Georgios Karagkounis, MD receives 2022 SSO Topic-Specific Young Investigators Award

The Society of Surgical Oncology (SSO) has awarded more than $150,000 to eight researchers through its Young Investigators Award (YIA) since 2016 when the first grant was awarded. This funding is intended to promote and recognize translational or clinical research that supports innovative ideas and concepts to improve health outcomes through advances in cancer care. The SSO Research and Education Fund, a restricted fund of the former SSO Foundation, supports the Society’s research grant program. This year, two $25,000 awards were given for one year, beginning April 1 of the award year and concluding March 31 of the following year. 2022 Award recipients were recognized in March at the SSO annual meeting in Dallas, where Georgios Karagkounis, MD was recognized for his research in gastrointestinal oncology. His proposal, the Role of Peritoneal Mesenchymal Cells in Promoting Appendix Cancer Peritoneal Dissemination and Treatment Resistance, was supported by a grant from the Appendix Cancer Pseudomyxoma Peritonei Foundation. SSO recently spoke with Dr. Karagkounis about his study.

Q. Tell us a little about your background, training, and area of specialization.

A. I completed my residency in general surgery at the Cleveland Clinic in Ohio and followed that with a fellowship in complex general surgical oncology at Memorial Sloan Kettering in New York. Currently I am in my first year of practice at the University of Texas Southwestern Medical Center in Dallas. My focus is on metastatic colorectal cancer and peritoneal surface malignancies, which involves the management of peritoneal carcinomatosis arising from different primary sites and the administration of intraperitoneal chemotherapy.

Q. How did you arrive at that topic?

A. Peritoneal carcinomatosis has always been a devastating stage of progression for gastrointestinal tumors. Typically, it has been viewed as a uniformly fatal end-stage disease for which palliative care was all we could offer. Over the past few decades, we have seen that a more aggressive treatment plan makes sense in terms of prolonged life and, in select cases, achieving a cure. Seeing these patients in my clinic and having the privilege of caring for them has increased my passion and commitment to find better treatment options. This particular study investigates the progression of appendiceal adenocarcinoma into peritoneal carcinomatosis.

While so much effort has been focused on addressing primary gastrointestinal cancers (e.g. primary colorectal or pancreas cancer), or  their liver metastasis, peritoneal carcinomatosis by itself has been less investigated. We don’t have as clear an understanding of what causes these tumors to spread within the abdominal cavity. We don’t really understand how best to address this phenomenon and which mechanisms we can leverage.

Appendix cancer is rare, and primarily metastasizes via peritoneal spread. Within this context, we can better understand the phenomenon of peritoneal spread with less intereference by disease spread via blood to the liver or lung. For this reason, I thought studying appendix cancer would be helpful as a focused platform to understand carcinomatosis.

My study focuses on peritoneal carcinomatosis of appendix cancer with a particular emphasis on how those cancer cells recruit the mesothelial cells that line the peritoneal cavity as they spread from the appendix. These cells play a supporting role in tumor growth, and we want to better understand how that happens. Secondarily, we want to figure out if there is a way to target that process to starve that cancer and deprive it of an important source of support.

Q. Are you exploring specific immunotherapy agents or other chemotherapy as you move forward with your targeting process? What does that look like?

A. That’s a great question. Perhaps down the line this is something we can explore. For now, we are focused on how a cancer cell migrates from the appendix– or from any GI adenocarcinoma—and attaches to the peritoneal cavity. From there the cell sends specific signals that convert the mesothelial cells into a subset of fibroblast that then supports the tumor. Our team has found a specific trait of those fibroblasts, which may potentially stimulate the immune system. However, for the time being, we are focused on interrupting communication between the cancer cells and the mesothelial cell fibroblasts by inhibiting the cytokines the cancer cells secrete to convert the mesothelial cells into cancer-associated fibroblasts.

Q. Were there pivotal studies or was it a lack of understanding that led you to pursue this research?

A. It was both. It was always my intent to focus on understanding peritoneal metastasis originating from gastrointestinal sources. Early on I was lucky to work with one of our scientists at UT Southwestern who discovered that, as pancreatic cancer cells grow, they recruit mesothelial cells and convert them into fibroblasts. Because the peritoneal cavity is entirely covered with mesothelial cells, we wondered if any metastatic cancer found in the peritoneal cavity could recruit these cells in a similar fashion to pancreatic cancer. Sure enough, we examined samples under the microscope and found that, the closer you are to the tumor, the more those mesothelial cells turned into fibroblasts. As one might expect, this dynamic weakens the farther one gets from the tumor.

Q. It sounds like you’re in the beginning stages of your study. How do you see your research evolving? What is your next step?

A. We’ve already come a long way in understanding what the microenvironment looks like for peritoneal metastasis, the role of mesothelial cells, and how they turn into fibroblasts. This is the first half of the study. The second half will leverage this interaction to enhance treatment or to target the peritoneal carcinomatosis tumors in vitro in the presence or absence of fibroblasts. Of course, we would like to expand this further into animal studies and clinical trials.

Q. Have you noticed anything unexpected so far?

A. Most of what we’ve seen so far has been consistent with our theory on how different cells recruit mesothelial cells to become fibroblasts. However, we have seen that this phenomenon is more pronounced among patients, or tumors, that have a more mucinous phenotype. We don’t have a solid understanding of this interaction yet, but we were surprised by this finding, and we will certainly look into it further.

Q. How do you think this research will help patient care in the future?

A. All of this only makes sense if we can translate it into something that helps patients. There are two outcomes that may help. The first is to better understand how these tumors, peritoneal metastases, and the microenvironment work so we can increase the efficacy of chemotherapy, immunotherapy, or any other treatment.

The bigger question is understanding certain key interactions between these populations and the cancer cells, one of which is interaction with cancer-associated fibroblasts. By identifying these key interactions and breaking them apart, we hope to inhibit disease progression. We might be able to leverage these targets after achieving complete surgical clearance, as an adjuvant therapy to keep the cancer from recurring, or as a palliative approach in patients with advanced disease whose cancers are not resectable. Ultimately, we would hope to slow down disease progression , extend the length of survival and improve quality of life.

Q. Is there anything else you want us to know?

A. Yes, I want to encourage my colleagues and aspiring surgeon-scientists to join the study of peritoneal carcinomatosis in order to improve care. To a certain extent this is an under-represented field of research. I would like to acknowledge my closest collaborator, Dr. Huocong Huang. He has been a wonderful friend and partner from the beginning. I’ve also been lucky to have senior mentors within our department and the support of our department chair, who have helped me. Our vice chair for research, Dr. Emina Huang, has been incredibly supportive from the beginning, so I’ve been blessed with a very supportive team. I also want to thank SSO and the Appendix Cancer Pseudomyxoma Peritonei Research Foundation for their generous support.

SSO’s research grant program is supported by the SSO Research and Education Fund, a restricted fund of the SSO Foundation. The availability of research grant funding is dependent upon the financial support of SSO members and donors. Please donate generously to ensure that SSO members have an ongoing source of funds for research projects. 100% of your donation supports this program.