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In Mice, New Drug Conjugate Suggests Promise for Hard-to-Treat Pediatric Cancers

, by NCI Staff

In two mice with sarcoma, more than 40 days after treatment, a mouse that received a placebo (top) has a large tumor, while the mouse treated with a new drug-conjugate (bottom) has no evidence of cancer.

Credit: National Cancer Institute

Findings from a study in mice suggests that a new type of drug conjugate—a cancer drug that is chemically linked to another drug that helps deliver it directly to cancer cells—may have potential as a treatment for two cancers that are often diagnosed in children.

Led by NCI researchers, the study showed that the drug conjugate, called STA-12-8666, completely eradicated tumors in mice with Ewing sarcoma and rhabdomyosarcoma.

Some of the mice, all of which had very large tumors at the time of treatment, are still alive 5 months later, with no obvious signs of toxicity from the treatment, explained the study’s lead investigator, Christine Heske, M.D., of the Pediatric Oncology Branch in NCI’s Center for Cancer Research (CCR).

The findings were presented in June at the American Society of Clinical Oncology (ASCO) annual meeting.

The drug conjugates that have been approved by the Food and Drug Administration (FDA)—brentuximab (Adcetris®) for the treatment of lymphoma and ado-trastuzumab emtansine (Kadcyla®) for the treatment of breast cancer—and most others in development are called antibody-drug conjugates (ADCs) because they use antibodies for their delivery component.

The delivery component of the drug conjugate used in this study, however, is a heat shock protein (HSP) 90 inhibitor. It is linked to the chemotherapy agent SN38, the active component, or metabolite, of irinotecan, a drug that has shown signs of efficacy in early stage trials in children with sarcoma.

HSPs are a family of “chaperone” proteins, so called because their primary role is to help with the folding and stabilization of other proteins so they can function properly. HSP90 is thought to assist in the maturation of several proteins that are directly involved in driving cancer development and growth.

Researchers have been studying HSP90 inhibitors as potential cancer treatments for more than two decades, since CCR’s Len Neckers, Ph.D., a co-author of the sarcoma study, and colleagues in his lab found that the natural product geldanamycin, which has anticancer activity, acts by inhibiting HSP90.

Although no drugs that inhibit HSP90 have been approved for cancer treatment, one, ganetespib, is being tested in mid- to late-stage clinical trials, including a phase III trial in patients with non-small cell lung cancer.

HSP90 is expressed in most cells, but HSP90 inhibitors have a particularly strong affinity for HSP90 in cancer cells. And, unlike most healthy cells, Ewing sarcoma and, to a lesser extent, rhabdomyosarcoma cells “are chock full of [HSP90],” Dr. Heske said, making a HSP90 inhibitor an excellent choice to target a linked anticancer drug to cancer cells.

STA-12-8666 was developed by Synta Pharmaceuticals, which also manufactures ganetespib. But the conjugate, Dr. Heske explained, uses a different HSP90 inhibitor that is 10 times less potent than ganetespib.

In the study presented at the ASCO annual meeting, STA-12-8666 was substantially more effective at shrinking tumors in mice with both types of sarcoma than ganetespib or irinotecan, although the longest-lasting tumor responses were in mice with Ewing sarcoma. Irinotecan did shrink tumors in both models. But, unlike the mice treated with the highest doses of the drug conjugate, tumors in the irinotecan-treated mice typically returned after a short period.

Similar results using STA-12-8666 in mouse models of other cancer types, including pancreatic and small-cell lung cancer, have been reported at recent research meetings.

According to a company spokesperson, in the first quarter of 2016, Synta hopes to file the regulatory submissions required by the FDA to begin human trials of STA-12-8666.

NCI is also in discussions with the company about early-phase trials to test the drug conjugate in children with sarcomas and possibly neuroblastoma, another pediatric cancer that is sensitive to irinotecan, Dr. Heske said.

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