As one of the crucial steps in metastatic progression requires tumor to successfully interact with its local microenvironment, it follows that targeting this cross-talk may be an attractive adjuvant to standard treatment approaches.We are currently focused on developing therapies that target the associated tumor recruited host stromal cells. We now have an IRB approved biological repository study to obtain blood, bone marrow and tumor and adjacent normal tissue when available from patients with malignancy and healthy donors. We continue our on-going studies of measuring and characterizing the circulating bone marrow-derived cells that may be altered in the setting of cancer and other chronic diseases. Utilizing both quantification and functional assays, including flow cytometry and colony forming unit assays, we are assessing the circulating bone marrow-derived progenitor cell populations in pediatric and adult patients with malignancies. We have identified that at the time of surgical resection of the primary tumor there is a surge in circulating bone marrow-derived cell populations that can enhance metastatic spread. We continue to collect blood samples from patients immediately before and within the week post-operatively to better understand the nature of the surge and how best to target it.We have established a new collaboration with Dr. Sharon Savage to examine these circulating bone marrow-derived cell populations in patients with Li Fraumeni syndrome, which is a high-risk cancer predisposition syndrome related to loss of tumor suppressor p53. We will determine if changes in these bone marrow-derived cell populations predict tumor development in these patients. We plan to monitor circulating levels of bone marrow-derived cells at the time of the yearly evaluation for cancer surveillance. We have performed a small microarray analysis of a subset of CD34 expressing bone marrow-derived cells from 5 patients with metastatic cancer compared to healthy controls. We plan to work with the bioinformatics core to distill a list of differentially regulated genes in these two populations. We also plan to isolate and analyze DNA and non-coding RNAs. The specific changes in these cells may help to serve as prognostic markers of disease progression as well as response to therapies. This year we have established a pre-clinical model system for testing microenvironment-targeting therapy in pediatric sarcomas. Utilizing a Ewings sarcoma xenograft tumor cell line we have performed flow cytometry and immunofluorescence to demonstrate the influx of myeloid cells into the tumor and pre-metastatic tissues. We plan to conduct pre-clinical investigations utilizing inhibitors targeting stromal cells specifically to assess impact on metastatic progression. We will perform these studies at the time of surgical resection of the primary tumor when overall tumor burden is low but metastatic risk is high. These pre-clinical studies will answer whether this approach to treatment may likely be a good window for targeting the recruitment of these bone marrow-derived tumor-associated cells that support tumor progression. Ultimately, I plan, in collaboration with Brigitte Widemann, to establish a phase I trial of tumor microenvironment targeting drugs in pediatric patients with relapsed solid tumors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC011334-03
Application #
8553112
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2012
Total Cost
$488,066
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Giles, Amber Jin; Reid, Caitlin Marie; Evans, Justin DeWayne et al. (2016) Activation of Hematopoietic Stem/Progenitor Cells Promotes Immunosuppression Within the Pre-metastatic Niche. Cancer Res 76:1335-47
Chang, Wendy; Brohl, Andrew S; Patidar, Rajesh et al. (2016) MultiDimensional ClinOmics for Precision Therapy of Children and Adolescent Young Adults with Relapsed and Refractory Cancer: A Report from the Center for Cancer Research. Clin Cancer Res 22:3810-20
Papaspyridonos, Marianna; Matei, Irina; Huang, Yujie et al. (2015) Id1 suppresses anti-tumour immune responses and promotes tumour progression by impairing myeloid cell maturation. Nat Commun 6:6840
Highfill, Steven L; Cui, Yongzhi; Giles, Amber J et al. (2014) Disruption of CXCR2-mediated MDSC tumor trafficking enhances anti-PD1 efficacy. Sci Transl Med 6:237ra67
Zhang, Hua; Maric, Irena; Diprima, Michael J et al. (2013) Fibrocytes represent a novel MDSC subset circulating in patients with metastatic cancer. Blood 122:1105-13
Chang, Qing; Bournazou, Eirini; Sansone, Pasquale et al. (2013) The IL-6/JAK/Stat3 feed-forward loop drives tumorigenesis and metastasis. Neoplasia 15:848-62
Peinado, Hector; Aleckovic, Masa; Lavotshkin, Simon et al. (2012) Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat Med 18:883-91
Acharya, Suchitra S; Kaplan, Rosandra N; Macdonald, Dan et al. (2011) Neoangiogenesis contributes to the development of hemophilic synovitis. Blood 117:2484-93