A team of investigators at Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine has shown for the first time that a combination of targeted therapies with immunotherapy addresses one of the major reasons pancreatic cancer is so notoriously treatment resistant.
Their laboratory findings, published recently in the high-impact journal Gastroenterology, are so compelling that the authors have started a clinical trial in humans who have treatment-resistant pancreatic cancer.
Pancreatic cancer is one of the most resistant cancers to any type of treatment. One of the reasons for this is that the scientific community has been unable to target one of its key genetic mutations, called KRAS."
Nipun Merchant, M.D., study senior author and founding director of the newly established Sylvester Pancreatic Cancer Research Institute
Until now, clinical trials of other targeted therapies that involve the KRAS pathway haven't succeeded because the cancer has outsmarted previous attempts, according to Dr. Merchant, a surgical oncologist.
"When you target a certain pathway in pancreatic cancer, other pathways get activated, rendering the treatment ineffective," Dr. Merchant said.
A Complex Picture
In the case of KRAS, Sylvester researchers have discovered a key resistance mechanism that can overcome a lot of the resistance associated with targeting KRAS and its downstream effectors.
But there's more to this complex picture in pancreatic cancer's treatment resistance. Pancreatic tumors are comprised not only of cancer cells but also of stroma, a dense, fibrous scar-like tissue.
"At first, scientists thought it was scar tissue that prevented drugs from getting into the tumor. So efforts were made to try and eliminate the stroma to enhance drug delivery to the tumor," Dr. Merchant said. "However, this actually resulted in making the tumors more aggressive."
Over the last several years, researchers have come to recognize that stroma is a very dynamic and heterogenous component of the tumor, with many different functions.
"It has distinct states that can either promote tumor growth or have protective effects," Dr. Merchant said.
Promising New Approach
The novelty of Sylvester's research paper is that investigators have shown that a combination of two targeted therapies, MEK and STAT3 inhibitors, overcomes the resistance to KRAS and alters the tumor microenvironment, reprogramming it to repress the stromal subpopulations that promote tumor growth and resulting in the reemergence of stromal cells that actually help restrain the tumor.
Furthermore, this modulation decreases the immunosuppressive cells in the tumor microenvironment and facilitates the action of immunotherapy drugs such as programmed death-ligand 1 inhibitors which are otherwise ineffective in pancreatic cancer treatment.
This approach has been so promising in the lab that Sylvester Pancreatic Cancer Research Institute researchers have accomplished something that few cancer centers have achieved, according to lead author and Sylvester surgical oncologist Jashodeep Datta, M.D.
"There are few groups in the country that can take work that is done in the laboratory and actually translate that to patients in clinical trials," Dr. Datta said. "These clinical trials are called investigator-initiated trials; they're not industry-sponsored. Rather, they are funded based on the strength of the science."
'We're Unraveling Some of the Mysteries'
To achieve the level of nuance and sophisticated analysis to look at different sub-compartments of the stromal cells, Sylvester used cutting-edge technology including single cell RNA sequencing and single cell mass cytometry.
"These technologies allowed us get to the subcellular resolution in pancreatic tumors, so we could understand the specific cells that were causing these changes in terms of the immune effect as well as the stromal related effects," Dr. Datta said. "In doing so, we're unraveling some of the mysteries that have been plaguing us in this disease."
Study co-author and medical oncologist Peter J. Hosein, M.D., co-leader of Sylvester's Gastrointestinal Cancers Site Disease Group, is leading the human trial at the Sylvester Pancreatic Cancer Research Institute.
"Pancreatic cancer quickly develops resistance to almost every therapy -; chemotherapy, targeted therapy, and especially immunotherapy," Dr. Hosein said. "A big part of the movement in the field has been to turn pancreatic cancer from an immunotherapy-unresponsive tumor to one in which patients get a lasting response from these promising options.
"We believe that sensitizing the tumors to immunotherapies by manipulating the tumor microenvironment and understanding this at a molecular level is really going to be the next frontier in this disease," Dr. Hosein said. "As a referral center, we get frequent calls for patients with advanced pancreatic cancer who have run out of standard treatment options, and we are excited to be able to offer this novel therapy to those who qualify in the context of this trial."
Datta, J., et al. (2022) Combined MEK and STAT3 Inhibition Uncovers Stromal Plasticity by Enriching for Cancer-Associated Fibroblasts With Mesenchymal Stem Cell-Like Features to Overcome Immunotherapy Resistance in Pancreatic Cancer. Gastroenterology. doi.org/10.1053/j.gastro.2022.07.076.