Elucidating Mechanisms of Rapid Metastatic Recurrence in Pancreatic Ductal Adenocarcinoma
Abstract
Pancreatic cancer is an aggressive malignancy that resists treatment. Only 1 in 5 cases is able to be surgically treated, but even after surgery, around one-third of patients have a recurrence within 6 months of their operation. Often, this is understood as the nature of the disease, but on a biological level, there is little that we know about why people recur rapidly. Our study seeks to understand why pancreatic cancer can return in the liver so quickly after surgery. This project aligns with the FY21 PCARP Focus Area Understanding the events that promote pancreatic cancer metastasis in several impactful, and innovative ways. We have created a new mouse model of pancreatic cancer that recapitulates human progression of the disease, yielding many insights and resources for studying pancreatic cancer and pancreatic cancer metastasis. Second, from this work, we have identified, in a robust patient dataset illuminated by primary tumor sequencing, that the cancer-driving master regulator MYC is involved in rapidly recurrent pancreatic cancer. Third, and perhaps most groundbreaking, is that we have utilized resources derived from our mouse model to develop ways to simulate rapid pancreatic cancer recurrence after surgery. Because human specimens are far and away mostly from the surgical specimen, there is a real lack of tissues available for analysis of rapidly metastatic pancreatic cancer. This contributes to the innovation and impact of our model and proposed study. We intend to carry out investigations into the gene and protein expression profiles of tumor cells and surrounding cellular compartments from rapidly recurring patients as compared to long-term non-recurrers, ultimately generating a gene signature that may be useful in directing treatment of patients with pancreatic cancer. We will also analyze systemic biomarkers for differences between these patient populations. We will use our novel mouse model to identify gene signatures of metastasis and to understand the effects of surgical intervention on circulating biomarkers of cancer. Finally, we will test proposed therapeutic interventions to intercept rapid recurrence. Our Center is well-positioned to support our proposed work, with a critical mass of experts working to understand and target this devastating disease. We are submitting this proposal for a partnering investigator award, combining the expertise of a distinguished cancer biologist in Dr. Sears with the clinical acumen and questions raised by Dr. Worth, a surgical oncologist. While the question, model, and resources highlight the innovative nature of this proposal, we also believe that our collaboration supports additional levels of impact and innovation. Better understanding of why pancreatic cancer sometimes returns with a vengeance in the liver would not simply provide insight into that disease but would potentially describe a novel paradigm for targeting oncologic problems associated with surgery and stratifying patients based on their risk of failing surgical treatment (as early metastatic recurrences are considered failures, i.e., surgery does no good). Our results may alter the way in which we select patients for pancreatic cancer surgery and potentially other malignancies treated by surgery. Our aim is to identify therapeutic targets for preventing rapid recurrence, thereby making surgical intervention more effective, improving outcome for this patient group, and extending the survival time post-surgery to allow more quality time for the patient and opportunities for additional life-extending treatments. Rapid recurrence is one of the more nihilism-inducing events for patients, providers, and families caring for patients with pancreatic cancer. Our goal to more deeply understand the biology of what may cause rapid recurrence has the potential to advance treatment that will reduce this devastating occurrence, and provide some nidus of hope for individuals, veter
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210711
Entities
People
- Patrick J Worth
Organizations
- Oregon Health & Science University
- United States Army