Research Investigator Award Recipients
Lewis Cantley, Ph.D., Weill Cornell Medical College
$1.5 million over 3 years (2015 - 2017) | Project: Targeting PIP4K2A/B for pancreatic cancer therapyOverview:
Mutations in TP53, a major tumor suppressor, occur in the vast majority of pancreatic cancers. Cancer cells expressing mutant TP53 adapt by having other genes or proteins compensate for its functional loss. This study aims at investigating the compensatory role of a protein, PIP4K2A/B, in the absence of a functional TP53, and targeting PIP4K2A/B as an indirect way to kill TP53-mutant pancreatic cancer cells."Current treatment options for pancreatic cancer extend patient survival for weeks or months, not years. p53 is frequently mutated in this cancer and we have demonstrated that cells lacking functional p53 are critically dependent on the activity of the phosphotidylinositol kinase PIP4K2B. We have developed inhibitors of this protein that are potent and selective. This proposal will identify whether PIP4K2B is a therapeutic target for p53 mutant pancreatic cancer. Our PIP4K2B inhibitors have the potential to greatly impact the survival of the majority of pancreatic cancer patients."
Channing Der, Ph.D., UNC Chapel Hill
$1.5 million over 3 years (2015 - 2017) | Project: Identification and validation of Raf inhibitor-based combination KRas-targeted therapiesOverview:
Mutated KRas is seen in greater than 90% of pancreatic cancer cases; however, efforts to target it have failed. This study aims to target the proteins that are directly affected by mutated KRas and to design an effective combination inhibitor strategy to block the cancer-causing effects of mutant KRas indirectly. "This Lustgarten grant will support our studies to apply an innovative chemical library strategy to identify therapeutic approaches to block Raf, the critical effector of KRas oncogene-dependent pancreatic cancer growth."
Stephen Fesik, Ph.D., Vanderbilt University
$1.5 million over 3 years (2015 - 2017) | Project: Discovery of small molecules that target the Ras/SOS complex for the treatment of pancreatic cancer
Mutated KRas is seen in greater than 90% of pancreatic cancer cases; however, efforts to target it have failed. This study aims to target other proteins that interact with the mutated KRas protein, such as SOS, by using specially designed small molecule inhibitors in hopes of indirectly killing KRas-expressing cancer cells. "The aim of this grant funded by The Lustgarten Foundation is to develop a drug that blocks KRas function. As KRas is over expressed in pancreatic cancers, the hope is that by blocking its action, the cancer cells will die."
Charles Fuchs, M.D., M.P.H., Dana-Farber Cancer Institute
Mandar Muzumdar, M.D., Massachusetts Institute of Technology
$1.5 million over 3 years (2015 - 2017) | Project: Obesity-driven PDAC - a comprehensive study to define new targets for prevention and therapy
Overview: Studies have shown a correlation between obesity and an increased risk for pancreatic cancer. Also, obese pancreatic cancer patients experience a significantly reduced survival, independent of other factors. These studies aim to better understand the biology of pancreatic cancer in the context of obesity, and what obesity-related molecular signaling pathways play a role in promoting the disease.
"This Lustgarten-funded grant aims to identify differences in metabolism between pancreatic cancer cells and normal cells. These differences can be useful in both identifying early detection markers as well as understanding ways to selectively 'starve' the pancreatic cancer cells."
Tony Hunter, Ph.D., Salk Institute for Biological Studies
$1,113,698 over 3 years (2015-2017) | Project: Interdicting reciprocal cytokine interactions between pancretic stellate cells and pancreatic tumor cells as a new therapeutic approach in pancreatic ductal adenocarcinomaOverview:
A pancreatic tumor consists of both cancer cells and stromal cells, or cells that surround the cancer cells and nurture them with growth factors. This study aims to more closely study the relationship between the cancer and stromal cells and identify the pro-cancerous growth factors, such as LIF, in hopes of targeting these factors to “starve” the pancreatic cancer cells. "Thanks to the support from The Lustgarten Foundation, my goal is to determine if LIF and other signaling molecules secreted by stromal cells plays a role in pancreatic cancer progression and resistance."
Tyler Jacks, Ph.D., Massachusetts Institute of Technology
$1.5 million over 3 years (2015-2017) | Project: Genome-wide CRISPR-based screens to identify unique vulnerabilities in KRas-dependent pancreatic cancer cells
KRas is a prominent pancreatic cancer-causing gene that is mutated in greater than 90% of cases; however, efforts to drug it have failed. This study proposes to use new-age, genetic screening technology called “CRISPR” to discover more easily “druggable” genes that mutant KRas-expressing cells are dependent upon to target instead of KRas itself. "The goal of this project supported by The Lustgarten Foundation is to better understand the role of KRas in pancreas cancer and to identify differences between pancreas cancers’ response to drugs targeting KRas pathways." Photo Credit: David Fox
Alison Klein, M.D., Johns Hopkins University
$738,215 over 3 years (2015 - 2017) | Project: Identification of individuals at high risk for pancreatic cancer
An early screening detection method for pancreatic cancer is greatly needed. These studies aim to create a highly specific and sensitive screening test in order to identify the population of people at greater risk for developing pancreatic cancer.
"This support from The Lustgarten Foundation will allow us to identify individuals at the highest risk of developing pancreatic cancer who should be targeted for early detection screening. We hope that by careful screening of these high-risk populations we will identify, we can prevent pancreatic cancer from developing and ultimately reduce mortality from pancreatic cancer."
Steven Leach, M.D., Memorial Sloan-Kettering Cancer Center
$1,412,671 over 3 years (2015 - 2017) | Project: Large-scale, systematic evaluation of combination therapies for pancreatic ductal adenocarcinoma
There is an unmet clinical need to find more and better drug combinations for treating pancreatic cancer. This study proposes to use a systematic approach to testing a very large number of different drug combinations in hopes of finding some that work best for certain groups of patients, and doing so based on identifying predictive biomarkers in patients that would make them great candidates for those drug(s).
"Funding from The Lustgarten Foundation will allow us to explore hundreds of different drug combinations for activity in our mouse models of pancreatic cancer; this is the type of effort that is so difficult to find funding for but so critical to improving the lives of our pancreatic cancer patients."
Scott Lowe, Ph.D., Memorial Sloan-Kettering Cancer Center
$1.5 million over 3 years (2015 - 2017) | Project: Target identification and validation in pancreatic ductal adenocarcinoma
There is a dire need to find more drugs and drug combinations to treat pancreatic cancer patients. This study focuses on using powerful genetic screening tools to identify genes that pancreatic cancer cells depend upon – their “Achilles heel” -- in hopes of more selectively and effectively killing cancer cells.
"Recent advances in genomics have produced a detailed understanding of the genetic changes that drive pancreas cancer development, yet this information has yet to produce new pancreas cancer therapies. With generous support from The Lustgarten Foundation, our project will implement powerful new technologies to develop a deeper understanding of how mutations in key pancreas cancer genes impact different stages of tumorigenesis and to systematically identify cellular vulnerabilities these lesions create. As such, the project will point to new therapeutic targets for pancreas cancer drug development."
Frank McCormick, Ph.D., FRS, University of California San Francisco
$1,496,702 over 3 years (2015 - 2017) | Project: New ways of treating pancreatic cancer based on reversing KRas-mediated stemnessOverview:
Mutated KRas is seen in greater than 90% of pancreatic cancer cases, and it allows cancer cells to behave more like a stem cell. This study aims to target the stem cell markers expressed on KRas expressing pancreatic cancer cells in hopes of sensitizing them to chemotherapy and more effectively killing them. "We will undertake pre-clinical testing of a monoclonal antibody and a small molecule natural product that we expect to destroy pancreatic cancers in mouse model systems. If either of these approaches is successful, we will initiate clinical testing in the near future. Indeed, the pathway from preclinical to clinical testing is rather straightforward. If successful, we will be able to offer a new option for treating patients, using therapies that are safe, well tolerated and effective."
Hidde Ploegh, Ph.D., Massachusetts Institute of Technology
$1,443,197 for 3 years (2015 - 2017) | Project: Non-invasive monitoring of inflammation and the immune response against pancreatic cancerOverview:
A hallmark of pancreatic cancer is the immense inflammation in the tumor. The goal of this proposal is to exploit the abundance of immune cells by using them as “markers” via PET imaging. Tracing antibodies that specifically bind these immune cells will be used in non-invasive PET imaging for diagnosis, to gain a better understanding of how the immune cells interact with the cancer cells, and to observe how a patient responds to treatment. "My Lustgarten project will focus on the development of single domain antibodies (VHHs), derived from camelid heavy chain-only antibodies, to visualize pancreatic cancer. The small size of these VHHs is expected to result in far better tissue penetration compared to their full-sized counterparts. We shall exploit this property to image pancreatic cancer non-invasively using positron emission tomography (PET), with VHHs directed against a variety of proteins of immunological interest to assess the presence and relative abundance of both myeloid and lymphoid cells. We shall also generate yet additional VHHs that may recognize surface molecules on pancreatic cancer cells. The ease with which VHHs can be modified to deliver a variety of payloads may enable the design of VHH-drug conjugates that could be used therapeutically. If successful, these approaches will provide new diagnostic and therapeutic tools in the fight against pancreatic cancer."
Julien Sage, Ph.D., Stanford University
$1,285,512 over 3 years (2015 - 2017) | Project: Protein methyltransferase signaling - Discovery of novel therapeutic targets in pancreatic cancerOverview:
There are many growth factor receptors that become highly activated in pancreatic cancer cells; however, inhibiting these growth factors has toxic effects and only temporarily inhibits tumor growth. This study aims to target a different class of proteins known as lysine methytransferases, or KMTs, that play a role in pancreatic cancer progression."Our work on pancreatic cancer stems from a simple idea: enzymes are often easy to target therapeutically but large families of enzymes have never been studied in depth in pancreatic tumors – thus, a number of “druggable” targets may have been missed. Specifically, we propose to investigate the role of the family of lysine methyltranferases (KMTs) in pancreatic cancer cells. We will determine which KMTs contribute to the growth of pancreatic tumors and investigate how these enzymes promote tumorigenesis. The identification of key KMTs and additional enzymes in their proximal networks will impact the fight against pancreatic cancer by elucidating new signaling pathways in pancreatic cancer cells and identifying new therapeutic targets for drug development."
Diane Simeone, M.D., University of Michigan
$1.5 million over 3 years (2015 - 2017) | Project: Personalized therapeutics using a novel circulating tumor cell ex vivo expansion modelOverview:
Discovering new, innovative ways to personalize a pancreatic cancer patient’s treatment is desperately needed in order to more effectively kill their cancer. This study aims to collect circulating tumor cells in a patient’s blood and then study them in the lab to develop an optimized treatment regimen. "My goal is to develop a non-invasive approach to expand metastatic PDAC cells in culture to develop personalized therapeutics, which target heterogeneous cancer cells, including circulating stem cells, in patient tumors."