Siamab Therapeutics‘ investigational antibody-drug conjugate ST1 has promising anti-tumor effects against chemotherapy-resistant ovarian cancer in cell and animal models, a study shows.
The study, “Treatment of ovarian cancer by targeting the tumor stem cell-associated carbohydrate antigen, Sialyl-Thomsen-nouveau,” was published in the journal Oncotarget.
Tumor chemoresistance and recurrence is a serious health-threatening issue, affecting most women with ovarian cancer. New treatment strategies are urgently needed to target chemoresistant disease that does not respond to current therapies.
Recurrent ovarian cancer is thought to occur because the body fails to eliminate rare cancer stem cells that are able to survive chemotherapy and lead to tumor relapse. Cancer stem cells are not unique to ovarian cancer and have been found in many other tumors. Given their key role in cancer progression, they have been pinpointed as important therapeutic targets.
Researchers have been investigating molecules expressed only in cancer stem cells, which can serve as markers to target this cell population. A series of studies have shown there are certain sugar molecules abnormally expressed in cancer, which are collectively called tumor-associated carbohydrates.
One of these sugar molecules is Sialyl-Thomsen-nouveau (STn), which appears on the surface of cancer cells and has been associated with chemotherapy resistance, metastatic disease, poor prognosis, and reduced overall survival. This molecule is found on the surface of several solid tumors, including prostate, pancreatic, gastric, and colon cancers.
Researchers believe that STn is also involved in chemotherapy resistance in ovarian cancer and hypothesized that this sugar is a good marker of ovarian cancer stem cells. If so, it would offer a new target for diagnostics as well as therapeutics.
“The ability to identify markers of chemoresistant cells is central to developing new therapeutic strategies that target these cells and ultimately provide clinical impact by reducing disease recurrence,” Bo Rueda, PhD, director of The Vincent Center for Reproductive Biology at Massachusetts General Hospital and senior author of the study, said in a press release.
In the study, the team demonstrated that a subset of ovarian cancer cells do produce STn, and these cells display characteristics of cancer stem cells.
One of the major findings was that cells positive for both STn and positive for CD133, a known marker of ovarian cancer stem cells, were resistant to platinum-based chemotherapy with Paraplatin (carboplatin).
Importantly, researchers showed that specific targeting of STn-positive cells using two of Siamab’s anti-STn antibody-drug conjugates based on ST1 prevented the growth and survival of ovarian cancer cells.
These antibody-drug conjugates target the sugar molecule STn but carry different toxic payloads into cancer cells. Treatment with both ST1 antibody-drug conjugates reduced viability of two human ovarian cancer cell lines in the lab.
Additionally, both treatments significantly reduced tumor burden in a mouse model of ovarian cancer, decreasing the number of STn-positive cells, compared with untreated mice.
No significant toxic effects from treatment were found in mice that received treatment.
Results showed that specific therapeutic targeting of STn using ST1 antibody-drug conjugates may be a new therapeutic option to treat ovarian cancer.
Previous research had already shown that Siamab’s anti-STn antibody-drug conjugates could safely and effectively halt tumor progression in chemotherapy-resistant ovarian cancer in animal models.
This new data reinforces the therapeutic development of ST1, Siamab’s lead therapy program, which is in late-stage preclinical development for the treatment of STn-expressing solid tumors.
“Combination or sequential coupling of anti-STn therapy with conventional cytotoxic chemotherapy could target both bulk tumor and chemoresistant cells that play an important role in disease recurrence,” said Jeff Behrens, president and CEO of Siamab and one of the authors of the study.