UCHL1 is a Novel Minimally Invasive Molecular Indicator and Therapeutic Target for Small Cell Lung Cancer
Abstract
Rationale, Objective and Aims: Small cell lung cancer (SCLC) accounts for approximately 15 percent of lung cancers, is characterized with high expression of neuroendocrine markers, and has an aggressive clinical course, with a median survival without treatment of 2-4 months and a 5-year overall survival rates of approximately 6%. SCLC usually presents with early metastasis and shows a rapid relapse after treatments. Therefore, there is a critical clinical need to identify new molecular indicators, therapeutic targets, and effective therapies for SCLC. Ubiquitin carboxy-terminal hydrolase L1 (UCHL1) is a protein that is involved in regulation of protein degradation and may lead to an increase in protein stability. UCHL1 has been implicated in cancer development. UCHL1 has been shown to play an oncogenic role in breast and lung cancer. Moreover, UCHL1 is a secreted protein; therefore, providing an opportunity for easy minimally invasive detection. However, the utility of UCHL1 as a minimally invasive biomarker and the therapeutic potential of UCHL1 in SCLC have not been explored and remain unknown. Here, we propose to investigate UCHL1 as a novel molecular indicator and therapeutic target for SCLC. Specific Aims: Aim 1. Test the utility of UCHL1 as a molecular indicator for SCLC. For the first time, we will test the levels of UCHL1 in a large cohort of patient-matched serum and tissue samples from patients with SCLC vs. NSCLC. Aim 2. Test the functional role of UCHL1 in SCLC growth and metastasis. Here, we will test the functional role of UCHL1 on SCLC tumor growth and metastasis. We will further define the molecular mechanisms through which UCHL1 signals in SCLC. Aim 3. Test the effect of UCHL1 inhibition on SCLC growth and metastasis. In this aim, we propose to test UCHL1 inhibition as a new therapeutic strategy to target SCLC and metastasis in preclinical settings. Areas of Emphasis: Here, we propose to test the utility of UCHL1 as a novel molecular indicators and therapeutic target for SCLC as well as the molecular mechanism of UCHL1 function in SCLC. Thus, the proposed project addresses the FY22 LCRP Areas of Emphasis: (1) identify innovative strategies for the screening and early detection of lung cancer, (2) understand the molecular mechanisms of initiation and progression to lung cancer, (3) identify innovative strategies for the treatment of lung cancer, and (4) develop or optimize biomarkers to assist with therapeutic decision-making. Applicability of the Research: Identifying new therapeutic strategies for lethal SCLC will significantly advance the field of lung cancer research. The goal of the proposed project is to identify and test the therapeutic potential of a new UCHL1 inhibitor that targets a highly overexpressed in SCLC protein, UCHL1. Thus, completion of the proposed study will lead to the development of a novel therapeutic strategy for lethal SCLC. Completion of the proposed study will direct new strategies regarding novel therapeutic interventions to combat the deadly form of the disease. Anticipated Long-Term Outcomes of the Proposed Research and Their Potential Impact on the Basic Health, Welfare, and/or Psychosocial Wellness of Active-Duty Service Members, Veterans, and Other Military Beneficiaries: The completion of the proposed project will lead to defining new therapeutic targets and uncover novel therapies for SCLC, which is the most aggressive lung cancer type and affects active-duty Service Members, Veterans, and other military beneficiaries. We recently identified UCHL1 as a new promising therapeutic target for SCLC. The proposed project will test the therapeutic potential of a novel UCHL1 inhibitor in SCLC in preclinical models, creating a critical translational link between the proposed research and the treatment of patients with SCLC. Completion of the proposed project may lead to the development of new and more effective therapies for SCLC an
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252311034
Entities
People
- Tanya Stoyanova
Organizations
- United States Army
- University of California