Focal Adhesion Kinase: Can Adding Fibroblasts and C-X-C Chemokine Help With Suppression? Arsen Osipov MD
By Arsen Osipov, MD
In our study, we wanted to further investigate specific proteins in the tumor microenvironment of pancreatic cancer to understand their implications, particularly in a unique subset of patients. As we all know, pancreatic ductal adenocarcinoma is a very treatment-resistant tumor, and this is due to many mechanisms of resistance, mainly related to the tumor microenvironment, which is very dismal and immunosuppressive. One protein that our lab is interested in is focal adhesion kinase, a non-receptor protein tyrosine kinase that is abundantly expressed in multiple cell types in the tumor microenvironment of pancreatic cancer.
We have done a lot of work in our lab on this protein, which is considered a master regulator of the tumor microenvironment, in terms of both targeting it in preclinical models and in translational studies that we have ongoing here at Cedars. We wanted to look at the expression of this protein in cell types in two unique patient cohorts. The first cohort consists of typical pancreatic cancer patients who are generally treatment-resistant, but we have a very unique subset of what are called exceptional responders, who have very unique clinical responses.
We took surgical specimens from these two patient groups and evaluated the tumor microenvironment using a unique multiplex IHC technique to better understand the expression of cell types and specific proteins in the tumor microenvironment. We focused on focal adhesion kinase and showed that in exceptional responders, there was a significant decrease in FAK expression among numerous cell types, specifically in the fibroblast population.
We also looked at other potential proteins and showed that potentially targeting CXCR4 or chemokine type 4 receptor could be another synergistic strategy. Targeting both focal adhesion kinase and CXCR4 provides synergy for therapeutic response to both chemotherapy and anti-PD1 therapy. We wanted to see if the CXCR4 expression changed between the exceptional and non-exceptional responders, and we showed that CXCR4 was significantly decreased in exceptional responders compared to non-exceptional responders.
In line with our preclinical data, we showed that CXCR4, particularly in the granulocyte population, is decreased in mice that have good responses. We also showed a similar finding in human patients who have exceptional responses, where they also have decreased CXCR4 expression in CD66 positive granulocytes as well as tumor-associated macrophages, and that both the decrease in phosphorylated FAK and CXCR4 in the granulocyte were associated with exceptional clinical outcomes. We also noticed that the CD T-cell populations were shifted more towards those that were the grand MV phenotype in the same patients that had the decreased CXCR4 and phosphorylated kinase expression.
What is the standard of care for patients with pancreatic ductal adenocarcinoma?
The standard of care for pancreatic ductal carcinoma usually encompasses three treatment modalities: surgery, occasionally radiation, and cytotoxic chemotherapy. Surgery is an option that is not offered to many patients, even at the time of diagnosis. Usually, it is offered to about 20% of patients who are diagnosed with pancreatic cancer, which are the most resectable category. The other 30-40% of patients are in the middle category and require some form of chemotherapy with the potential for future surgery. Regardless, chemotherapy is always a part of the treatment, either preoperatively or postoperatively. For the large majority of patients, around 50%, who are diagnosed with stage 4 advanced disease, cytotoxic chemotherapy is the mainstay. There are really two backbone regimens: folfirinox and gemcitabine and paclitaxel. The third big weapon in our arsenal is clinical trials. There is a lot of research going on at Cedars-Sinai, as well as other major academic centers, looking at novel combinatorial approaches.
In our lab, one of our focuses is whether we can sensitize this tumor to immune therapy. Immune therapy has been the paradigm shift in multiple other cancers, such as non-small cell lung cancer or melanoma. But in pancreatic cancer, single or dual checkpoint inhibitors, by and large, haven’t shown promise. There hasn’t been any real good, great clinical efficacy. So the focus of this current project that we have is to present that, in these exceptional responses, these immunosuppressive cell populations are decreased. This really supports the other projects that we have that there’s a rationale that you have to modify the tumor microenvironment to make the tumor more sensitive to either immune therapy or even chemotherapy, for that matter. This project really does support our previous publication where we propose that targeting both FAK, as well as CXCR4, as a synergistic strategy to sensitize this tumor to checkpoint inhibition because we see that the exceptional responses and the shift of the CD8 cells really happen through CXCR4 and FAK. The way to decrease it in the exceptional patients is decreased by the near nature of their cell biology.
But how do you emulate that in the non-exceptional patients? The way to do that is by actually targeting these specific proteins. So we are in the process of developing clinical trials that target both focal adhesions and CXCR4 to modulate the immunosuppressive tumor microenvironment, decrease these fibroblasts that express FAK, and decrease the granulocytes that express CXCR4 to emulate those exceptional responses in the non-exceptional patients.
What are the most common questions you are asked about the focal adhesion kinase study?
One question that is commonly asked, and that we alluded to earlier, is how can you apply the translational outcomes that you find from exceptional and non-exceptional responders to future prospective patients? That generally falls into the bucket of non-exceptional response. My answer to that specifically is that we are showing that the decreased expression of focal adhesion kinase, as well as CXCR4 expression in granulocytes, leads to an association with better clinical outcomes. The way to translate that for future prospective patients is to design clinical trials that specifically target these proteins in conjunction with other agents that we believe can increase clinical response, whether it’s chemo or ideally checkpoint inhibitors. If you’re able to modulate immunosuppressive cells, the goal is that you’ll have an increase in the CD8 population or ideally more effector type CD8 T-cells to be able to exert an anti-tumor effect. That’s the way I think this data can be applied for the future.
Another common question that comes up is colleagues say that there are current studies, some of which we are investigating and running these clinical trials where we are actually targeting focal adhesion kinase, and they’re asking us about what we are seeing. We have some data that will soon be presented at the ASCO annual conference this year, looking at some of the translational data of an ongoing clinical trial where we target focal adhesion kinase through a small molecule inhibitor with immunotherapy with anti-PD-1 antibody with pembrolizumab. So that data will be important and forthcoming at the ASCO annual conference this year, which will be presented. They’ll be able to answer that question about what we are actually seeing happen to patients who are treated with one of the targets that we discuss in the current project with the FAK and CXCR4 and exceptional responders.
What is the next step for this focal adhesion kinase research?
In this project, what we’ve done is we’ve looked at two very specific biomarkers or proteins that are of interest to our lab because they’re mechanisms by which we’re targeting the TME. The next step is actually to fully analyze the tumor microenvironment, looking at multiple other proteins, multiple other cell types. For example, we’re going to be looking at the regulatory cells. We are going to be looking at other immunosuppressive myeloid cells. We are going to be looking at dendritic cells, other players in the TME that may have an impact on response, and seeing how those cell populations change along with other proteins of interest that may be identified as decreased or increased in the exceptional patient cohort.
These are both hypothesis-generating and also give us insight into current approaches that we have with targeting the tumor microenvironment as a strategy to overcome resistance. So we’re going to be doing further multiplex IHC in a larger cohort of patients. In the current study that we had, we used 40 biomarker specimens, and we only reported on data of some of the biomarkers. We’re going to report on the rest of the biomarkers, and we reported on 20 patients. We will be expanding this to closer to 50 patients in the subsequent expansion of the project.
Did anything surprise you or that you found exciting about this focal adhesion kinase study?
I really do find it exciting that just even one year, less than a year ago, we published a great preclinical project and a model of metastasis for pancreas cancer. When we were investigating, actually beyond targeting focal adhesion kinase, is there another dual stromal targeting strategy that leads to better outcomes? Even in that publication that was in gastroenterology in 2022 by our group, we showed that actually CXCR4 in mice that are treated with stromal targeting is decreased in the neutrophil population and that leads to improvement in survival of the mice. We knew that this was a protein of interest, particularly in the granulocyte population. What’s interesting is that later on, we go back and analyze these exceptional human responders, and we see that again, CXCR4 is a very relevant protein/target in the neutrophil population in human patients that have great responses. So it is just another kind of affirmation that the pathway and what we’re thinking is accurate and requires further investigation, i.e. in the sense of a clinical trial, which we are working on developing currently.
Is there anything you would like to add in closing about the focal adhesion kinase study?
Just add that this type of research, conducted by our group and other groups throughout the country, is essential to truly advance translational science. In other words, taking the information we’ve learned from the bedside and confirming findings in the lab which were initially discovered at the bench site, is a hallmark of future success. This approach moves the needle of science forward. We are very happy and proud of the research that’s going on here, as well as with our colleagues. We believe that this pathway not only goes from the bench side to the bedside, but also often involves going backwards to confirm our findings. This approach helps propel the clinical development of novel targets, and we’re excited about it.
What is phosphorylated focal adhesion kinase + fibroblasts and C-X-C chemokine receptor type 4 expressing granulocytes in pancreatic ductal adenocarcinoma?
Pancreatic ductal adenocarcinoma (PDAC) is a type of cancer that originates from the cells lining the ducts of the pancreas. In PDAC, there are certain molecules that are present in abnormal amounts, leading to the progression of the cancer.
One such molecule is the phosphorylated focal adhesion kinase (p-FAK). FAK is a protein that helps cells to attach to their surrounding environment, and when it is phosphorylated (modified by the addition of a phosphate group), it becomes more active. In PDAC, the levels of p-FAK are increased, which may help cancer cells to migrate and invade other tissues.
Fibroblasts are a type of cell found in connective tissue that play a role in wound healing and tissue repair. In PDAC, fibroblasts can also contribute to the progression of the cancer by secreting molecules that promote the growth and invasion of cancer cells.
C-X-C chemokine receptor type 4 (CXCR4) is a protein kinase that is expressed on the surface of certain immune cells called granulocytes. CXCR4 helps granulocytes to migrate to areas of the body where they are needed to fight infections or other threats. However, in PDAC, cancer cells can secrete molecules that attract CXCR4-expressing granulocytes to the tumor. Once at the tumor, these granulocytes may actually help the cancer to grow and spread.
Overall, the presence of p-FAK, fibroblasts, and CXCR4-expressing granulocytes in PDAC all contribute to the progression of the cancer by promoting invasion and growth of cancer cells.
10 Key Takeaways from the Focal Adhesion Kinase Clinical Trial
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The suppression of phosphorylated focal adhesion kinase (pFAK) and fibroblasts is linked to exceptional clinical outcomes in pancreatic ductal adenocarcinoma (PDAC).
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The study also showed that C-X-C chemokine receptor type 4 (CXCR4) expressing granulocytes play a significant role in the development of PDAC.
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FAK is a protein that helps cells adhere to their surroundings and is overexpressed in many cancers, including PDAC.
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Fibroblasts are cells that produce collagen and other extracellular matrix components and contribute to tumor growth and progression.
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The study found that patients with lower levels of pFAK and fibroblasts had significantly longer overall survival and progression-free survival.
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CXCR4 is a receptor protein found on the surface of certain immune cells and is involved in the cell migration and homing of these cells to active sites of inflammation and cancer.
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The study demonstrated that CXCR4-expressing granulocytes are present in high numbers in PDAC tumors and contribute to the tumor’s growth and metastasis.
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Targeting pFAK and fibroblasts or CXCR4-expressing granulocytes may be a promising approach for PDAC treatment.
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The findings suggest that combining therapies that target both pFAK and CXCR4 may have a synergistic effect and improve treatment outcomes.
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Further research is needed to fully understand the role of pFAK, fibroblasts, and CXCR4-expressing granulocytes in PDAC and to develop effective therapies that target these components.
Arsen Osipov, MD – About The Author, Credentials, and Affiliations
Arsen Osipov, MD is a medical oncologist who specializes in gastrointestinal cancers. He is the Program Lead for the Cedars-Sinai Pancreas Cancer Multidisciplinary Clinic and Precision Medicine Program. In addition, he works as a clinical-translational investigator for the Gastrointestinal Disease Research Group and Pancreas Cancer Research Group at the Samuel Oschin Cancer Center at Cedars-Sinai.
Dr. Osipov’s approach to his work is multidisciplinary, which means he collaborates with colleagues from different medical fields, such as hepatobiliary surgery, gastroenterology, radiation oncology, radiology, and basic science. By doing this, he hopes to improve scientific discovery and patient care. Dr. Osipov’s research focuses on finding ways to use immunotherapy to treat pancreatic cancer, which could potentially lead to better treatment strategies and outcomes for patients with this disease.
Cedars-Sinai – About the Company
The Gastrointestinal Disease Research Group and Pancreas Cancer Research Group are two research teams based at the Samuel Oschin Cancer Center at Cedars-Sinai in Los Angeles, California. These groups are focused on advancing the understanding of gastrointestinal diseases, with a specific focus on pancreatic cancer.
The Gastrointestinal Disease Research Group is dedicated to studying a wide range of gastrointestinal disorders, including inflammatory bowel disease, colorectal cancer, and pancreatitis. The team of researchers, led by Dr. David Dawson, utilizes a multidisciplinary approach to develop novel diagnostic and therapeutic strategies to improve patient outcomes.
The Pancreas Cancer Research Group, led by Dr. Andrew Lowy, is specifically focused on pancreatic cancer, which is one of the deadliest forms of cancer. The team is dedicated to advancing the understanding of this disease and developing new treatments that can improve patient outcomes. The group has made significant progress in developing new diagnostic tools and identifying potential therapeutic targets.
Both of these research groups collaborate closely with other departments and teams at the Samuel Oschin Cancer Center, as well as with other leading institutions and experts around the world. Their work is funded by a combination of grants and private donations, and they are committed to making a real impact on the lives of patients with gastrointestinal diseases and pancreatic cancer.