Targeting Advanced Lung Cancer Using Lethal Hyperactivation of the Unfolded Protein Response to Induce Tumor Cell Death and Immune Cell Activation
Abstract
Rationale, Objective and LCRP Area of Emphasis Addressed: Most newly diagnosed lung cancers cannot be completely removed by surgery. While treatment with chemotherapy agents and immunotherapy, in which the patient’s immune cells attack the lung cancer cells, slows the growth of these cancers, over time, they usually become resistant to treatment with poor therapeutic options. Currently, most patients with advanced lung cancer die within a few years. Thus, there is a compelling need for new approaches in the Lung Cancer Research Program Area of Emphasis: Identify innovative strategies for the treatment of lung cancer. We propose a therapeutic strategy that uses a novel small molecule that both directly attacks metastatic lung cancer in a new way, and also harnesses the innate power of the immune system. What We Did: We showed that hormones that make cancers grow, such as epidermal growth factor (EGF) and estrogen act via the proteins receptors they bind to prime cancer cells for growth. Activating this stress response pathway protects cancer cells and makes them harder to kill with anticancer drugs. To exploit this pathway, we developed a small molecule, called ErSO, that overactivates, or hyperactivates, this pathway, converting it from protective to lethal for the cancer cells. Because cancer cells contain elevated levels of the pathway proteins and it is already partially on in cancer cells, ErSO is selective and only kills cancer cells. Because ErSO works through a protein called estrogen receptor (ER) that has been extensively studied in breast cancer, we initially tested ErSO against advanced breast cancer. Using a protein that gives off light and enables us to visualize tumors in live mice, ErSO caused many breast tumors to shrink by more than 100,000 fold to undetectable levels, and they did not come back after many months. ErSO caused complete regression or disappearance of most breast cancer that had spread, or metastasized, to lungs, bones, and liver. Tumors that shrank dramatically and did grow back were not resistant to ErSO and remained completely sensitive to a second treatment with ErSO. Moreover, ErSO kills cancer cells in a specific way that causes debris from the dead cells and the corpses of the dead cells to activate immune cells. ErSO is a novel drug and is entirely unrelated to drugs that target estrogen, such as tamoxifen and fulvestrant, which do not usually work in lung cancer. Since most lung cancers produce ER protein, we looked at the effect of ErSO in ER-positive lung cancer cells grown in the laboratory. ErSO was just as effective in killing lung cancer cells as it was in killing breast cancer cells. ErSO hyperactivated the stress response pathway and rapidly and efficiently killed most of the lung cancer cells. How Does ErSO Activate Immune Cells? ErSO kills cancer cells in a specific way that enables debris released from the dying cells and corpses of dead cells to powerfully activate immune cells. What We Propose: We will evaluate and develop a novel therapeutic strategy in which ErSO kills most lung cancer cells, causing dramatic shrinkage, or regression, of advanced lung cancers in mice. Then activated immune cells target and destroy any lung cancer cells that survive initial treatment with ErSO. Although, highly ambitious, a substantial body of work provides a strong foundation for these studies. Who Benefits? Since most lung cancers contain ER and all lung cancer cells contain components of the stress response pathway, most patients with advanced lung cancer can potentially benefit from ErSO. Impact on Military Service Members and Their Families: Lung cancer has a devastating impact on military personnel and their families. This work has the long-term potential for extending and perhaps saving lives of military service personnel. Successful therapy for metastatic lung cancer will reduce stress on military families and allow Service personnel to ret
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210555
Entities
People
- David J. Shapiro
Organizations
- United States Army
- University of Illinois Urbana–Champaign