Pancreatic Cancer Action Network-AACR Research Acceleration Network Grants
The goal of the Pancreatic Cancer Action Network-AACR Research Acceleration Network (RAN) Grants is to provide funding and strategic assistance to research projects with the potential to double survival for pancreatic cancer by the year 2020. Projects must be implemented by multi-institutional teams and include a clinical component with an endpoint relevant to improving the detection or treatment of pancreatic cancer.
New cancer treatment strategies utilizing the body’s own immune system to target cancer cells have revolutionized the care of patients with melanoma and other select tumor types. However, these approaches have not yet achieved success in pancreatic cancer patients. Our combined Memorial Sloan Kettering/Weill Cornell Medical Center Research Acceleration Network proposes to accelerate already initiated collaborative immunotherapy research being conducted by a network of investigators at these institutions. Our network is dedicated to bringing seminal preclinical immunotherapy discoveries to the clinic, in a manner that will directly benefit pancreatic cancer patients. Among these exciting discoveries, Dr. Fearon’s group recently discovered that pancreatic tumors secrete a protein known as CXCL12. This protein effectively eliminates immune cells from the local tumor environment, thereby protecting cancer cells from immune attack. Dr. Fearon’s group has further demonstrated that a drug blocking CXCL12 sensitizes mouse pancreatic cancers to immune attack, leading to rapid tumor destruction. Based on these seminal findings, our group has obtained funding to initiate a clinical trial investigating the safety and efficacy of this drug (AMD3100) in pancreatic cancer patients. Using the resources of MSKCC’s new Rubenstein Center for Pancreatic Cancer Research, including a new facility for the high volume production of pancreatic cancer mice, Drs. Leach and Fearon have now partnered with Bristol Myers Squibb to initiate preclinical studies of longer-lasting antibodies targeting CXCL12 and its receptor, known as CXCR4. At the same time, our clinical co-investigators Eileen O’Reilly, Jedd Wolchok, Manish Shah, and Peter Allen are preparing to launch two additional clinical trials evaluating this antibody-based approach in patients with either localized or metastatic pancreatic cancer. As a critical foundation for these trials, Dr. Leach and co-investigator Tim Chan will chart the neoepitope landscape of pancreatic cancer by determining the quantity and quality of effective T-cell neoepitopes in a series of patients with resected pancreatic cancer. Our team’s collaborative efforts have already generated significant shared funding, allowing us to initiate the work contained in the current proposal. By allowing pancreatic cancer patients to benefit from recent advances in immunotherapy, we believe that the studies enabled by this RAN grant will directly contribute to the Pancreatic Cancer Action Network’s goal of doubling pancreatic cancer patient survival by 2020.
The frequent mutation of the KRAS gene in pancreatic cancer (95 percent), together with compelling evidence that “correction ” of this gene defect can significantly halt pancreatic cancer growth, has made the development of anti-KRAS drugs one of the top four priorities identified by the NCI 2013 Pancreatic Cancer Working Group. The frequent mutational activation of two key KRAS effectors (BRAF and PIK3CA), and their well-validated roles as cancer drivers, has led to extensive ongoing clinical trials evaluating a large roster of inhibitors of these pathways. However, significant hurdles remain. First, although substantial cell culture and mouse model analyses indicate that combinations that concurrently block both pathways can have significant synergistic antitumor activity, the same antitumor activity has not been seen in patients, and normal tissue toxicity is also an issue. Second, even if an effective anti-KRAS therapy can be developed, experience with other successful targeted therapies is that resistance arises quickly. This proposal hypothesizes that novel additional combinations will be needed to overcome these limitations. However, the best combinations often cannot be found by logical deduction, largely because the knowledge of the full complexities of signaling dynamics and cross-talk remains very much incomplete. Instead, the identification of unexpected but successful combinations has often been fortuitous. In this proposal state-of-the-art innovative unbiased functional screens will be applied to identify combinations that will effectively suppress the RAF-MEK-ERK and PI3K-AKT-mTOR effector pathways. Finally, the best available preclinical models will be applied for prediction of therapies that will be most effective in pancreatic cancer patients. It is anticipated that distinct effector signaling-targeted combinations for specific molecularly-defined subsets of KRAS-mutant pancreatic cancer will be identified, to provide the first critical step in developing superior treatment options by the year 2020.
The development for targeted therapeutics can take over a decade and cost over a billion dollars to take an agent from the bench to the bedside. Accordingly, the success of the various cytotoxic chemotherapy regimens is often diluted, and any success of targeted therapy is lost altogether when agents are tested in a large, unselected patient population. The inability to translate the significant benefits seen in some patients to the pancreatic cancer population at large is due to the fact that promising therapies are never administered to select patients who are most likely to respond based on their tumors’ molecular profile. This work’s mission is to immediately enhance patient outcomes by incorporating candidate and novel predictive biomarkers into therapeutic decision making, providing a realistic platform for physicians to precisely select from a shelf of currently available therapies for their patients.
The expected outcome of the clinical trial is that molecular tailored therapy will improve patient outcomes, as compared to standard of care selection. Recently, the use of multi-omic (proteo-genomic) profiling has been shown to increase survival of patients with metastatic breast cancer, which demonstrates functional feasibility of our approach. A successful trial could lead to direct adoption of commercially available molecular testing for patients with metastatic pancreatic cancer, and/or concurrently provide the justification for a definitive phase III trial to confirm the results of this phase II trial. Thus, the complementary in silico work described in will leverage our findings from the clinical trial to interrogate and define a set of network models representing major relevant changes in pancreatic cancer cells that associate significantly with response and/or resistance to standard therapies. This work will culminate in a version 2.0 (v2.0) molecular algorithm for the next, larger clinical trial. Finally, additional work will take an unprecedented approach at defining novel chemoresistance mechanisms and identifying targets to overcome such resistance in pancreatic cancer cells. The datasets will be loaded to G-DOC (an established Georgetown based network) as a mechanism for visualization and exploration by collaborators followed by immediate public availability upon publication.