The Use of Microfluidic Lung Cancer on a Chip in Investigating Novel Drug Resistance
Abstract
LCRP Areas of Emphasis and Military Relevance: This proposal addresses three of the FY22 LCRP Areas of Emphasis: (1) identification of innovative strategies for the treatment of lung cancer, (2) understanding mechanisms of resistance to treatment, (3) understanding predictive markers to assist with therapeutic decision-making. The incidence of lung cancer among Veterans is higher and the survival rate is alarmingly lower compared to civilian populations. Since lung cancers are often diagnosed at an inoperable late stage, developing effective therapies is necessary to improve the survival of this particularly vulnerable group. This study will help develop a novel strategy and device to ensure effective drug delivery to all types of lung tumors regardless of mutation status. In lung cancer treatments, the therapeutic efficacy is evaluated radiographically using CT assuming that the drug concentration in the tumors has reached to its optimal level. This is due to the fact that frequent lung tumor biopsies to assess the drug concentration are not feasible as they are a burden to the patients. This poses an interesting yet important question regarding the tumors that do not respond to therapy: did the tumors not respond as the drugs failed to reach the optimal concentration or are the tumors resistant to the drugs? Alarmingly, we have published that a subset of lung cancers reacts to drug treatment by secreting endothelin-1 (EDN1), which shrinks the diameter of tumor feeding blood vessels. The consequence of this response is the reduction of blood flow that carries drugs to the tumors. We genetically engineered lung cancer cells that are unable to express EDN1. Compared to the control cells that express EDN1 in response to drug treatment, tumors with the engineered cells with no EDN1 production maintained the blood flow to the tumors and increased the concentration of the drug in the tumors. We propose a novel concept that tumors secrete EDN1 to shrink blood vessels around the tumors to reduce the blood flow carrying drug to the tumor, which will create a unique niche for the therapy-resistant tumors. In this proposal, we test the hypothesis that inhibiting the EDN1 binding to the EDN receptors (EDNR) on the tumor blood vessels will improve the tumor blood flow increasing the drug penetrance to the tumors. To test this hypothesis, we will evaluate whether inhibiting the EDN1–EDNR axis using FDA-approved pulmonary hypertension drugs improves the drug delivery in NSCLC cells. We will test the drug combination using conventional mouse model and unique tumor and tumor supporting cells on a chip technology. The efficacy of drugs or drug combination have been tested using mouse models, which has been laborious, time consuming and expensive. The tumors on chip is scalable with individual cells that associate with tumors in human so that we could analyze which supporting cells are impacting drug resistance. The chip has small channels simulating blood vessels to carry nutrients and drugs to the cells. The chip uses significantly less NSCLC patient-derived cells compared to the usual tissue culture method and it take much less time than animal models to evaluate drugs on patient tumors. We will also investigate mechanisms by which a subset of lung cancer cell promotes secretion of EDN1. Results collected from this proposal will facilitate the discovery of prognostic and therapeutic tools to inhibit EDN1 activity that promotes drug resistance due to poor drug delivery, and to provide a rationale to stratify NSCLC patients whose tumors stop responding to therapies for EDN1-EDNR targeted therapeutics. EDNR inhibitors have never been accessed for their therapeutic potentials to modulate blood flow and drug delivery to NSCLC tumors. Consequently, through studying the EDN1-mediated drug resistance, we will develop a new therapy to improve drug delivery and help develop tumor on a chip device to accelerate the eva
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310497
Entities
People
- Takeshi Shimamura
Organizations
- United States Army
- University of Illinois at Chicago