Modulation of Lung and Bone Microenvironments to Treat Breast Metastases
Abstract
Overarching Challenge: Our goal is to eliminate the mortality associated with metastatic breast cancer. If we could induce a patient’s own immune cells to eradicate metastatic tumor cells in a localized manner, it would revolutionize treatment regimens by replacing them with ones that are more effective and less toxic. Which patients will be helped? Tumors recruit macrophages and induce their wound healing functions to provide extra blood supply and minimize immune responses. However, we found using inducible transgenic mice that increasing signaling by a pathway known as NF-kappaB (NF-kB) specifically in macrophages resulted in killing of tumor cells in breast tumor models. This suggests the exciting possibility that we can turn the very cells that tumors have recruited to help them into agents that fight back against them. The benefits to this approach include: (1) the tumor cells are actually killed as opposed to slowed, precluding adaptations to escape the treatment; (2) induction of the cell killing effect is localized to the dense population of macrophages immediately adjacent to the tumor thus minimizing collateral damage; (3) even micro-tumors or occult metastases could be attacked by this treatment; (4) a patient’s normal immune defenses are mobilized against the tumor such that the mutation driving the tumor is irrelevant and other immune therapies (like T cell-based treatments) could be more effective; (5) because the outcome is not dependent on the mutations driving the tumors cells, the therapy should be able to help a broad range of patients with different subtypes of breast cancer. Potential clinical applications, benefits and risks? To translate these findings into new patient treatments, we are developing and testing two novel therapeutic approaches. In the first, we are testing a method of increasing NF-kB activity in macrophages based on a drug that is approved in Europe for osteosarcoma treatment. This drug has very manageable side effects and has passed appropriate human safety trials. In the second, we have developed nanoparticles capable of very specific delivery of an agent (termed siRNA) that increases NF-kB activity by blocking an inhibitor of NF-kB to the macrophages that are being educated close to tumors to change them back into anti-tumor immune cells. We propose to test both intravenous delivery and direct introduction of these treatments into the lungs by intubation (an approach that is in regular clinical usage for treating patients with lung inflammation). We hope that intravenous treatment will have efficacy against bone metastases and that direct intubation will be an optimal strategy to treat lung metastases. Benefits include the ability to treat small metastatic foci without knowing their precise location by using the fact that the tumors are recruiting the macrophages into close proximity and the ability to minimize systemic effects. As with T cell-based treatments and systemic activators of immune responses, the risk is the potential for uncontrolled, systemic inflammation. The same anti-inflammatory treatments that are used as part of existing T cell therapies could also be employed for this new approach. However, the strategies being explored are being designed specifically to minimize this risk. Projected time to achieve patient-related outcome? Because one of the drug treatments is already in clinical use for alternative applications, early-stage clinical trials could be envisaged rapidly. Nanoparticle delivery approaches are also already in clinical usage (although, not these specific formulations) and therefore, early safety and toxicity trials would be supported by the data from these studies. Impact on mission to end breast cancer? Our hope is that this new strategy could be paired with other treatment approaches to achieve eradication of breast tumors. Even the ability to limit metastatic breast cancer would allow patients to survive for longer and have more preci
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2211087
Entities
People
- Julie Sterling
Organizations
- United States Army
- Vanderbilt University