Despite decades of research, breast cancer still represents second most deadly malignancy for women in the United States. Furthermore, current therapeutic options can cause disfigurement and malaise, potentially reducing quality of life. Therapies that lead to durable remission with minimal side effects are urgently needed. We propose that an integrated approach to cancer research that considers both tumor heterogeneity and associated cells in the tumor microenvironment may reveal novel therapeutic approaches. A population of cancer cells, termed cancer stem cells, has been proposed to be resistant to therapies and lead to relapse. Very little work has examined the sensitivity of breast cancer stem cells to different methods of immune-mediated killing or their ability to suppress local immune responses. We first intend to ensure that the breast cancer stem cell population we plan to study is likely to be the chemoresistant population of cells in patients with breast cancer. We will then measure the sensitivity of these cells to different mechanisms of immune-mediated killing along with their ability to protect neighboring cells from attack by immune cells. We will identify how these breast cancer stem cells interact with the immune system in order to identify potential weaknesses that can be targeted clinically to sensitize breast cancer stem cells and their neighboring cancer cells to immunotherapy approaches.
We have recently discovered that tumors cells with integrin αvβ3 on their surface are particularly difficult to treat because αvβ3 triggers reprogramming events that make tumors immune to certain anti-cancer therapies. Because we identified the pathways by which integrin αvβ3 drives these changes, we were able to reverse this behavior in preclinical research models by re-purposing FDA-approved drugs developed for other indications. Now, funding from the V Foundation will allow us to test whether this strategy can be translated to improve the response to therapy for patients with non-small cell lung cancer.
To do this, we will first look for the presence of integrin αvβ3 on circulating tumors cells that may be present in blood samples from patients who have become resistant to a targeted form of cancer therapy called Erlotinib. Once optimized, this assay could be used as a non-invasive blood test to identify the earliest emergence of drug resistance in lung cancer patients. Next, we will conduct a Phase II clinical trial to test if patients who have developed resistance to Erlotinib can be “re-sensitized” to the drug by adding a second drug, an inhibitor of the NFκB pathway known as VELCADE. According to our preclinical animal studies, we expect the addition of this FDA-approved drug will allow patients to respond to Erlotinib therapy for a much longer time.
Since there is no clearly defined standard of care therapy for Erlotinib-resistant lung cancer, our project will address this unmet need and, if successful, would change the way lung cancer patients are diagnosed and treated.
