Preclinical and Human Correlative Studies of a Novel Bruton Tyrosine Kinase Inhibitor in Pancreatic Cancer
Abstract
What is the scientific objective and rationale for this project? The objective of this proposal is to determine how a novel agent ACP-196, which blocks a molecule known as Bruton Tyrosine Kinase (or BTK) expressed on immune cells, can impact the growth of pancreatic cancer. Pancreatic cancer is a notoriously difficult disease to treat, and current treatment options have minimal impact on long-term survival. In many diseases like melanoma or lung cancer, a form of treatment called "immunotherapy," which turns the body s immune system against the cancer cells, has shown dramatic effects on survival. Unfortunately, many of the same drugs that are showing profound effects in these other cancers have failed to elicit meaningful responses in pancreatic cancer. The main immune cell type in the body that destroys cancer cells are known as T cells. However, there are many other cell types in the immediate milieu surrounding pancreatic cancer that block the function of these cancer fighting T cells. These latter cell types express the molecule BTK, and our compound ACP-196 specifically and potently blocks this key pathway needed by such cells that dampen T cell response. By removing the compendium of immune suppressive cells, ACP-196 allows T cells to function and "reject" the tumor. ACP-196 is already undergoing clinical trials in many blood cancers where it has shown dramatic effects. In this proposal, we will, for the very first time, test how ACP-196 functions in pancreatic cancer patients, especially when combined with other agents that might further enhance its effects. As mandated by the Peer Reviewed Cancer Research Program (PRCRP), our proposal is "translational" in that our team will directly work with patients that will be receiving ACP-196 as part of two clinical trials, and the funds from the PRCRP will allow us to conduct extensive laboratory tests on their samples (blood and tissue) to determine which patients will respond, which patients will not, and how we can use such information to ensure optimal patient selection in future immunotherapy trials. We will also conduct additional tests in laboratory animals to determine what other novel treatments can be combined with ACP-196, with an eye towards "translating" these combinations to the clinic for pancreatic cancer patients. What is the ultimate applicability of this research? Currently, 85% of pancreatic cancer patients present with advanced, surgically inoperable disease, and the treatments offered are able to extend survival by only a few months for most patients. Thus, there is a dire and urgent need to develop new therapies for this lethal disease. We believe that the two clinical trials that are being conducted by our partner Acerta Pharmaceuticals using the novel agent we are studying in this proposal (ACP-196) will form the basis for a new approach to how we treat advanced pancreatic cancer. Most importantly, the laboratory studies our team will be conducting using ACP-196 in animal models will help inform our clinicians which patients are most likely to benefit from combination therapies that incorporate ACP-196. If successful, our proposal will entirely change the paradigm as to how we treat patients with advanced pancreatic cancer within the next 5 years. How will the success of our proposal benefit active duty members and their families? Numerous studies have shown an increased incidence of pancreatic cancer in our active duty and retired Armed Forces, which represents a confluence of numerous factors. For example, smoking and long-standing diabetes are both associated with a higher lifetime risk for pancreatic cancer. Unfortunately, smoking is quite prevalent in our active duty personnel, especially those on overseas tours of duty. Similarly, many of our Veterans, especially those of African American or Hispanic heritage, suffer from long-standing diabetes. Together, these factors have likely contributed to the higher pancreatic c
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610122
Entities
People
- Anirban Maitra
Organizations
- United States Army
- University of Texas at Austin