Cyclin-Dependent Kinase 9, A Potential Therapeutic Target in Gastric Adenocarcinoma: An In Vitro and In Vivo Efficacy Study
Abstract
Researcher Development: The Principal Investigator?s (PI?s) career goal is to establish herself as an independent investigator in the area of gastric adenocarcinoma (stomach cancer), one of the Fiscal Year 2016 Peer Reviewed Cancer Research Program PRCRP topics. The Horizon Award will advance the PI?s career by providing hands-on experiences with state-of-the-art molecular laboratory techniques and mouse models that will help her in developing innovative and practical research approaches to improving the outcomes of patients with stomach cancer. The researcher development plan includes honing of the PI?s skills in gene editing and protein knockdown strategies. These in combination with using a drug (BAY1143572) to inhibit cyclin-dependent kinase 9 (CDK9) will support the PI in achieving her objective of identifying molecules that can be targeted to treat stomach cancer. The unique mouse model of metastatic stomach cancer to be used in this study will allow the PI to assess whether this drug?s dominant effect is repressing tumor growth or inhibiting metastasis, a critical gap in knowledge on the efficacy of CDK9 inhibitors. Workshops and conferences will allow the PI to learn new techniques and develop collaborative multidisciplinary research approaches with her counterparts at other institutions, which will help her in creating a foundation for innovative ideas to combat gastric adenocarcinoma. Research Plan: Stomach cancer is a leading cause of death worldwide. The standard therapy has limited clinical benefits, and the survival rates of patients with advanced tumors are low. Targeted therapy, a fairly recent innovation in cancer therapy, disrupts a cancer-specific function within cells, thus sparing normal cells and reducing side effects. Targeted therapy holds great promise in improving outcomes for patients with stomach cancer. Unfortunately, attempts at targeted therapy in stomach cancer so far have had limited success because of variations within tumors and a lack of well-defined targets. CDK9, an important regulator of cancer progression, is expressed at high levels in several cancers, including stomach cancer, and targeting (inhibiting) CDK9 has been shown to block other cancers. We hypothesize that targeting CDK9 may block stomach cancer. The two major objectives of this study are to (1) test the antitumor effects of BAY1143572, a selective CDK9 inhibitor, and (2) identify a molecular biomarker that will predict response to anti-CDK9 therapy in stomach cancer. BAY1143572 will be tested first in stomach cancer cell lines and then in mouse models, including a new metastatic cancer model that will help determine the anti-metastatic potential of CDK9 inhibition for patients with advanced stomach cancer. The biomarker identified in Objective 2 will be used for identifying the subgroup of stomach cancers whose tumors are most likely to respond to anti-CDK9 therapy. The biomarker will be identified by correlating clinical and pathological factors of each tested cell line with its response to anti-CDK9 therapy. In future, selecting patients in this way will reduce treatment failures and avoid exposing patients who are unlikely to have a response to the drug?s side effects. The ultimate goal (practical application) of the proposed project is to promote repurposing of CDK9-inhibiting drugs already approved by the Food and Drug Administration for new clinical applications, in this case stomach cancer. Such drug repositioning strategies avoid the prolonged drug development process, providing the quickest possible transition to use in human patients. The planned cell and animal studies complement each other, increasing the likelihood that the results can be translated for stomach cancer patients and paving the way for clinical trials of BAY1143572 in stomach cancer. Significance: The most critical scientific contribution of this study is increased understanding of the implications of targeting CDK9
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710273
Entities
People
- Omkara Lakshmi Veeranki
Organizations
- United States Army
- University of Texas at Austin