A team of researchers at Yale School of Medicine have identified, characterized and cloned ovarian cancer stem cells and have shown that these stem cells may be the source of ovarian cancer’s recurrence and its resistance to chemotherapy.

“These results bring us closer to more effective and targeted treatment for epithelial ovarian cancer, one of the most lethal forms of cancer,” said Gil Mor, M.D., associate professor in the Department of Obstetrics, Gynecology & Reproductive Sciences at Yale School of Medicine.

Mor presented his findings recently at the annual meeting of the American Association for Cancer Research (AACR) Meeting in San Diego, California.

Cancerous tumors are made up of cells that are both cancerous and non-cancerous.  Within cancerous cells, there is a further subclass referred to as cancer stem cells, which can replicate indefinitely.

“Present chemotherapy modalities eliminate the bulk of the tumor cells, but cannot eliminate a core of these cancer stem cells that have a high capacity for renewal,” said Mor, who is also a member of the Yale Cancer Center.  “Identification of these cells, as we have done here, is the first step in the development of therapeutic modalities.”

Mor and colleagues isolated cells from 80 human samples of either peritoneal fluid or solid tumors.  The cancer stem cells that were identified were positive for traditional cancer stem cell markers including CD44 and MyD88.  These cells also showed a high capacity for repair and self-renewal.

The isolated cells formed tumors 100 percent of the time.  Within those tumors, 10 percent of the cells were positive for cancer stem cell marker CD44, while 90 percent were CD44 negative.

Mor and his team were able to isolate and clone the ovarian cancer stem cells.  They found that these cells were highly resistant to conventional chemotherapy while the non-cancer stem cells responded to treatment.  “Isolating and cloning these cells will lead to development of new treatments to target and eliminate the cancer stem cells and hopefully prevent recurrence,” said Mor.

A new drug compound leads to the death of ovarian cancer cells resistant to chemotherapy.

Dr. Gil Mor, Associate Professor in the Department of Obstetrics, Gynecology & Reproductive Sciences at Yale School of Medicine.

Credit: Yale University

In a discovery that may be useful for maintaining remission in chemo-resistant ovarian cancer, Yale scientists report that pre-clinical studies have shown the drug compound NV-128 can induce the death of ovarian cancer cells by halting the activation of a protein pathway called mTOR.

Gil Mor, M.D., associate professor in the Department of Obstetrics, Gynecology & Reproductive Sciences at Yale School of Medicine, and associate research scientist Ayesha Alvero, M.D. presented the data April 15 during an oral presentation at the annual meeting of the American Association for Cancer Research.

In cancer cells, mTOR signals enhance tumor growth and may be associated with resistance to conventional therapies.  Inhibition of mTOR could shut down many of these survival pathways, including proteins that protect the mitochondria of cancer cells.

NV-128, developed by Novogen Limited, holds promise as a more targeted therapy for ovarian cancer because it works differently from traditional therapies that are dependent on enzymes known as caspases to trigger cell death.  Therapies using caspases to kill cancer cells can be ineffective in chemo-resistant cancer cells due to mutations that short-circuit signals that trigger cancer cell death.

“We consider that the capacity of NV-128 to trigger caspase-independent cell death, in otherwise chemoresistant ovarian cancer cells, opens new possibilities for the use of NV-128 as a potential addition to conventional chemotherapy targeting ovarian cancer cells,” said Mor.

In the context of developing therapies for late stage ovarian cancer, Mor said, the finding may be “a key step to the development of alternative targeted therapy for patients with cancer recurrence.”