Breast cancer remains the most common cancer in North America and the second leading cause of cancer death in women. Radiation therapy (RT) plays an integral part in the treatment of breast cancer with more than half of all breast cancer patients receiving radiation sometime during the course of their treatment. The conventional view of RT has largely focused on the effect of RT on the tumor cells themselves. However, recent studies have demonstrated a critical role for the immune system in determining the response of tumors to RT. Further, multiple studies have identified the bacterial and fungal microbiomes as key regulators of systemic immune responses in various in states of inflammation including post-chemotherapy immunogenic cell death and asthma respectively. The microbiome consists of trillions of organisms and a multitude of different species that can either support or suppress an ongoing immune response and our preliminary data suggests that targeting intestinal bacteria reduces the efficacy of RT whereas targeting gut fungi can enhance the efficacy of RT. The objective of this research proposal is to address the mechanism(s) by which intestinal bacteria and fungi shape the response to RT. The proposal tests the hypothesis that the composition of the bacterial and fungal microbiome regulates RT-induced immune responses and that the efficacy of RT can be enhanced in vivo by targeting specific species with the fungal microbiome. To evaluate this hypothesis, the following Aims are proposed:
Aim 1 : Characterize the effect of antibiotic- or antifungal-induced intestinal dysbiosis on the efficacy of radiation and chemotherapy;
Aim 2 : Define immune mechanism(s) of bacterial and fungal microbiota regulation of tumor responses to RT;
and Aim 3 : Examine the role of specific intestinal fungi in modulating the efficacy of RT. We will accomplish these aims using focal RT delivered with an advanced small animal irradiator in a murine model of breast cancer and studying the effects of RT in the setting of bacterial or fungal dysbiosis using a combination of flow cytometry, immunohistochemistry, quantitative PCR and ELISA to determine the changes in the immune profile of tumors. We will also determine the role of specific fungal species in mediating the RT-mediated anti-tumor immune response. The significance of this research is that it will provide insights into the tumor immune responses to radiation that may lead to new microbiome-based therapies for the treatment of breast cancer and the multiple other solid tumors in which RT plays an integral therapeutic role.

Public Health Relevance

Breast Cancer affects an estimated 200,000 women in North America and is the second leading cause of cancer death with 39,000 deaths attributed to breast cancer. This proposal examines the role of the bacterial and fungal microbiome in regulating the tumor response to radiation, a treatment received by more than half of all patients diagnosed with breast cancer. Information obtained from this study will allow insight into how the microbiome shapes the immune responses to radiation that potentially could lead to the development of novel microbiome- based therapeutics for breast cancer and other solid tumors treated with radiation. !

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA220000-02
Application #
9560707
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Ahmed, Mansoor M
Project Start
2017-09-08
Project End
2022-08-31
Budget Start
2018-09-01
Budget End
2019-08-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Cedars-Sinai Medical Center
Department
Type
DUNS #
075307785
City
Los Angeles
State
CA
Country
United States
Zip Code
90048