State: New York

Funded by the NBA and NBA Referees Association
In honor of Ron Olesia

Abeloff V Scholar*

Cancers are a diverse collection of diseases that are caused by distinct gene mutations. Effective cancer treatment has to be tailored for these patient-specific aberrations. To this end, the cancer genome project has systematically identified mutations in various cancer types and provided a foundation for personalized cancer medicine. However, the cancer genome can be littered with mutations simply due to the fact that cancer cells are highly unstable. Therefore, it is critical to understand which mutations play a causal role in driving cancer progression, i.e. acting as drivers, and which mutations are merely bystanders.

To address this question, we have developed a novel technology for generating personalized breast cancer models that contain mutations found in human patients. Using these models, we will decipher which mutations are functional important, and thus can be useful therapeutic targets. Our work is like to identify novel breast cancer genes and provide new therapeutic targets and biomarkers for selecting most effective treatment.

Successful outcomes of our study will pave the way for developing therapeutic agents for targeting these new breast cancer genes. In addition, the technology perfected through this study will be highly valuable for investigating mutations of other cancer types to identify a catalog of cancer targets that can be tailored for personalized medicine.

Cancer arises when mutations to our DNA alter the genetic information and change the way our cells normally function. DNA in our body witnesses thousands of lesions on a daily basis. Among these lesions are breaks that occur on both strands of a chromosome, known as double stranded breaks (DSBs), which are highly toxic. In fact, cells in our body have evolved special ways to ensure that when DSBs occur, they are repaired faithfully and promptly to avoid errors in the coding sequence. There are three pathways to repair a DSB in mammalian cells. The preferred pathway is homology-directed repair (HDR) that fixes DNA breaks without altering the original sequence and is hence error-free. DSBs can also be repaired by two additional pathways that are error-prone – the classical Non-Homologous End-Joining (NHEJ) and the alternative NHEJ (alt-NHEJ) pathways. The activity of HDR pathway is absent in many breast cancer cells, and evidence suggests its replacement by the highly mutagenic alt-NHEJ pathway. Hence, the main focus of our proposal is to study the poorly characterized alt-NHEJ pathway of repair and establish its role in breast cancer progression. Using high throughput technology, we plan to uncover novel genes in this pathway and characterize the mechanism by which this repair pathway operates. Ultimately, we will assess the de-regulation of its key components in inherited and sporadic breast cancers. This will provide key steps towards revealing specific targets that can guide more favorable and effective breast cancer treatment strategies.

Over the last 10 years, great progress has been made in identifying the genetic alterations present in the blood systems of patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). One of the most important and unexpected findings from these studies has been the identification of mutations in genes which perform RNA splicing. Mutations in these genes are the single most frequent category of mutations seen in MDS patients but are currently not well understood. Under normal conditions, RNA splicing is responsible for ‘processing’ RNA so that the genetic code can be effectively translated to produce normal proteins. It has been postulated that mutations in this pathway impair RNA splicing. However, how precisely these mutations dysregulate splicing and how this actually results in the development of leukemia is unknown. More importantly, how this genetic knowledge can be translated to yield novel drug targets in leukemia has yet to be investigated. The protein SRSF2 is particularly important, since it is associated with the most clinically dangerous forms of MDS and AML. We have recently generated a number of mouse and human cell leukemia models with and without mutations in SRSF2. We now propose to utilize these models to understand how mutations in SRSF2 cause leukemia and how we can treat the leukemia caused by these mutations.