Targeting the Stromal Compartment to Limit Breast Cancer Progression and Abrogate Therapy-Induced Morbidities
Abstract
The road that leads to cancer is long and requires not only changes to the cell traveling the road but also changes in the “sites” along the road that we refer to as normal cells or stromal cells. While cancer therapy has historically been targeted to the cancer cell, more recent work has shown that stromal cells can be important targets as well. We have spent years studying the normal cells that support cancer cell survival and growth in the metastatic site and found that the p38MAPK pathway in these stromal cells plays a critical role in not only directly supporting metastatic tumor growth but also driving bone loss. Stromal cells can drive bone loss in patients with metastatic disease as well as patients with localized disease undergoing chemotherapy treatment. Unfortunately, bone loss and metastatic tumor growth in bone can lead to fractures and bone pain that significantly impact a patient’s quality of life. It is our intent to increase the effectiveness of chemotherapy to kill cancer cells while at the same time reducing its side effects. Here, we propose to take up the challenge to “revolutionize treatment regimens by replacing them with ones that are more effective, less toxic, and impact survival.” To accomplish our goal, we will launch a Phase I/II clinical trial utilizing a novel inhibitor, ATI-2231, that targets an important component of the p38MAPK pathway called MK2 in stromal cells. Our trial will combine ATI-2231 with paclitaxel or capecitabine in patients with bone metastasis. We will measure both progression free survival and bone loss and incorporate a quality of life study to our trial. This will determine not only how our approach treats the disease but also how it impacts the patient and ultimately the survivor. We also propose to carry out important preclinical studies that will be guided by the trial results. The preclinical component of the proposal will establish how ATI-2231 limits metastatic tumor progression and disease- and therapy-induced bone loss. This information will allow us to identify additional stromal targets for future trials that treat not only the disease but improves a survivor’s long-term quality of life.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110117
Entities
People
- Sheila Stewart
Organizations
- United States Army
- Washington University in St. Louis