The long-term goal of our laboratory is to improve the dismal survival rates for patients with pancreatic cancer, which is now the 3rd most common cause of cancer-related deaths in the United States. Our laboratory has been an integral part of the team that sequenced the genomes of pancreatic ductal adenocarcinoma (PDAC) and other variant tumors, including pancreatic cystic neoplasms and neuroendocrine tumors of the pancreas. The research performed in our laboratory is entirely translational in that we always keep a line of sight to the clinic as one of the overarching objectives. The broad areas of research in the Maitra laboratory can be summarized as follows:
Functional annotation of epigenetic drivers in pancreatic cancer
In addition to the widespread genetic alterations, it is now apparent that epigenetic mechanisms are also central to the evolution and progression of human cancers. Numerous epigenetic drivers have been implicated as being aberrantly altered in PDAC, including members of the COMPASS-like complex (MLL3, KDM6A, SETD2) and SWI/SNF family members (ARID1A, PBRM1). Our laboratory is currently performing a rigorous audit of epigenetic drivers and their effector pathways in PDAC, using a combination of in vitro and genetically engineered animal models. These studies are done as a collaboration with the Gupta laboratory in the Ahmed Center. In addition to functional annotation of driver mutations, we are also exploring novel synthetic lethal relationships that would lead to targeted therapies in genetically stratified patient populations.
Mouse models of pancreatic cystic neoplasia
Pancreatic cancers do not arise de novo, but rather through histologically discernible lesions that are either microscopic (Pancreatic Intraepithelial neoplasia or PanIN) or macroscopic cysts (most commonly, Intraductal Papillary Mucinous Neoplasms or IPMNs). Our laboratory has been involved in elucidating the molecular underpinnings of PDAC precursor lesions for many years, including identification of key driver genes in IPMNs. We are currently developing animal models that recapitulate the cognate genetics of human IPMNs, with the intent of using these mice as biologically relevant platforms for early detection, quantitative imaging and targeted therapies in early stage pancreatic neoplasia. Salient examples include conditional models that express mutant Gnas and Kras alleles, which are together found in as many as 96% of human IPMNs. These mice ubiquitously develop cystic lesions with progression to invasive cancers in a subset.
Liquid Biopsies for Therapeutic Stratification and Disease
Our laboratory has implemented a robust pipeline for obtaining liquid biopsies from PDAC patients at all stages of disease at MD Anderson. From these liquid biopsies, we are obtaining cell-free DNA (cfDNA), exosomes and circulating tumor cells (CTCs). We have generated optimized protocols for isolating exosomes that have highly preserved nucleic acids amenable to next generation sequencing (NGS), as well as microfluidics-based platforms for isolating viable CTCs. These studies are performed under the umbrella of the Pancreatic Cancer Moon Shot® (co-led by Maitra), and provides an unprecedented insight into spatial and temporal heterogeneity of PDAC during its natural history of treatment and progression.
Example of tumor genome evolution in metastatic PDAC through the course of therapy, as assessed by whole genome sequencing and copy number analysis on exosomal DNA (ExoDNA).