The focus of the Brody lab is to research pancreatic cancer. In particular, the lab aims at studying the molecular aspects of this disease, how tumor cells adapt to microenvironmental stimuli, and importantly, at developing and optimizing targeted, personalized therapies for this disease. Currently, the lab is funded to study post-transcriptional gene regulation driven by the RNA-binding protein, HuR. Our work has previously demonstrated that tumor cells exploit HuR function to stabilize and enhance expression of genes pivotal for adaption to the tumor microenvironment (i.e., low glucose, hypoxia, and chemotherapeutic exposure). Additionally, we are expanding our research portfolio to understand the role of HuR in other major aspects of tumorigenesis, such as onset, metastasis, and regulation of essential oncogenic pathways (i.e., YAP1 & MYC), with the goal of developing functional strategies to target HuR, directly.
Another major focus of the lab is based upon developing and optimizing novel and personalized therapeutic strategies to target this disease. Conventionally, the approach has been to sequence the DNA of tumors and attempt to match these alterations with an available targeted cocktail of agents. Dr. Brody has been involved with some of these initial studies in pancreatic cancer and he realizes that a more comprehensive approach is needed. Based on this premise the following projects are available to work on in the laboratory:
Novel Therapeutic Strategies for pancreatic cancer
- Pursuing novel strategies to take advantage of the Achilles’ heel of a subset of pancreatic cancer (e.g. tumors that harbor BRCA1/2 mutations). For instance, we identified novel targets that we believe to be more promising than current options, such as targeting PARP1 and using promiscuous (chemotherapy) DNA damaging agents such as oxaliplatin and gemcitabine for the treatment of these cancers. We will pursue small molecule inhibitors such as PARG inhibitors, via collaboration with industry to evaluate these compounds in vitro and in vivo. (NIH funded and PanCAN funded)
- Additionally, we are studying the various therapeutic resistance mechanisms that pancreatic cancers use to avoid these targeted therapies.
- Identifying ways to enhance the antigen suite and burden in homologous repair deficient pancreatic cancers. (collaborating faculty member Robert Eil and with Johns Hopkins)
- The Brody lab is closely collaborating with the Sears’ and the Coussens’ labs to evaluate how patient-derived models of pancreatic cancer can be utilized to reach the therapeutic objectives described above. (NIH funded)
- Using these models, we will develop and evaluate nanotherapeutic strategies (Code Bio) and designed molecules (with Sanjay Malhotra, OHSU) to target this important pro-survival protein. (NIH funded)
- We have strong data that targeting mitochondria in pancreatic cancer cells could represent a potent strategy to cutting off the metabolic tendencies of pancreatic tumors. We have identified FDA approved compounds that are targeting different aspects of the mitochondria, and will continue to investigate this aspect of pancreatic cancer.
Understanding the molecular aspects of pancreatic cancer
- We will continue our work in identifying the mechanism by which HuR and YAP1 supports pancreatic cancer cell development (i.e., tumorigenesis) and pancreatic cancer cell survival under austere conditions (including the effects of DNA damage).