Ligand-Mediated Detection and Treatment of Metastatic Lung Cancer, Including Tumors Localized in the Central Nervous System
Abstract
Scientific Objective and Rationale: Lung cancer is often diagnosed at a late clinical stage with prominent metastatic disease. While metastatic lesions in the periphery of an individual are difficult to resect and treat on their own, lung cancer brain metastasis is nearly impossible to resect and treat. Yet lung cancer is the most common cancer that metastasizes to the brain, and nearly 100% of lung cancer patients diagnosed with brain metastasis will die. These unwavering poor statistics highlight a critical need to develop efficient tools that can be used to (1) guide surgical resection of primary lung cancer and metastatic disease, specifically brain metastasis, and (2) treat lung cancer. The overarching goal of this high-risk and extremely high-reward study is to fulfill both of these needs. To accomplish this, we take advantage of a protein that is overrepresented on the surface of >75% of lung adenocarcinomas. Using this protein, the folate receptor, as well as a small molecule attached to a fluorophore that binds the folate receptor tightly, allows us to light up tumor tissue so that surgeons can more accurately resect it. The small molecule used can cross into the central nervous system, delivering the fluorescent tag to tumors in the brain. While detection and resection of lung cancers is beneficial, there is also a need for better lung cancer therapeutics. Indeed, the survival of lung cancer patients has only increased marginally over the past three decades. Thus, the same small molecule will be used to deliver an anti-cancer agent, in this case an RNA. The RNA acts as a multi-drug cocktail due to its ability to destroy production of multiple cancer-causing proteins. We hypothesize that this therapeutic will be highly successful in treating primary lung cancer and metastatic disease in the periphery, but also intend to test its ability to treat tumors in the brain, another high-risk, high-reward aspect of this study. LCRP Areas of Emphasis addressed include: (1) identifying innovative strategies for screening and early detection of lung cancer, (2) identifying innovative strategies for the treatment of lung cancer, (3) identifying innovative strategies for the prevention of recurrence of or metastases from lung cancer, and (4) developing or optimizing prognostic or predictive markers to assist with therapeutic decision-making. The benefit for patients from this work is enormous. Overexpression of the folate receptor occurs in >75% of lung adenocarcinomas, the most common primary lung cancer in the United States. Adenocarcinomas develop due to a plethora of reasons; however, there is a strong association with previous smoking. Without question, active military, especially those deployed, have a higher incidence of smoking than their civilian counterparts. Adenocarcinoma is also the most common lung cancer diagnosed in non-smokers, again, highlighting the sheer number of patients that this diagnostic and therapeutic will benefit. Potential Clinical Applications, Benefits, and Risks: With >80,000 people diagnosed with adenocarcinoma per year in the U.S. alone and accounting for the 75% that express the folate receptor, the clinical application includes ~60,000 new patients/year. The benefits include increased survival and quality of life, as these agents are not anticipated to have toxic side effects. Nonetheless, an expensive toxicity study is proposed to identify and mitigate risks. Time to Achieve Clinically Relevant Outcome: Once fully developed, the outcome will be nearly instantaneous, especially for the diagnostic. The outcome of the therapeutic is anticipated to be fairly rapid as well, but as with any agent, the resulting effect will likely vary between patients. We may also find that combining our new agent with already used standard-of-care results in a more favorable outcome, as has been observed for other combinatorial therapeutic approaches. In this case, the time to
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2211085
Entities
People
- Andrea Kasinski
Organizations
- Purdue University
- United States Army