Non-small cell lung cancer (NSCLC) is one of the leading forms of cancer-related deaths in the United States. Chemotherapy is a major strategy for treatment, but fails due to the absence of efficient drug delivery and the variability patients show in response to a given therapy. Many current immune checkpoints blocking immunotherapies despite being very promising treatment regimens only benefit a set of patient populations. High-precision delivery of therapeutics to tumor sites can improve the treatment efficacy and, importantly, knowledge about the status of treatment response can also help clinicians devise a more effective treatment strategy. This will help patients from expensive treatment and save them from unnecessary pain. With the proposed project, I will fulfill two crucial areas of emphasis of DOD Lung Cancer Research Program, e.g.:

a. Identify innovative strategies for the treatment of lung cancer and

b. Develop or optimize prognostic or predictive markers to assist with therapeutic decision-making.

As an early-career cancer biologist, I am trying to transition from my present junior faculty position to an independent research investigator position. My ultimate goal is to develop a robust translational research program. My research program will focus on translating various discoveries made on laboratory benches to assets of clinical applications to benefit patients of lung and other cancers. This project will be beneficial in achieving my career goal by:

a. Allowing me to be trained in animal-based studies, which are essential components to perform any translatory research.

b. Providing me protected time to generate convincing data for applying to large grants to support my research and propose clinical trials.

c. Allowing me collaboration and learning from seasoned scientists on various aspects of running projects and doing scientific research.

EVs are nano-sized cellular vesicles that can carry therapeutic cargo in different parts of the body and can even cross-stringent membrane barriers like blood-brain barriers etc. EVs conventionally also show a typical organotrophic effect called homing effect, i.e., they tend to go towards the cells or tissues from where they have been produced. Superparamagnetic iron oxide (SPIONs) are 10-20 nm-sized nanoparticles used for magnetic resonance imaging (MRI). This project proposes combining EV biology and nanotechnology to create an advanced multifunctional modality for simultaneous drug delivery and tumor imaging. We will load EVs derived from normal lung tissues with therapeutic siRNA, SPIONS conjugated with anti-cancer drugs, and a tumor-targeting moiety.

This theranostic system will lead to a very aggressive therapeutic intervention with better efficiency than conventional treatment methods and diagnosis of lung cancer. Lung cancer patients are diagnosed at a very advanced stage of the disease, and most of them are more than 60+ years old. Age and burden of disease on the body often render them physically weak and challenging. The proposed theranostic system will enable clinicians to optimize a precise treatment regimen and monitor treatment response. By its imaging and efficient drug delivery capabilities, the developed theranostic system could revolutionize the precision medicine approach in treating lung and other cancers. Besides, the proposed EV-based theranostic is structurally and functionally very similar to some of the recently developed COVID19 vaccines, consisting of synthetically produced lipid vehicles encapsulating therapeutic RNA molecules and delivering them to the body. In the proposed system, the EVs are organically produced by the body; are more stable, non-toxic, and personalized; elicit no immunogenic response; and show better delivery efficacy. The success of COVID-19 vaccines is an indicator of the prosperous future of EV-based theranostic in lung cancer treatment.

The new treatment regimen is expected to give a new dimension to lung cancer care, reducing stress among Veteran Service Members and their dependents suffering from this disease.