GRANT TERM

November 2018–December 2019

INFO

Reactivation of the immune system’s anticancer function has dramatically improved outcomes for several solid tumor types but has not yet shown similar efficacy for pancreatic cancer. Pancreatic cancer tissue has a high level of transforming growth factor beta (TGF-β). TGF-β effectively counteracts the immune system.

Team researchers have developed methods to isolate the few tumor-specific killer T cells (called tumor-infiltrating lymphocytes, or TILs) from pancreatic cancer tissue and greatly expand their numbers in the laboratory. They can then transfer these TIL cells back to the patient for maximal impact against the tumor cells. They have used this approach very successfully in metastatic melanoma and shown that 42% of treatment-resistant patients derived benefit from the therapy.

The Team is now developing TIL therapy for pancreatic cancer patients, using engineered TILs that are made resistant to the suppressive effect of TGF-β. In the 14-month period of this grant, they are focusing on demonstrating feasibility and potential efficacy of this approach in the laboratory.

GRANT TERM

November 2018–December 2019

INFO

There is no effective, FDA-approved precision therapy for pancreatic cancer (pancreatic ductal adenocarcinoma or PDAC). The standard of care for most PDAC patients remains conventional cytotoxic chemotherapy, which offers high toxicity with little clinical benefit. The Team has discovered that the survival of pancreatic cancer cells relies on two biochemical processes: 1) Intracellular signaling by the RAS pathway; and 2) Autophagic recycling of the cells’ interior contents to generate building blocks for cancer cell metabolism.

Blocking either one of these processes alone has been shown to have negligible effects. But combined blockade of both the RAS pathway (with trametinib, T) and autophagy (with hydroxychloroquine, HCQ), has displayed synergistic antigrowth effects against pancreas cancer cells in vivo. Although both of these FDA-approved drugs have previously been tested in pancreatic cancer patients with little or no effect, they have never been tested in combination.

The Team is working toward two goals: 1) elucidating the mechanism(s) by which autophagy is regulated by the RAS pathway, in order to identify predictive biomarkers and new autophagy inhibitors that might be tested in clinical trials; and 2) performing a clinical trial of the T/HCQ combination therapy.

GRANT TERM

November 2018–December 2019

INFO

Building on recent large-scale sequencing efforts demonstrating deficiencies in DNA repair in pancreatic cancer, the team is evaluating DNA repair inhibitors in pancreatic cancer. While clinical trials of therapy using PARP inhibitors alone have shown modest activity in pancreatic cancer, the team aims to improve upon PARP inhibitor monotherapy by developing strategies that will combine DNA repair–targeted therapies and be effective in patients experiencing PARP inhibitor resistance.

To accomplish this goal, the researchers are first studying three classes of DNA repair–targeted therapies—CHK1, ATR, and PARP inhibitors—as single agents in organoid cultures of patient-derived pancreatic cancer tumors. They are then identifying the most promising combination of DNA repair–targeted therapies and performing drug testing using patient-derived mouse models of pancreatic cancer. Through the organoid and animal model drug sensitivity experiments, the molecular mechanisms of sensitivity and resistance will be analyzed. A goal of these mechanistic studies is to develop biomarkers that can be used in clinical trials to pinpoint the pancreatic cancer patient population most likely to benefit from these therapies.

GRANT TERM

November 2018–December 2019

INFO

The goal of this team is to develop a cellular therapy that exploits novel cell engineering to manufacture highly selective anticancer T cells on an individual-patient basis. The approach is similar to T cell therapies recently approved by the FDA that target leukemia and lymphoma, except the team is targeting mutant KRAS in pancreatic cancer.

The Team has been able to isolate T cells specific for mutant KRAS and has successfully grown these cells from multiple donors. In this study the researchers are isolating more KRAS T cells obtained from three groups of people: normal individuals, patients with mutant KRAS tumors, and pancreatic cancer patients who are being treated with vaccines against mutant KRAS. Their ultimate goal is to test in the clinic the effectiveness of individualized infusions of KRAS T cells against pancreatic cancer in patients.

GRANT TERM

November 2018–December 2019

INFO

The majority of pancreatic cancer patients will present with metastatic disease. The protein called integrin αvβ6 is significantly up-regulated in pancreatic cancer, including in metastases. αvβ6 is a particularly attractive target for peptide receptor radionuclide therapy (PRRT).

PRRT with lutetium-177 radiolabeled peptides have been shown to be promising for treatment of advanced neuroendocrine tumors and castration-resistant prostate cancer. Team researchers have developed 18F-αvβ6-binding peptide, a radiolabeled peptide for PET imaging, and have successfully imaged metastases. They now aim to further develop this peptide construct into a PRRT using lutetium-177.

The Team is performing all the necessary preclinical testing including in vivo imaging and assessment of therapeutic efficacy in murine models of pancreatic cancer, toxicology studies, preparation of chemistry manufacturing, control documentation, and preparation of a clinical protocol, culminating in the submission of an investigational new drug to the U.S. FDA for a first-in-human therapy trial. The completion of phase I will allow the researchers to rapidly move

GRANT TERM

November 2018–December 2019

TERM

More than 90% of pancreatic tumors carry a mutation in the KRAS oncogene. The RAS pathway may be essential to promote the growth of pancreatic cancerous cells. This pathway helps transmit proliferation-promoting signals from the cell’s surface receptors toward the nucleus, where these signals affect the regulation of other key genes that instruct the cell to divide. Mutant RAS genes become more active in signaling, and therefore keep pushing the cell toward uncontrolled proliferation. So far, no targeted therapies are clinically available against the active protein encoded by the mutant RAS gene.

The Team has discovered that that tumors carrying an activating KRAS mutation are sensitive to the inhibition of SHP2, a protein that helps the transmission of the growth-promoting signal from the cell surface receptors. Moreover, the team has found that SHP2 inhibitors cooperate with inhibitors of MEK, a key RAS downstream effector, to achieve better control of tumor growth. Given these findings, the researchers have proposed a combination of SHP2 inhibitors and MEK inhibitors for the treatment of KRAS-mutant pancreatic cancer patients.

GRANT TERM

November 2018–December 2019

INFO

There is a critical need to identify new therapeutics that can more effectively block tumor growth and metastasis in pancreatic cancer. This team has identified a subpopulation of cells in pancreatic cancer that have some characteristics of stem cells and display the capacity to drive disease progression and therapy resistance. A particular regulator of inflammation and the immune response has been found to be highly enriched in pancreatic cancer stem cells and critically required for their ability to drive tumor growth and progression.

Based on these findings, the team is testing whether delivery of a pharmacological inhibitor can block growth and progression of pancreatic cancer in genetically engineered models of the disease. This work has the potential for rapid translation and high impact because these inhibitors are already in clinical trials for autoimmune diseases, including two that are delivered orally. Thus, this Team’s studies will pave the way for a clinical trial testing of the efficacy of targeting a regulator of inflammation and the immune response in pancreatic cancer therapy.

GRANT TERM

2018

INFO

The team is building on the work started under a Convergence 1.0 grant but further explore the underpinnings that constitute pancreatic survivorship. By looking at few individuals who survive pancreatic cancer for long periods of time, the team identified an initial set of high-quality neoantigens, or protein tags, on cancer cells that the immune system recognizes. This project will continue the work to understand what makes a high-quality neoantigen and how the microbiome influences how the immune system recognizes it, with the goal of developing a method for creating vaccines to treat pancreatic cancers. This research will have a significant impact on understanding neoantigen-T cell immunobiology and could improve the treatment prospects of pancreatic cancer patients. This Convergence Research Team will work in collaboration with Microsoft Research, utilizing Artificial Intelligence (AI) and machine learning.

GRANT TERM

November 2017 – October 2021

INFO

This Interception Research Team is evaluating unique and new approaches in combination with radiation therapy and surgery. The team is utilizing SU2C’s unique “tumor organoid” technology in which an individual patient’s tumor cells are grown in the laboratory, creating “mini tumors” which can then be tested to see if a particular treatment is optimal. The team is also studying changes in the tumor microenvironment – the cells that support cancerous cells in a tumor – to see if there are changes and the environment is more or less “inhabitable” following treatment.

GRANT TERM

May 2017 – April 2020

INFO

Immunotherapies have shown benefits across a range of human cancers, but so far have not worked well in pancreatic cancer patients. Recent evidence suggests that one major roadblock for the effective use of immunotherapies in pancreatic cancer patients is that the tumors are effectively hidden, preventing the immune system from recognizing and killing them. Research from this team suggests that therapies targeting the vitamin D receptor will perhaps “unmask” the pancreatic tumors and allow the immune cells to reach them, creating the possibility that immunotherapies will be effective.

The goal is to test if targeting the vitamin D receptor will unlock the potential of immunotherapies to kill pancreatic cancer tumor cells and potentially establish a therapeutic combination for controlling advanced pancreatic cancer, extending patient survival, and reducing patient side effects. Additionally, this team hopes to identify features that drive patient responses to immunotherapy and gain insight into additional strategies for converting immunotherapy resistant tumors into tumors that respond to treatment.

GRANT TERM

April 2017 – March 2018

INFO

This Research Team is studying CAR T cell immunotherapy in metastatic pancreatic cancer patients, looking for changes in DNA “on and off switches” (epigenetic changes) following treatment with CAR T. The team ultimately seeks to identify epigenetic changes for better understanding of why certain patients respond to treatment compared to non-responders.

GRANT TERM

January 2016 – December 2018

INFO

This Dream Team is continuing the work started on the original SU2C Pancreatic Cancer Dream Team, which found that vitamin D receptor plays an important role in determining pancreatic cancer susceptibility to chemotherapeutic agents. This Team is studying vitamin D receptors to determine if it is an effective “super-enhancer” which improves patient response to chemotherapy.

GRANT TERM

September 2015 – August 2019

INFO

The Research Team’s long-term goal is to understand the factors that lead to resistance or response in patients treated with various forms of cancer immunotherapy. In particular, the goals are to investigate patient epigenetic variation that influences the response to immunotherapy and to use epigenetic therapeutics alone or in combination with immunotherapy to inhibit tumor progression as well as to overcome resistance to immunotherapy.

The team will identify genetic and epigenetic features in CAR T cells and/or cancer cells that will help predict which patients will respond to the immunotherapy, with an eventual goal of initiating clinical trials that employ a combination of approaches to therapy. This will create strong synergy for a unified, multidimensional project aimed at generating more effective CAR T cells therapy for pancreatic cancer patients, with potential broad implications for immunotherapy directed toward other cancers.

GRANT TERM

July 2014 – June 2017

INFO

This Dream Team has been investigating combinations of treatments, focused on different and unique pathways involved in immune response to treatment found in the tumor and the “stroma” or the supportive environment that sustains cancer cells in tumors. This team has achieved durable responses to treatment, with a treatment vaccine they developed.

GRANT TERM

December 2009 – May 2015

INFO

This Dream Team evaluated combinations of treatments, seeking better patient outcomes. The Dream Team’s work led to the first approval for a new pancreatic cancer drug in 30 years. The FDA approved a new combination of drugs that enables longer survival in patients with advanced pancreatic cancer on September 6th, 2013. Pancreatic cancers are scavengers, after “eating” sugars it eats proteins to sustain itself. This drug creates a Trojan horse for the cancer to feed on and it eventually dies. This Dream Team also developed a new method of identifying pancreatic tumors that have spread to the brain and liver, which could significantly aid in diagnosis.

The combination of Abraxane and Gemcitabine is now being explored for other types of cancers. This Dream Team was also able to identify that vitamin D receptor plays an important role in determining pancreatic cancer susceptibility to chemotherapeutic agents, under continued investigation by the SU2C-Cancer Research UK-Lustgarten Dream Team.