Decoding Metabolic Programs Underlying Pancreatic Cancer Progression
Abstract
Career Goal: I have been fortunate to have training in outstanding scientific environments throughout my doctoral and postdoctoral studies. My PhD training in the laboratory of Dr. Nissim Hay (University of Illinois, Chicago) aimed at studying the role of metabolic enzymes in cancer. This provided me with expertise in molecular and cellular oncology and gave me an interest in both discovering basic cancer mechanisms and in employing this information in applications that have potential for clinical translation. I was fortunate to have been supported by a Department of Defense fellowship for these studies, based on their high significance to human health. To advance my career in cancer metabolism research, I joined the laboratory of Dr. Nabeel Bardeesy, an expert in genetic models of pancreatic cancer. As there is an unmet need of model systems to study the diversity of pancreatic cancer subtypes, I focused on developing an animal model of a highly detected pancreatic cancer. In 2 years, I have made important discoveries, which not only extends our understanding, but also points out alternative therapeutic interventions for this disease. The environment at the Massachusetts General Hospital (MGH) provides me with unsurpassed opportunities to advance my skills as a researcher through continuous interactions with other outstanding scientists and clinicians (seminars, retreats, large programmatic grants and symposia) and through collaborations with leading research teams from around the world. I am confident that my pursuit of the current project and the environment of the Bardeesy lab will eventually place me in an excellent position to apply for independent faculty positions. My future goal is thus to pursue an independent academic career in cancer research. I will extend my research initiative for decoding basic mechanisms that will help to discover therapies against devastating cancers. Project Description: Pancreatic cancer is one of the lethal cancers in United States. Among the many subtypes of pancreatic cancer, intraductal papillary mucinious neoplasms (IPMNs) is one of the most poorly understood, yet is being detected at increasing frequency. Moreover, IPMNs serve as a precursor to the most aggressive subtype of pancreatic cancer, referred to as pancreatic ductal adenocarcinoma (PDAC). IPMNs are characterized by pre-cancerous cysts of the pancreas, which are found in 3% of healthy individuals and in ~ 10% of people above age of 70. If untreated, these cysts possess a high risk of developing into malignant cancer. Moreover, patients detected with these cysts require lifelong surveillance with MRI or CT, which creates an extraordinarily high public health cost. Surgery is the only treatment option for this cancer, but can be associated with fatal post-surgical complications. More than 70% of these cystic tumors have an activating mutation in the GNAS gene. By engineering a mouse model that harbors the GNAS mutation, I discovered that tumors aroused in this model recapitulate the characteristics of human IPMNs. Utilizing various modern scientific tools, I found that these tumors are very different from other well-studied pancreatic cancer subtypes in terms of their nutrient metabolism. These tumors have increased mitochondria and fat/lipid metabolism and are dependent on these processes for growth, in contrast to other kinds of pancreatic cancers, which use glucose as their primary nutrient. In the first part of this proposal, I aim to understand the metabolic programs of IPMN that distinguish it from other pancreatic cancers. The second portion is intended to unravel how GNAS mutation causes these metabolic alterations. This study not only will provide a detailed understanding of this frequently detected, yet poorly cancer, but also will open avenues for novel drug discovery. Understanding the influence of gene mutations on the progression of IPMN may guide clinical decision-making (surgery vs
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610285
Entities
People
- Krushna Patra
Organizations
- Massachusetts General Hospital
- United States Army