A New Molecular Target for Small Cell Lung Cancer
Abstract
The objective of the proposed studies is to analyze a newly discovered vulnerability of small cell lung cancer (SCLC) for the purpose of exploiting it for therapeutic intervention. SCLC is a type of aggressive lung cancer that disproportionately affects members of the US Armed Services. There is currently no established therapeutic target for SCLC. As a result, treatment options for SCLC patients are limited to traditional chemotherapies, which often cause degrading and debilitating side effects. Despite their frequent initial response to chemotherapy, most SCLC patients relapse within 2 years. The survival rate of SCLC patients is substantially lower than that of other lung cancer patients. There is a significant unmet medical need for novel therapy to improve the treatment outcome of SCLC patients. Proliferating cell nuclear antigen (PCNA) is a protein that plays an essential role in regulating DNA synthesis and repair. It is essential to the growth and survival of all cancer cells. Therefore, PCNA is considered an attractive molecular target to develop broad-spectrum anti-cancer agents. While studying this target, we discovered a cancer-associated isoform of PCNA (caPCNA), which is ubiquitously and highly expressed in a broad range of cancer cells and tumor tissues. In contrast, this PCNA isoform is not significantly expressed in non-malignant cells. Based on this discovery, we designed a cell permeable peptide (R9-caPep) that blocks caPCNA interaction with its binding partners and found that R9-caPep effectively and selectively kills SCLC cells without causing significant toxicity to a broad range of non-cancerous normal cells. We also found that SCLC cells harboring amplification of a specific family of cancer-causing genes are particularly sensitive to R9-caPep treatment. These observations indicate that there exists a crucial vulnerability in SCLC cells that may be exploited for treating this deadly disease. The proposed study will analyze this vulnerability in SCLC cells. It will enable us to understand the molecular mechanism that makes SCLC cells susceptible or resistant to therapeutic treatment. If successful, this work will provide mechanistic insight into how to exploit molecular vulnerability in SCLC for therapeutic intervention and could lead to novel therapies that directly benefit members of the US Armed Services.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510471
Entities
People
- Linda Malkas
Organizations
- Beckman Research Institute of City of Hope
- United States Army