The additional support builds on a first round of funding announced in November 2018. These four teams originally received up to $1 million each to pursue preclinical work over 13 months, including several projects seeking to repurpose drugs approved for other uses for their potential to treat pancreatic cancer. These teams demonstrated the most promising preliminary results to allow them to take potential therapies into clinical trials. Pancreatic cancer is one of the deadliest forms of cancer, with a five-year survival rate of about 9 percent, according to the National Cancer Institute.
“These ‘Challenge Grants’ seeking new treatments for pancreatic cancer are working exactly as intended,” said Phillip A. Sharp, PhD, the Nobel laureate and MIT scientist who serves as chair of the SU2C Scientific Advisory Committee. “These are important new investigations that have the potential to save lives with new approaches to therapy.”
Each team will receive up to $4 million over a three-year term for the studies focused on clinical trials.
“We are impressed by the results of the first round,” said David A. Tuveson, MD, PhD, chief scientist of the Lustgarten Foundation and director of the cancer center at Cold Spring Harbor Laboratory in New York. “Under this phased ‘Challenge Grant’ approach, teams are accelerating pre-clinical work and we are very eager to take the next step to bring new applications for pancreatic cancer treatment to clinical studies.”
“It is gratifying to see the initial success of the New Therapies Challenge project, which we created to accelerate the research process and bring improved treatment options to patients,” said Kerri Kaplan, president and CEO of the Lustgarten Foundation. “Through the Pancreatic Cancer Collective, these two leading cancer organizations have demonstrated the strength of collaboration. We are excited for the potential for breakthroughs in effective pancreatic cancer treatments and, eventually, a cure for this deadly disease.”
The AACR will support the administration of these projects receiving funding for the second round, including:
Targeting SHP2 in Pancreatic Cancer: Team leader: Rene Bernards, PhD, Netherlands Cancer Institute; co-leaders: Hana Algül, MD, PhD, Technical University of Munich, and Emile E. Voest, MD, PhD, Netherlands Cancer Institute. The team focuses on pancreatic tumors that have a mutation in the KRAS gene and has conducted preclinical testing of drug combinations that inhibit certain proteins in the malignant cells. In the second stage, the team will move into a phase I/Ib clinical trial to test the combination of SHP2 inhibitors (RMC4630) and ERK inhibitors (LY3214996). The results are expected to lay the basis for a phase II clinical trial.
Exploiting DNA Repair Gene Mutations in Pancreatic Cancer: Team leader: Alan D’Andrea, MD, Dana-Farber Cancer Institute; co-leader: James Cleary, MD, PhD, Dana-Farber Cancer Institute. The team has been seeking to evaluate DNA repair inhibitors and improve the use of PARP inhibitors, which interfere with the ability of cancerous cells to increase in number. The team’s preclinical data suggests that combining gemcitabine with inhibitors that target regulatory proteins involved in DNA repair could be an effective therapy in platinum-resistant pancreatic cancer. Based on these laboratory findings, the team is developing three pancreatic cancer clinical trials testing gemcitabine-based combinations: gemcitabine/ATR inhibitor BAY1895344; gemcitabine/CHK1 inhibitor LY2880070; and gemcitabine/WEE1 inhibitor AZD1775. The most promising combinations will be identified for potential validation in larger trials.
Immunotherapy Targeting Mutant KRAS (mKRAS): Leader: Robert H. Vonderheide, MD, DPhil, Abramson Cancer Center at the University of Pennsylvania; co-leaders: Elizabeth M. Jaffee, MD, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, and Beatriz Carreno, PhD, Abramson Cancer Center at the University of Pennsylvania. The team is developing an immunological approach to target mutations in the molecule KRAS, an underlying cause of most cases of pancreatic cancer. In the first round of funding, the team used innovative strategies in bioinformatics, biochemistry, and cell biology to identify specific mKRAS protein sequences that can be recognized by T cells. They then isolated a series of molecular receptors that enable T cells to home in on cancer cells expressing mKRAS. Based on these findings, the team is conducting two different clinical trials with novel vaccines aimed at triggering mKRAS immune responses in patients with resected pancreatic cancer. In round two of funding, the team plans to use the most promising T-cell receptor identified and conduct a clinical trial of engineered T-cell therapy for patients with metastatic pancreatic cancer.
Molecularly Targeted Radionuclide Therapy via the Integrin αvb6; Team Leader: Julie Sutcliffe, PhD, University of California Davis; co-leader: Richard Bold, MD, University of California Davis. The team has been working to develop a peptide receptor radionuclide therapy (PRRT) that involves homing in on a protein called integrin αvβ6, a cell surface receptor that can be found in pancreatic cancers. The team has synthesized in the laboratory a pair of related peptide constructs that are tagged with two different radiolabels. One radiolabel facilitates the imaging of pancreatic cancer lesions in patients that can more likely benefit from the PRRT. The other radiolabel can facilitate the killing of the pancreatic cancer cells. The team has obtained promising results in the laboratory testing of the peptide constructs. In the second round of funding, the team will conduct a phase 1, first-in-human study to evaluate the feasibility, safety and efficacy of the two peptide constructs. The study will determine if one construct can detect lesions in patients with locally advanced or metastatic pancreatic cancer; establish the safety and tolerability of the pair; evaluate the maximum tolerated dose of the second construct; and, using pre-clinical models, establish an optimal dosing regimen.
The Lustgarten Foundation and Stand Up To Cancer have collaborated closely since 2012, jointly funding more than 400 investigators from nearly 70 leading research centers in the United States and the United Kingdom. These efforts include 18 multi-institutional teams, including Convergence Teams bringing together computational experts with clinical oncologists, and cancer interception — research supporting the earliest diagnosis of pancreatic cancer, even before the cancer may have fully formed. All told, these collaborative teams have planned, started, or completed nearly 30 clinical trials. The Pancreatic Cancer Collective is building on this momentum to push the boundaries of what can be accomplished even further.