The past few decades have brought forth a renaissance in cancer research. New technologies and breakthrough findings have transformed how scientists and clinicians understand and diagnose the disease, and many cancer types are now treatable.
However, pancreatic cancer remains one of the deadliest forms of the disease. With symptoms such as weight loss, nausea, or back pain, it’s often detected only after cancer cells have spread to other parts of the body. And once identified, the tumors are incredibly complex and difficult to target with drugs.
Yale University’s Luisa Escobar-Hoyos, M.Sc., Ph.D., hopes to change this reality. The 2023 Pew-Stewart scholar’s pioneering research explores how a critical cellular process called alternative RNA splicing (AS) could be leveraged to combat this challenging cancer type.
This interview with Escobar-Hoyos was edited for length and clarity.
Most tumors arise when cells acquire mutations in two genes called KRAS and TP53. Pancreatic tumors have these same mutations, but that’s where the similarities end. While most tumors develop resistance to treatment by developing additional mutations, pancreatic cancers don’t commonly acquire new mutations—yet they still develop resistance to drugs.
Pancreatic cancer has behaved like a black box in the clinic, meaning that every effective therapy we use for similar tumor types in other cancers has not worked in pancreatic cancer.
One reason is that pancreatic cancer cells are hard to reach anatomically. And the tumors themselves are extremely complex. Only 10% of the tumor’s mass is made up of cancer cells, which are embedded throughout a variety of noncancerous cells. Not only is this a physical barrier—because it prevents immune cells or drugs from reaching cancer cells—but chemically, all these different cells secrete particles that make the tumor a very hostile environment for any therapies to work effectively.
It depends on when the disease is diagnosed. Roughly 15% of pancreatic cancer patients are diagnosed when the tumor is still confined to the pancreas, so they’re often eligible for surgery. Unfortunately, the remaining 85% of patients are diagnosed with systemic disease, meaning that the cancer has spread to other parts of the body. Therapeutic options for these patients are very limited. We use two chemotherapies palliatively, which have been around for decades, but they don’t cure the disease.
Exactly. The mystery behind how pancreatic tumors develop drug resistance led me to think there must be another pathway or mechanism used by these cells to become so aggressive. This brought me to alternative RNA splicing (AS).
AS is an intermediate step between transforming genetic information from DNA into proteins. RNA splicing is a process where noncoding regions (introns) are removed, and protein coding regions (exons) are joined together to produce mature RNAs that will give rise to proteins. With AS, different combinations of exons can be spliced together, leading to the production of multiple RNA variants and proteins from a single gene, which can allow cells to adapt.
When I was just starting my postdoctoral training, new studies were demonstrating that the most aggressive and therapy-resistant pancreatic tumors were all diagnosed the same way. Yet some had better responses to chemotherapy than others. The tumors that didn’t respond well were increasing the production of certain proteins involved in the pathway of RNA splicing. This gave me the first inclination that AS was a potential mechanism these cells were using to overcome treatment.
That through AS controlled by the TP53 gene, the KRAS mutation was fully unleashed. This was the first scientific evidence for how these two critical mutations cooperate at a molecular level, and it also opened an opportunity to target splicing to treat the cancer by hitting both mutations at once.
Yes, we developed a technique in the lab called Splicing-Hit Oligonucleotide Therapy, or SHOT. This technique allows us to precisely manipulate or “hide” certain sequences within RNA. Then, when AS occurs, we force the cells to produce the “good” form of the protein rather than proteins that fuel tumor growth.
We started this conversation by saying that it’s so hard to bring any given therapy to these tumors because they’re hard to reach. So even if we have the most beautiful SHOT that works in the lab, we still face this challenge of bringing SHOT to the tumors in patients.
We’re exploring this through a collaboration with another lab at Yale. Together, we’ve modified a lupus-derived antibody that can penetrate cells and deliver RNA directly into pancreatic tumors. We’re super excited because this could revolutionize the way that we use RNAs as drugs for tumors; we even launched a company so other scientists can use this delivery platform in their own research.
I really want to cure this disease. I feel that we’re getting to an exciting point for pancreatic cancer treatment: In my lab alone, we’re making a few targeted therapies that we’re bringing to phase one clinical trial testing. I think we’re going to make a breakthrough soon, and I’m excited to see how this is going to change the reality for the many patients and families navigating this incredibly challenging disease.