Role of Smac in Lung Carcinogenesis and Therapy
Abstract
Localized advanced and metastatic non-small cell lung cancers (NSCLC) are treated with chemotherapy and radiotherapy. However, resistance to standard therapy has been a major challenge in curing these patients. This project will investigate whether a molecular target (SMAC) mediates lung cancer progression through regulating host immune system. The proposal will also investigate a novel therapeutic approach of activating host immune system by combining a drug (SMAC mimetic) that activates SMAC and radiotherapy. This therapeutic strategy may eliminate lung cancer resistance to standard therapy. Outcomes of this project may benefit military Service members, Veterans, and their families, who suffer from lung cancer. Recent development in combining immunotherapy and radiotherapy has shown the potential of rescuing therapeutic immunity against lung cancer as recent immunotherapeutic trials utilizing immune checkpoint inhibitors, such as anti-CTLA4 or anti-PD-1, have yielded impressive and durable responses among certain lung cancer patients. In this case, the release of cancer antigens following radiotherapy may synergize in the induction of cancer cell-specific immune responses, which may impact distant metastases. While confirming that the approach has merit, completed clinical trials have documented that only 20%-30% of patients with NSCLC respond to PD-1 inhibitors, highlighting the need for alternative approaches to improve the outcome, particularly for poor responders to PD1 inhibitors. As the leader for the lung cancer working group through National Cancer Institute radiation research branch, we intend to promote the development of novel therapeutics to be combined with radiotherapy. In this proposal, we show preliminary data that the combined use of a SMAC mimetic and radiotherapy results in therapeutic synergism in a lung cancer model through a CD8-dependent mechanism. We propose to extend this work by determining the role of SMAC in lung cancer progression and its resistance to therapy. We will also determine immunological mechanism by which combining a SMAC mimetic and radiotherapy yields therapeutic synergy and whether and how this combination yields abscopal effects from radiotherapy in a novel lung cancer model. An active host immune system can deter cancer progression and enhance the efficacy of cytotoxic cancer therapy. We are encouraged by our preliminary data showing that a Smac mimetic and radiotherapy activate host immune system and synergize the therapeutic effect in an immune-dependent manner. We hypothesize that SMAC modulates both lung carcinogenesis and subsequent therapeutic response to chemotherapy and radiotherapy. Furthermore, we hypothesize that combining a SMAC mimetic with stereotactic body radiotherapy, a form of precision radiation treatment for cancer, induces systemic overall therapeutic effects against lung cancer. We will test these hypotheses in part through the generation of a novel transgenic mouse model. By investigating this novel approach of activating host immune response against lung cancer, we aim to eradicate deaths from lung cancer. The proposed study investigates a novel therapeutic approach of combining a SMAC mimetic and radiotherapy in inducing host immune response again lung cancer. This study will be conducted through utilization of an image-guided mouse irradiator and novel mouse lung cancer model with and without SMAC.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610205
Entities
People
- Bo Lu
Organizations
- Thomas Jefferson University
- United States Army