Evolution of the Pleural Secretome Associated with Breast Cancer Pleural Metastasis
Abstract
Overarching Challenges: 1) Identify why some breast cancers become metastatic to the pleura. 2) Revolutionize treatment regimens by replacing them with ones that are more effective, less toxic, and impact survival. 3) Eliminate the mortality associated with metastatic breast cancer. According to the latest SEER (Surveillance, Epidemiology and End Results) data (2011-2017) from the National Institutes of Health, the 5-year overall survival for patients with ER-positive/HER2- (Luminal A) breast cancer is 100% for patients with localized disease, 89.9% for patients with regional disease, and 30.6% for patients with distant disease (seer.cancer.gov/explorer/). However, when hormone receptor positive (HR+) breast cancer metastasizes to the pleura, it is uniformly fatal (median survival 6 months), and quality of life is diminished by dyspnea, pain, and discomfort. There is currently no curative treatment once metastatic disease has occurred (The Breast Cancer Landscape 2021). Current standard of care treatment for malignant effusions is exclusively palliative, consisting of drainage, followed by systemic therapy (chemotherapy or endocrine therapy). Why does HR+ breast cancer take on a significantly more aggressive phenotype within the pleural space, and why is this aggressive, therapy-resistant phenotype conserved when it has metastasized to extra-pleural sites? We hypothesize that the unique pleural environment drives this transition and that it can be controlled and perhaps mitigated by treating the pleural environment locally with protein drugs that remain concentrated in the pleural space. The incidence of malignant pleural effusion (MPE) and lack of effective treatments has created an urgent unmet need to develop an effective treatment. What types of patients and how it will help them? This therapy will help patients with HR+ breast cancer metastatic to the chest cavity (pleural space). Once HR+ breast cancer metastasizes to the pleural space, it becomes more aggressive and therapy-resistant. This proposal attempts to explain this dramatic change in tumor behavior as the result of the interaction of HR+ tumor and the unique pleural environment. We hypothesize that the physical barriers that protect the metastatic tumor can be exploited to concentrate antibody-based drugs in the pleural space, breaking the cycle that promotes invasive tumor growth. What are the clinical applications, benefits, risks? The clinical application is to change the pleural environment in HR+ breast cancer patients with MPE in such a way that it reverses aggressive tumor behavior and restores treatment sensitivity. Although the approach that we are developing has not been tested in humans, there is good reason to believe that localized treatment with protein drugs will be well tolerated. Many drugs, including antibody-based therapeutics, have been delivered straight to the pleura and were well tolerated, but none were designed to condition the environment. Although there are always risks with new therapies, we have the potential benefit of developing an effective treatment for a uniformly fatal condition. What is the projected time for a patient-related outcome? Our goal in this study is to generate proof-of-concept data to warrant further investigation into this novel therapeutic approach. If successful, the projected time frame to the clinic could be as short as 3 years because the anticipated therapeutics are already used for other conditions. How will this lead to a breakthrough? If successful, the proposed treatment strategy will not end breast cancer. However, it has the potential to extend the lives, and offer better quality of life for a significant number of patients for whom there is currently no effective treatment.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2211069
Entities
People
- Vera Donnenberg
Organizations
- United States Army
- University of Pittsburgh