Fox Chase Cancer Center Researcher Find New Treatment Targets in Microenvironment of Small Cell Lung Cancer

A study led by a researcher at Fox Chase Cancer Center provides new insights into the cellular composition and microenvironment — the noncancerous cells and molecules surrounding tumor cells — of small cell lung cancer. The research team also identified two cellular signaling pathways that play a significant role in the cancer’s aggressiveness.

The pathways show promise as potential targets for inhibitors to slow tumor growth and make the cancer more vulnerable to chemotherapy, said first author Parth A. Desai, MBBS, MD, an Assistant Professor in the Department of Hematology/Oncology at Fox Chase. He said the findings are especially significant because so little has previously been known about the disease at the cellular level.

“The tumor microenvironment has never been studied so closely in small cell lung cancer,” said Desai, who conducted the study with researchers from several other institutions, including Anish Thomas, MBBS, MD, of the Developmental Therapeutics Branch of the National Cancer Institute (NCI), part of the National Institutes of Health (NIH).

Small cell lung cancer is aggressive and has a high mortality rate. A major challenge in treating it is its cellular makeup — tumors are not uniform but are made up of different cell types. Cells also change their shape and function in response to chemotherapy drugs, helping the cancer evade treatment.

Compounding the problem is the fact that small cell lung cancer has historically been difficult to study. By the time the cancer is detected, many patients will no longer benefit from surgery, and so the tumors are never removed, causing a shortage of tumor samples for research.

For the new study, researchers obtained samples through the NCI’s rapid autopsy program, in which cancer patients choose to donate their bodies for research immediately after death. Prior to joining Fox Chase last year, Desai was a Clinical Hematology and Oncology Fellow at the National Heart, Lung, and Blood Institute within the NIH. Several NIH researchers collaborated with Desai on the study.

They examined samples from 36 small cell lung cancer tumor segments taken from 10 deceased patients and analyzed gene expression to classify different types of tumor cells. They identified two types of cells, high-neuroendocrine and non-neuroendocrine, that had previously been known.

However, they also identified a previously unknown type of cell that combined the features of the other two types. They named this group hybrid neuroendocrine cells. When they looked further, they found that these hybrid cells were associated with pathological budding, a feature of tumors that causes them to branch outward and grow, which is an indicator of poor prognosis in other cancers.

Next, researchers examined the tumor cells’ microenvironment by studying noncancerous cells found nearby. Surrounding the hybrid cells, they found high numbers of cancer-associated fibroblasts, cells that form a tough, fibrous barrier that protects tumors from attack. While these cells are known to play a significant role in pancreatic cancer and breast cancer, it’s the first time they’ve been documented in small cell lung cancer.

The researchers studied signaling between the cancer cells and the microenvironment. They found that the non-neuroendocrine cancer cells were driven by a signaling pathway for fibroblast growth factor. Because inhibitors for this pathway already exist, they then targeted it with drugs in cell lines.

“We saw that these tumor cells changed their shape and lost their non-neuroendocrine status, which is associated with aggressiveness and chemotherapy resistance,” said Desai.

The researchers hope to conduct a clinical trial exploring a combination of a fibroblast growth factor signaling inhibitor and immunotherapy to make the cancer more vulnerable to treatment.

The study, “Microenvironment Shapes Small-Cell Lung Cancer Neuroendocrine States and Presents Therapeutic Opportunities,” was published in Cell Reports Medicine.