Dual Benefit of TGFB Inhibition on Tumor Control in the Context of Radiotherapy for Breast Cancer Brain Metastases
Abstract
The improved control of systemic disease has prolonged the lifespan of women with metastatic breast cancer. Of particular concern is the increasing incidence of brain metastases in breast cancer patients, for which the total incidence is now about 30%. The goal of this proposal is to revolutionize therapy regimens for women with brain metastases and thereby reduce the mortality associated with metastatic breast cancer. In the case of life-threatening symptoms, brain surgery prolongs life but carries considerable mortality and morbidity risk. Radiation therapy is employed for patients present with minimally symptomatic or multiple brain metastases with good local control, though dependent on patient and disease factors. In patients with one to three metastases (i.e., oligometastases), gamma-knife stereotactic radiosurgery (GKSRS) delivers high doses to small volumes that provides substantial benefit to some patients. The highly focal delivery of radiation by GKSRS spares normal brain and reduces cognitive consequences of whole brain irradiation that is used when there are numerous or large (>3 cm) lesions. A treatment regime that increased the efficacy of GKSRS for women with brain metastases would revolutionize outcomes from this life-threatening scenario. Moreover, recent studies suggest that radiation therapy can have systemic actions by eliciting an immunological signal that "re-awakens" the immune system that eliminate tumor cells throughout the body. The idea of an "in situ vaccination," as framed by Dr. Silvia Formenti, could provide systemic control of metastatic disease in the context of immunotherapy. Based on extensive preclinical data, we postulate that transforming growth factor beta (TGFbeta) inhibition will confer dual benefit for patients with brain metastases treated with GKSRS. Our published studies show radiotherapy (RT) induces TGFbeta activation whose has diverse effects impede tumor control. On one hand, TGFbeta enables cells to survive the DNA damage inflicted by RT, thus its inhibition increases cell kill (i.e., radiosensitizes) breast cancer cells and amplifies tumor control by RT, and may enable treatment of women with more extensive brain disease. On the other hand, TGFbeta activity is usually very restricted in the brain, and the high levels of TGFbeta induced by RT also increase neuroinflammation and suppress infiltrating immune cells, both of which impair to immune responses that can prolong and expand tumor control throughout the body. Our hypothesis is that TGFbeta inhibition during RT for breast cancer brain metastases will (1) prolong tumor control, (2) expand the applicability of GKSRS for women with metastases, and (3) promote the response to immunotherapy. However, the biology of TGFbeta in the metastasis bearing brain before and following irradiation remains largely unstudied. Aim 1, conducted by Dr. Barcellos-Hoff and Dr. Braunstein, will treat preclinical models of brain metastasis with and without TGFbeta inhibition using a small animal radiation research platform that delivers radiation in a clinically relevant fashion. We will determine the biological consequences of RT and TGFbeta inhibition on the tumor and immune system and test the addition of immunotherapy in these preclinical models. Rapid translation of preclinical approaches to manipulate the irradiated tumor bed for immunological benefit is hampered by the "black box" of the irradiated tumor, that is, the inability to readily identify whether tumor control is being extended by immunological mechanisms. To address this significant shortcoming, we have partnered with investigational radiologist Dr. Benjamin Franc, who will implement innovative functional imaging of the immune response using novel imaging reagents to jointly identify tumor burden and immunological activation. Aim 2, conducted by Dr. Franc, will test the benefit of TGFbeta inhibition by assessing of neuroimaging. Notably, TGFbeta i
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710032
Entities
People
- Mary Barcellos-hoff
Organizations
- United States Army
- University of California, San Francisco