Reprogramming the Metastatic Microenvironment to Combat Disease Recurrence
Abstract
In spite of recent advances in personalized therapy and the application of targeted adjuvant therapies, 10%-20% of breast cancer (BC) patients with invasive tumors will eventually develop metastatic disease. These data suggest that our current adjuvant therapies, which have been developed to attack highly proliferative primary tumors, are not completely effective in metastatic locations. Therefore, the development of new clinical approaches that are effective at preventing and/or treating metastatic BC is of paramount importance. One promising approach is "reprograming" the tissue microenvironments that provide "safe harbors" for disseminated tumor cells during adjuvant therapy. Our approach to destroying these "safe harbors" is to modulate the patient s immune system. To do this, we must understand how the immune system recognizes tumor cells in metastatic locations such as the bone marrow. The human immune system has evolved to sense and destroy tumor cells. This capacity is spearheaded by responses from cytotoxic T cells. As their name implies, these cells are professional-grade tumor killers for the immune system. Early in breast cancer development, these killer cells effectively restrain disease progression. However, over time, malignant cells can evolve to avoid destruction by cytotoxic T cells. One major mechanism by which malignant cells accomplish this is by co-opting other immune cells, including macrophages, to protect themselves. While this is a major challenge for immunotherapy, it also presents a major therapeutic opportunity. If we could reawaken the immune programs that destroy tumors, especially during adjuvant therapy when tumor cells are most vulnerable, we could truly eliminate "residual disease" and prevent metastatic recurrence. We believe we found a way to "reawaken" the immune system and destroy metastatic disease by inhibiting colony-stimulating factor-1 receptor (CSF1R) with clinically available therapeutics. These therapeutics agents were originally developed to treat rheumatoid arthritis (RA), and thus, the safety profile of these inhibitors is well suited for adjuvant therapy. Highlighting the safety of this approach >250 RA patients were treated with two different classes of CSF1R inhibitors without significant adverse events. CSF1R inhibitors were recently evaluated in combination with chemotherapy in safety studies involving cancer patients, and this approach may even prevent some of the deleterious effects of chemotherapy-associated inflammation. Our own studies using breast cancer mouse models found that by inhibiting the CSF1R, we can re-awaken the immune system to destroy malignant cells. This strategy has been very effective in improving the efficacy of neoadjuvant chemotherapy in mouse models of primary breast tumors. Based on the strong efficacy observed in these animal models and the relative safety of the clinical agents, our work has already led to a clinical trial in locally recurrent breast cancer (NCT01525602). Based on exciting new mechanistic findings from our laboratory, we discovered that this approach may be even more effective at preventing metastatic BC recurrence. Overarching Challenge: This grant s primary aim is to "eliminate the mortality associated with metastatic breast cancer." We will do so by (1) preclinically testing a novel combination of clinically available CSF1R-targeted therapeutic agents for the prevention and treatment of metastatic disease and (2) use existing breast cancer patient samples to identify biomarkers based on disseminated tumor cell populations and immune response characterization. We believe this novel strategy will not only distinguish patients who need aggressive adjuvant therapy from those patients with indolent disease, but also lead to "actionable" immunotherapeutic targets to prevent metastatic relapse. Impact: Our firm belief is that the approach being tested, if successful and translated to patients, woul
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510385
Entities
People
- David Denardo
Organizations
- United States Army
- Washington University in St. Louis