Research
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
Monitoring
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).