The overall goal of this Program remains to understand how basic cellular processes are altered to
promote tumor initiation and progression and how such alterations might make tumor cells vulnerable to
specific, targeted interventions. Initiated by James Watson in 1968, the program focused on the action of
DNA tumor viruses and in many ways powered the molecular biology revolution. Throughout its history, it
revealed the underpinnings of basic biological processes central to cancer development and revealed key
oncogenic mechanisms affecting their action. Taking advantage of new biological concepts and technologies
emerging from its investigators, the Program has continued to innovate and evolve, with an ever greater
focus on mechanisms of immediate biological and therapeutic relevance to the human disease. Over the last
funding period, the Program produced fundamentally new insights into DNA replication its coordination in
normal and cancer cells, and established that aberrant alternative RNA splicing is an important oncogenic
mechanism. The Program has been at the forefront of non-coding RNA biology, providing some of the first
evidence that microRNAs can act as oncogenes and tumor suppressors, and influence other key cancer
phenotypes. Lastly, the Program has developed and implemented innovative mouse models and used them
to identify new oncogenes and tumor suppressors of broad relevance to human cancer. Armed with new
technologies developed by Program investigators over the last several years, we will implement a multi
pronged approach towards identifying novel oncogenic mechanisms, with an eye towards revealing the
vulnerabilities they create. Some elements of the Program are driven from the standpoint of particular
cellular processes, such as chromosome replication and segregation or pre-mRNA splicing (Projects 1 and
2), and others implement unbiased approaches informed by changes in the cancer genome or alterations in
regulatory networks to focus their studies (Projects 3-5). All Projects converge on potential anticancer
targets, whose efficacy can be predicted based upon the nature or state of the cancer cell or its
microenvironment. All of the Projects benefit from demonstrable interactions among themselves, taking
advantage of complementary approaches and expertise. Moreover, each Project benefits from the four
innovative Cores, each of wtiich is lead by outstanding and experienced researchers. Finaily, the Program
benefits from, and contributes to, the collaborative environment fostered by the Coid Spring Harbor
Laboratory Cancer Center and is at the heart of its activities. |