasis 33:325-37
Bianchi-Frias, Daniella; Basom, Ryan; Delrow, Jeffrey J et al. (2016) Cells Comprising the Prostate Cancer Microenvironment Lack Recurrent Clonal Somatic Genomic Aberrations. Mol Cancer Res 14:374-84
Yamazaki, Tomoko; Sugisawa, Ryoichi; Hiramoto, Emiri et al. (2016) A proteolytic modification of AIM promotes its renal excretion. Sci Rep 6:38762
Nghiem, Belinda; Zhang, Xiaotun; Lam, Hung-Ming et al. (2016) Mismatch repair enzyme expression in primary and castrate resistant prostate cancer. Asian J Urol 3:223-228

Showing the most recent 10 out of 16 publications