Cancer Drivers and Intrinsic Vulnerabilities

Pancreatic tumors are remarkably diverse in character and behavior, and patients’ responses to therapy may differ substantially. Developing effective, precise treatments will demand that we understand and control for these differences. We are seeking to understand the complex biology of pancreatic cancer at a cellular and molecular level. We also collaborate with our clinical programs, in order to provide a true bedside-to-bench (and back) infrastructure by obtaining serial blood, tumor samples, and research imaging throughout the course of a patient’s treatment.

A strong component of our research program is focused on understanding drivers and identifying novel vulnerabilities in pancreatic cancer for targeting. We also focus on generating patient-derived models that can be used to study the roles of these pathways in cells, animal models, and 3D bioprinting.  The ultimate goal is to move these studies into clinical trials.

Ongoing Research Projects

We also have strong research programs focused on the tumor intrinsic signaling pathways and gene regulation that promote pancreatic tumor growth and survival. 

Dr. Rosalie Sears has a long track record of discoveries in MYC biology and has led the efforts of its role in pancreatic cancer biology. Most recently, she showed that MYC is critical for aggressive spread of pancreatic cancer to the liver. Dr. Patrick Worth is investigating the importance of MYC in pancreatic cancer recurrence, after a patient has their pancreatic tumor surgically removed.

Dr. Jonathan Brody has developed a program studying an RNA binding, stress-response protein HuR. Through investigating this stress response pathway, Dr. Brody has identified WEE1, IDH1, PARG, and YAP1 as key targets in pancreatic cancer and is pursuing these druggable targets with pre-clinical, translational studies.

Dr. Jonathan Brody established this consortium in 2021 to create a shared resource of tumor samples, biospecimens, and clinical data from patients with BRCA 1/2 pancreatic cancer mutations. As these mutations are present in ~5% of tumors, creating a shared resource of specimens, patient-derived models, and knowledge will accelerate progress towards identifying resistance mechanism in these patients, identifying novel targets and therapeutic agents, and establishing multi-site clinical trials to test candidate therapies. This provides a powerful framework for collaboration that can be expanded to additional areas of focus for pancreatic cancer translational research.

Led by Dr. Charles Lopez, WOO is a precision oncology clinical and research program that uses comprehensive molecular and architectural analysis of individual tumors to assess how patients are responding to their targeted therapy treatment. The WOO trial is part of the Serial Measurements of Molecular and Architectural Responses to Therapy (SMMART) program designed to understand tumor heterogeneity and to develop targeted therapeutic approaches. Our researchers gain valuable information on therapy-induced tumor evolution, development of novel therapeutics, and resistance mechanisms in pancreatic cancer. Dr. Gordon Mills is the Director of SMMART Trials and Director of Precision Oncology at the Knight Cancer Institute.

  • Developing therapeutic screens on patient-derived samples – Rosalie Sears
  • Developing an improved replication stress assay for use in patient samples – Gordon Mills
  • Comparative patient-derived models of cancer: Correlation of genomic, transcriptomics, and IHC phenotyping from individual tumor specimens and paired patient- derived models – Rosalie Sears, Lisa Coussens, Emek Demir, & Jonathan Brody
  • Nanoparticle imaging and phototherapy in pancreatic cancer – Khashayar Farsad
  • Targeting the DNA repair enzyme, poly (ADP-ribose) glycohydrolase (PARG), for the treatment of pancreatic cancer – Jonathan Brody
  • Investigating the role of MYC, PIN1, and PP2A in pancreatic cancer progression, metastasis, and therapeutic resistance – Rosalie Sears
  • Investigating the mechanistic and therapeutic role of PIN1 in pancreatic diseases – Brett Sheppard & Vidhi Shah
  • Developing IHC/IF CLIA validated methods for pathway biomarker analysis and clinical decision support – Lisa Coussens, Koei Chin, Gordon Mills
  • Predictive markers for therapeutic response (PRECEPTS) – Emek Demir
  • Circulating hybrid cells as a marker of therapeutic response – Melissa Wong