Pancreatic cancer is notorious for its rapid clinical course. It’s highly aggressive, invasive, and after metastasis, is nearly always fatal. Most patients will die within a year of diagnosis. Treatment options are limited, largely because the molecular pathways driving the disease are still unknown. This has stalled development of pharmacological inhibitors; targeted therapies are all but absent from any pancreatic cancer treatment plan, because they don’t exist.

Dr. Jason R. Pitarresi has devoted the majority of his career to understanding the genetic landscape of pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer. In his new paper just published in Cancer Discovery, he and his team identified a previously unappreciated oncogene that appears to play a role in driving PDAC metastasis, and could, they hope, serve as a therapeutic vulnerability. I sat down with him to talk more about this incredibly exciting finding.

Rachel: Can you tell us a little about your research background?

Dr. Pitarresi: I began my research career when I was 17, in a lab at Roswell Park Cancer Institute in my hometown of Buffalo, NY and have continued my immersion in cancer research throughout my undergrad, grad school, and postdoctoral training. As a Research Associate at the University of Pennsylvania, I am now studying how PDAC evolves over time, with a primary focus on the PTHLH gene’s role in tumorigenesis and metastasis. My ultimate goal is to become faculty at a leading academic research institute and start my own cancer biology lab.

R: As you discuss in the paper, pancreatic cancer is well known for quickness to metastasize and high mortality rate. Can you talk about the unique traits that make it so deadly?

Dr. P: There are a few reasons, but the most often evoked is the fact that it is hard to detect early on, with the majority of patients presenting with metastatic disease. Moreover, my mentors showed in seminal work nearly a decade ago that pancreatic cancer can actually begin to metastasize at very early stages of disease progression.

I have spent a good portion of my postdoctoral training trying to uncover novel drivers of the metastatic cascade in this disease, to hopefully lead to new therapeutic strategies. We hope that the anti-PTHrP monoclonal antibodies used in the study might be an efficient way to block metastases in PDAC patients and are continuing to test this hypothesis in pre-clinical models of pancreatic cancer.

R: You decided to narrow in on PTHLH as a potential oncogene, and found that its deletion “…delays primary tumor growth, reduces metastatic colonization, and increases overall survival.”

In other words, you found a new PDAC oncogene and were able to verify its cancer-causing mechanisms. These are major findings with definite clinical implications. Were you surprised by the significance of your findings?

Dr. P: We were quite surprised by the ability of PTHrP (the protein encoded by the PTHLH gene) to enhance tumor growth as well as epithelial-to-mesenchymal transition (EMT). One subtype of PDAC, called the squamous subtype, appears to be more aggressive than the others. Previous studies had identified PTHLH as a squamous lineage gene that may be important for defining the squamous subtype, but did not delete or inhibit the gene to show its potential roles.

At the same time, others were demonstrating that amplifications of KRAS often correlated with more metastatic disease in PDAC patients. Once we discovered that PTHLH was co-amplified along with KRAS, it was natural to link the pro-metastatic phenotype of the KRAS amplicon with the more aggressive squamous subtype potentially brought about, in part, through PTHrP—and we set about performing functional experiments to confirm these ideas.

In this way, we were able to establish oncogenic and pro-metastatic traits for PTHLH and we then performed anti-PTHrP antibody therapy experiments to test the potential for this as a new therapeutic agent. Using a combination of mouse models and 3D patient-derived organoid systems, we were able to show that we can block PDAC growth at the cellular level and also block the ability of cells to enter into the metastatic cascade.

R: “In a broader sense, we have uncovered a targeted therapeutic vulnerability that emerges from amplification of a “passenger” oncogene and offer a new paradigm to look at genes in close proximity to other commonly amplified oncogenes.”

Can you expand on the importance of this approach – investigating neighboring “passenger” genes of major oncogenes to see if they’re playing their own role in disease development?

Dr. P: PTHLH was initially thought to be a passenger gene that undergoes amplification along with KRAS, thus it was assumed to have no functional roles in the disease. Instead, we describe a phenomenon called collateral amplification, whereby a supposed passenger gene, PTHLH, is shown to have oncogenic and pro-metastatic functions during PDAC progression brought about by its co-amplification with a known driver oncogene, KRAS.

This phenomenon is something that may be more broadly applicable across different cancers and is something we are currently investigating. Specifically, there are other cancers that are known to harbor KRAS amplifications—such as colorectal, lung, and breast amongst others—and the efficacy of anti-PTHrP therapy in these settings is something we are very interested in. On a more global scale, genes that are adjacent to other oncogenes that are known to be amplified should also be examined.

R: What do you hope other researchers and clinicians take from your study? Do you have any plans to follow up on it yourself?

Dr. P: We hope that basic scientists and clinicians can appreciate the wholistic approach that we tried to take with this story. We identified two seemingly unrelated clinical phenomena—(i) PTHLH is a marker of the squamous PDAC subtype and (ii) KRAS amplicons are potential drivers of metastasis in PDAC—and married them to show that one observation may be explained by the other. We followed up on this hunch and performed the functional studies in the most applicable model systems that we could. This bedside-to-bench and back again approach is something we often strive for and are excited by studies like this where the experimental evidence we provide is able to answer a clinical need.

We have plans to follow-up the research through some newly launched spin-off projects in the lab. The obvious experiments are further characterization of signaling networks downstream of PTHrP that might uncover new nodes of regulation in the pathway, hopefully leading to new windows of opportunity for novel therapeutics.