Cancer Research and Discoveries

Pancreatic ductal adenocarcinoma (PDAC) — the most common form of pancreatic cancer — is projected to be the second leading cause of cancer-related death in the United States, with an overall five-year survival rate of less than 9%. Patients are often diagnosed in late clinical stages and are seldom eligible for surgery, since the disease has already spread throughout the body. 

As a result, most cases are predominantly managed through chemotherapy, which improves survival, though nearly all tumors have or will develop some degree of drug resistance. Therefore, median survival remains low — 6 to 12 months.

“Immunotherapy has revolutionized cancer treatment in the last decade, and strategies to re-activate anti-tumor immunity are now standard of care in several malignancies,” according to Dr. Rana. “Despite the rapid progress for immunotherapy in most solid cancers, progress for immunotherapy in PDAC has been exceptionally difficult. Pancreatic tumors are poorly immunogenic, with diminished antigen presentation and a highly immunosuppressive tumor microenvironment. As a result, immunotherapies such as immune checkpoint inhibitors have yet to show clear efficacy in the treatment of pancreatic cancer.”

Gemcitabine, a chemotherapy agent first approved by the Food and Drug Administration for pancreatic cancer in 1996, is now used in combination with albumin-conjugated (nab) paclitaxel as a first-line treatment option for metastatic PDAC. Gemcitabine-based chemotherapy was considered the only effective treatment for PDAC patients until 2013, when the FDA approved the multidrug FOLFIRINOX (folinic acid, 5-fluorouracil, irinotecan and oxaliplatin) regimen, which is also widely used in treating metastatic PDAC. The treatment approach shows “superior efficacy but has a high rate of serious adverse effects,” he said.

“While both regimens offer a modest survival benefit to the majority of patients, nearly all will eventually progress on treatment,” Dr. Rana explained. “With no FDA-approved third-line medications, patients who progress on these treatments are eventually provided only symptomatic or hospice care. As such, there is an urgent clinical need to identify novel therapeutic approaches for patients in the second- or third-line setting.”

To identify an effective treatment strategy for patients who have exhausted all current treatment options, Dr. Rana, along with Daniel Principe, MD/PhD student at the University of Illinois at Chicago, explored how long-term care with gemcitabine alters the PDAC tumor microenvironment. 

Using a combination of transgenic mouse models, primary cell line-derived xenografts and established cell lines, they discovered that long-term treatment with gemcitabine-based chemotherapy enhances the presentation of tumor antigen, thereby allowing tumor cells to become more easily recognized by cytotoxic T-cells.

Through these experiments, Dr. Rana’s laboratory also discovered that long-term treatment with gemcitabine-based chemotherapy increases the expression of negative immune checkpoints such as PD-L1, a protein that inhibits the effector function of cytotoxic T-cells by binding its receptor (PD-1). Gemcitabine treatment also enhanced the biosynthesis of the soluble immunosuppressant transforming growth factor beta (TGFβ), which cooperates with PD-L1 to help tumor cells escape immune surveillance despite the increased presentation of self-antigen.

“Combining gemcitabine and anti-PD-1 treatment in genetically modified mouse models of PDAC failed to alter the course of the disease unless the mice also underwent genetic or pharmacologic ablation of TGFβ signaling,” Principe said. “In the setting of TGFβ signaling deficiency, gemcitabine and anti-PD-1 led to a robust anti-tumor immune response, with a corresponding decrease in tumor burden, which markedly enhanced overall survival.”

These results suggest that gemcitabine successfully primes PDAC tumors for immune checkpoint inhibition by enhancing antigen presentation, only following the disruption of the immunosuppressive cytokine barrier.

“Given the lack of third-line treatment options, this approach warrants consideration in the clinical management of gemcitabine-refractory PDAC,” Principe said.

Dr. Rana and Principe were assisted in the research by:

• Matthew Narbutis, Sandeep Kumar, Alex Park, Navin Viswakarma, Matthew Dorman, and Paul Grippo, the University of Illinois College of Medicine
• Suneel Kamath and Hidayatullah Munshi, Feinberg School of Medicine, Northwestern University
• Melissa Fishel, Indiana University School of Medicine
• Rosa Hwang, MD Anderson Cancer Center
• Dinesh Thummuri, Patrick Underwood, and Jose Trevino, University of Florida
• Jesse Brown VA Medical Center, Chicago (Rana is also affiliated with the Jesse Brown VA Medical Center.)

The work was supported by Veterans Affairs Merit Award I01BX002703 and Career Scientist Award IK6 BX00485 to Rana, by NIH F30CA236031 to Principe, and by NIH R01CA217909 and Veterans Affairs Merit Award I01BX002922 to Munshi.

According to the American Cancer Society, Ovarian cancer ranks fifth in cancer deaths among women in the US. Additionally, it accounts for more deaths than any other cancer of the female reproductive system. A woman’s risk of getting ovarian cancer during her lifetime is about one in 78, while her lifetime chance of dying from the disease is about one in 108. (These statistics don’t reflect low malignant potential ovarian tumors).

In the University of Illinois Cancer Center’s catchment area, Cook County, from the years 2013 to 2017:

• Ovarian cancer diagnosis rates were 11 out of 100,000 women. Of those, 11.8 per 100,000 were white women, while 11.1 per 100,000 were Black women.
• Ovarian cancer mortality rates numbered 7 per 100,000 women. Of those, 7.3 per 100,000 were white women, while 7.1 per 100,000 were Black women.

Emerging evidence indicates that high grade serous ovarian cancer (HGSOC) — the most common and deadliest form of ovarian cancer — begins in the epithelium of the fallopian tube. The tumors’ presence in the ovary suggests its primary spread to other organs throughout the body. 

Preliminary data compiled by Dr. Burdette identified that transplanting cells or tissues from one species to another — xenografting — near the ovary contributes to the aggressiveness of the disease. The tumor cells spread to the peritoneal organs, primarily the omentum.

“We believe that the biological problem of primary and secondary high grade serous cancer metastasis is partially caused by chemical communication between the cancer cells and the metastatic organ,” Dr. Sanchez said.

Employing mass spectrometry, Dr. Sanchez’s laboratory has enhanced 3D cell culture models derived from the fallopian tube and changed them so they can identify the communication that begins from the small molecules, known as metabolomics, during primary colonization of the ovary that spreads the cancer to the omentum, the sheet of fatty tissue that stretches over the abdomen. Several metabolites that enhanced high grade serous tumor migration, invasion, and adhesion to the ovary were identified through the technology.

Dr. Sanchez’s study will disclose the methods that allow the tumor cells in the fallopian tube epithelium to seize the stress hormone norepinephrine that is produced by the ovary to increase their ability to enter and cling to the reproductive organ during the initial spread of the disease. The research will be conducted using both mouse and human cell models derived from the epithelium, with the tumors being treated with beta adrenergic receptor antagonists to try and translate the findings that will provide a new way to block ovarian colonization.

By using proteomics in collaboration with co-investigator Stephanie Cologna, PhD, Assistant Professor of Chemistry at the University of Illinois at Chicago, Dr. Sanchez will also identify and describe a newly discovered protein that is secreted from tumor cells in the fallopian tube that are responsible for producing ovarian norepinephrine causing the attack and bonding of tumor cells, along with the genetic deletion of the protein from the fallopian tube’s epithelium. This will be used to study the role in ovarian colonization. 

The team will also build upon their existing technologies of 3D organ and tumor cell communication models and expand into secondary metastasis.

“We have now optimized our technology for co-culture of the omentum together with tumor cell models and have an inventory of metabolites that are unique and do not include norepinephrine,” Dr. Sanchez said. “Instead, a novel metabolite found to be produced in significantly more abundance when tumor cells were grown with the omentum corresponded to folate, the ligand for the folic acid receptor that is overexpressed in the tumor cells. Taken together, our innovative experimental approach will yield new pathways and targets tomitigate primary metastasis of high grade serous cancer to the ovary.”

This research was supported by Dr. Sanchez’s $1.9 million five year grant from the National Cancer Institute (ACC 19-214) to conduct her latest research on ovarian cancer.