Cyclin E1 in Gastric Cancer
Abstract
Stomach cancer is a devastating illness that kills over 700,000 people each year. Current treatments work poorly because we do not understand how this cancer forms nor what are its weaknesses that we can exploit with new therapies. My research focuses on understanding how a normal stomach cell transforms into a cancer cell, with the ultimate goal of using this knowledge to develop new, more effective therapies that attack stomach cancer cells where they are most vulnerable. I come to cancer research with the perspective of both a developing scientist and a medical oncologist who treats patients with these deadly cancers. The research plan outlined in this proposal will be a stepping stone toward my long-term career goal of becoming a physician-scientist leading a laboratory studying stomach cancer at an academic medical center. Motivated by my clinical experience caring for patients with gastrointestinal malignancies, I purposely chose an area of gastrointestinal oncology where there are large gaps in our knowledge and treatment of cancer. I also selected a research mentor, Dr. Adam Bass, who is a pioneer in the stomach cancer field with an outstanding academic record and a strong commitment to mentorship and career development for his trainees. Furthermore, by training at the Dana-Farber/Harvard Cancer Center, I am immersed in a collaborative, resourceful research environment that nurtures the free exchange of creative ideas to propel science and medicine forward. A major challenge for any physician-scientist in training is the need to protect sufficient time to focus on pursuing research when there are also needs for junior physicians to perform clinical work. At this important point in my career, a Horizon Award will be truly pivotal in providing time for me to focus on research and advance toward an independent research career. The research that we are pursuing aims to address what we believe to be a fundamental cause of most stomach cancers. Each cell in our body has the same genome, or set of chromosomes, that we inherited from our parents. However, work from our laboratory has shown that most stomach cancers are formed immediately following an apparently catastrophic disruption of the genome where the cancer cell acquires extra copies of many chromosomes. There are two fundamental questions that we wish to answer that follow our observations about these DNA alterations in stomach cancer cells. The first question is about the cause of these alterations. Why do some cells develop such horribly deranged genomes? The second question is about how we can use knowledge about these deranged genomes to identify new approaches for stomach cancer therapy. Admittedly, this problem of exploring the abnormal stomach cancer genome is substantial. Fortunately, we have identified one particular gene, called Cyclin E1, which we believe to be playing a critical role in this process and which leads us directly to a possible new therapeutic target that we can exploit in these cancers. In this proposal, we will specifically investigate how this gene can act to promote genomic disruption and the formation of stomach cancer. We will do this by generating a mouse model where we hyperactivate Cyclin E1 in cells of the mouse stomach. Additionally, we will use both this mouse model and stomach cancer cells that came from patients to test our idea about a new therapeutic target that we believe may be important in many patients with stomach cancer, a protein called CDK2 that is a critical partner to Cyclin E1. As there are now companies developing inhibitors to CDK2, our work to demonstrate a role for this target in stomach cancer could lead to rapid development of new clinical trials. Furthermore, the mouse models we are building will allow us to more deeply investigate CDK2 inhibitors and identify other drugs we can use in combination with these inhibitors to increase their effectiveness in stomach cancer. Therefore,
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710222
Entities
People
- Ankur K Nagaraja
Organizations
- Dana–Farber Cancer Institute
- United States Army