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Massey researchers, led by principal investigator Chuck Harrell, Ph.D., member of the Cancer Biology research program at Massey and professor in the Department of Pathology at the VCU School of Medicine, will look to define what enables responses and resistance to ADCs in order to identify predictive biomarkers and establish therapeutic strategies to optimize TROP2-targeted ADC efficacy in both triple-negative breast cancer (TNBC) and pancreatic ductal adenocarcinoma (PDAC).  

Researchers have previously demonstrated that sacituzumab govitecan (SG), an FDA-approved TROP2-directed ADC, shows substantial activity in treating TNBC and has been given Orphan Drug Designation for PDAC studies.

What are Massey’s goals with this grant?

• Inform precision oncology
• Improve patient selection
• Guide rational clinical trial design to extend patient survival

“We hope to develop a mechanism where we can predict a patient’s drug response before even starting them down a treatment path,” said Harrell, who is also an assistant professor in the VCU School of Medicine. “We could develop a test to tell the patient ‘You don’t need this drug, but you definitely want to take this one.’”

“Additionally, if a patient isn’t cured from the initial drug treatment, we should be able to tell them a secondary drug they should immediately be treated with. We hope that the ADCs we create through this study can be used next if and when a tumor becomes resistant to the original ADC.” 

How will Massey researchers look to achieve those goals?

• Massey researchers will utilize a rigorously characterized panel of TNBC and PDAC patient-derived xenograft (PDX) and organoid (PDXO) models with integrated genomic, transcriptomic, and proteomic datasets to support mechanistic and translational studies.
• The research team will integrate multi-omic analyses with high-throughput drug response data.
• The studies will have three main research goals:
  • Identify proteogenomic biomarkers that predict SG sensitivity and resistance, enabling development of SG-PREDICTOR, a machine-learning tool for clinical prediction of ADC response.
  • Define cellular and molecular mechanisms of acquired resistance using SG-resistant PDX and PDXO models to uncover alterations in TROP2 expression, internalization, drug efflux, and DNA repair.
  • Test therapeutic strategies to enhance and prolong SG efficacy, including rational drug combinations and next-generation ADC payloads, with validation in lab tests.

Why does this grant matter?

• Breast cancer is the most common cancer in women in the United States besides skin cancers, per the American Cancer Society, accounting for about 1 in 3 new cancers in women each year.
• Triple-negative breast cancer is a type of invasive breast cancer in which the cancer cells don’t have estrogen receptors, progesterone receptors, or too much of the HER2 protein. TNBC tends to grow and spread faster than most other types of invasive breast cancer and has fewer treatment options.
• Pancreatic cancer accounts for about 3% of all cancers in the United States, per the American Cancer Society, and about 8% of all cancer deaths.
• Pancreatic ductal adenocarcinoma is the most common type of pancreatic cancer and is usually found at an advanced stage because it usually does not cause symptoms early on.

Co-Investigators on the grant are:

• Harry Bear, M.D, Ph.D., surgical oncologist and member of the Developmental Therapeutics research program at Massey, and professor in the VCU School of Medicine
• Mikhail Dozmorov, Ph.D., member of the Cancer Biology research program at Massey, assistant professor of Biostatistics in the VCU School of Public Health
• Jose Trevino, M.D., surgeon-in-chief, member of the Developmental Therapeutics research program, and Geoffrey R. Shudtz Chair in Pancreatic Cancer Research at Massey, and associate professor in the VCU School of Medicine

Additional VCU collaborators on this research include:

• Nina Dashti-Gibson, M.D./Ph.D. student
• Anna Gibson, M.D., surgeon and Ph.D. student
• Josh Haeuis, MS, research associate
• Dylan Hite, research associate
• Rachel Myrick, research technician
• Jadon Porch,D. student
• Jessie Tignor, Master’s student
• Carson Walker,D. student
• Dhanvin Yajaman, undergraduate researcher
• Emily Zboril, MS, Ph.D. student

Written by: Bill Potter