Led by researchers at the Translational Genomics Research Institute (TGen), the study, “Ponatinib shows potent antitumor activity in small cell carcinoma of the ovary hypercalcemic type (SCCOHT) through multi-kinase inhibition,” was published in the journal Clinical Cancer Research.
Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare and highly malignant ovarian cancer that has been diagnosed in women from 14 months to 47 years of age.
The most effective treatment is surgery followed by high doses of chemotherapy, radiation, and stem cell replacement, but the treatment is very toxic and response rates are low.
“Current treatment for this devastating cancer has such poor response rates and extreme toxicity that we must find better therapeutics,” Jeffrey Trent, PhD, TGen’s president and research director and senior author of the study, said in a press release. “Our work identifies a new treatment strategy that could provide these young women with improved patient benefit.”
SCCOHT tumors are triggered by mutations and silencing of the SMARCA4 gene, a combination that disturbs a protein complex — the SWI/SNF — highly important for gene expression. The consequence is broad dysregulation of several genes in SCCOHT cancer cells.
Despite the crucial role of these genetic alterations, no approved anti-cancer treatments have been found to fight them.
Researchers found that survival of SCCOHT tumors depend on a specific cell pathway, called the receptor tyrosine kinase (RTK) pathway.
Using drug screens, the team identified medicines already approved by the U.S. Food and Drug Administration (FDA) that hit the RTK pathway and might be effective against this cancer.
“We identified ponatinib as the most effective clinically approved RTK inhibitor,” said Jessica Lang, PhD, a TGen post-doctoral fellow and co-lead author of the study, adding that “it holds the potential for rapidly improving outcomes for these young patients.”
Researchers found promising results when testing ponatinib in laboratory models of SCCOHT both in vitro and in vivo.
Researchers tested the therapy’s effectiveness in patient-derived xenograft models, tumor cells from patients that were transferred into mice. Ponatinib delayed tumor growth fourfold, compared with controls without treatment.
After 30 days of treatment with ponatinib, tumor size was significantly reduced from 58.6 to 42.5%.
“We show the ability of ponatinib to significantly delay tumor progression in a cell line xenograft model of SCCOHT and markedly reduce tumor growth of patient-derived xenograft models of SCCOHT, thereby prioritizing ponatinib for a clinical trial in SCCOHT patients,” researchers wrote in the study.
Ponatinib was approved in the U.S. in 2012 for use in leukemias, but was taken off the market after reports of serious adverse vascular events. In 2016, the FDA granted full approval after completion of the Phase 2 PACE clinical trial (NCT01207440).
Currently, the treatment is on trial for many other cancers, including solid tumors.
The findings “might be more broadly applicable to a larger set of ‘SWI/SNF-omas,’ or cancers with mutations in the SWI/SNF complex. This group accounts for up to 20% of all cancers, and therefore has potential for broader translational relevance,” the team said.
“Clinical investigation of this FDA-approved oncology drug is warranted in SCCOHT,” said William Hendricks, PhD, assistant professor at TGen and the other co-lead author of the study.