Targeting the TWIST1/HOXA9 Axis to Induce PARP Inhibition Treatment Sensitization and Synthetic Lethality in Lung Cancer Cells
Abstract
Scientific Objective and Rationale: Lung carcinoma is the highest cause of cancer mortality in the United States and throughout the world. Non-small cell lung carcinoma (NSCLC) accounts for 80% of lung cancers. Active military and Veteran populations have a high prevalence of smoking, and NSCLC remains a critical cause of morbidity and mortality. In the last decade, important progress has been realized to improve the outcomes following radiation and chemotherapy for NSCLC. Nevertheless, treatment resistance and recurrence remain common. Thus, the goal of this proposed research is to understand the different mechanisms of NSCLC aggressiveness and treatment resistance in an attempt to identify new targets and define new approaches for NSCLC treatment. Recently, PARP inhibition therapy represents a key tool to fight lung cancer in patients with DNA damage response/DNA repair factor deficiency, owing to induction of tumoral cell synthetic lethality. To further develop this strategy, it is now critical to develop approaches that sensitize proficient patients for DNA double-strand breaks repair to PARP inhibition. Interestingly, patients presenting aggressive and poor prognosis cancer are also positive for the overexpression of markers of interest, the TWIST1/HOXA9 axis, which also controls the efficiency of DNA damage response/DNA repair. Thus, we aim to target these markers in order to mimic DNA damage response/DNA repair factor deficiency and then restore the sensitivity to PARP inhibition therapy for these patients. The identification of a pharmacological candidate of interest for future clinical use is expected. In the hope of successful results, this project will open a promising new approach to treat lung cancer and, hopefully, will increase the number of patients who will benefit from PARP inhibition therapy. LCRP Area(s) of Emphasis: This project and its future directions address the following LCRP Areas of Emphasis: (1) Understand susceptibility or resistance to treatment and (2) Understand predictive and prognostic markers to identify responders and non-responders. Ultimate Applicability of the Research: This research aims at defining a new therapeutic option for patients with aggressive NSCLC. Targeting the TWIST1/HOXA9 axis in combination to PARP inhibition therapy is believed to represent this option. What Types of Patients Will It Help, and How Will It Help them? This project is dedicated to enlarging the number of candidates for PARP inhibitor therapy to those that are proficient for DNA damage response/DNA repair, but present aggressive lung cancer, as they are positive for TWIST1/HOXA9. What Are the Potential Clinical Applications, Benefits, and Risks? The potential clinical applications and benefits are that targeting these markers would mimic DNA damage response/DNA repair deficiency and would allow inducible sensitization to PARP inhibition therapy, thus opening a new and important strategy to treat lung cancer without intrinsic DNA damage response/DNA repair deficiency. As these markers are relatively cancer cell-specific, the expected risk is an absence of therapeutic effect. What is the Projected Time It May Take to Achieve a Clinically Relevant Outcome? If successful, transitioning our findings to the clinic will demand several years after pharmacological and clinical studies and Food and Drug Administration approval. What are the Likely Contributions of This Study to Advancing the Field of Lung Cancer Research? This project, in addition to opening a new therapeutic strategy, thanks to a combinatorial targeting of PARP1 and TWIST1/HOXA9, will improve our knowledge of the mechanism of aggressiveness and treatment resistance of NSCLC. How Is the Project Relevant to Military Service members, Veterans, and their families? Veteran populations and active military have an elevated prevalence of smoking, and NSCLC is a serious cause of morbidity and mortality
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810435
Entities
People
- Audrey Lafargue
Organizations
- Johns Hopkins University
- United States Army