Combination Therapy Halts Cancer Progression

Combination of sialidase and cucurbitacin I shows substantial antitumor activity in sarcoma therapy.

Researchers found a promising treatment method utilizing a specific inhibitor to effectively halt cancer progression during a recent study.

The study, published in the journal Immunity, analyzed inhibitors of signal transducer and activator of transcription (STAT3), which is responsible for transcription by the STAT3 gene and may influence T-cell immune responses.

Immature myeloid cells called myeloid-derived suppressor cells (MDSCs) play a role in regulating immune responses and tissue repairs. During inflammation, infections, and cancer, these cells begin to expand rapidly.

Once it migrates to a tumor, the cells can develop into tumor associated macrophages (TAMs). TAMs have the ability to stimulate blood vessels in tumors to form and enhance tumor cell invasion and motility.

"Studies pointed to STAT3 being an important target in the development of cancer," said lead study author Dmitry I. Gabrilovich, MD, PhD. "Clinically speaking, we do not observe the robust results that we would expect. The purpose of this study was to discover why this is happening and figure out a way to make these therapies as effective as our research would suggest."

The researchers analyzed cancer patient blood samples to determine the level of activity.

STAT3 has previously been found to play a role in the expansion of MDSCs and the immune response by the cells. However, the results of the current study showed that high levels of STAT3 activity prevent MDSCs from developing into TAMs. This is due to the low levels of STAT3 found inside the tumor, however, it is not low enough to effectively target STAT3.

When tumors outgrow their blood supply, a lack of oxygen, occurs. This allows for the activity of CD45 to increase and for the STAT3 levels to decrease. The increase of activity and the lowering of levels is what allows for the differentiation of MDSCs to TAMs.

Next, researchers looked to explore whether STAT3 inhibitors would be more effective when CD45 is targeted. They used a combination of sialidase, an ezyme that disrupts CD45 activity, and an experimental STAT3 inhibitor called JSI-124 (cucurbitacin I), to treat a form of sarcoma resistant to STAT3 inhibitors.

When these drugs were used individually, it had no effect on tumor growth or enhanced progression. When used in combination, the drugs showed substantial antitumor activity.

"Our results suggest that sialidase could sensitize myeloid cells in tumors to previously ineffective STAT3 inhibitors," said first author of study Vinit Kumar, PhD. "We confirmed that STAT3 is indeed a great potential target for cancer immunotherapies as long as we account for the other factors affecting the tumor microenvironment."