Multitargeted Tyrosine Kinase Inhibitor Shows Activity in Small Cell Carcinoma of the Ovary
An multitargeted tyrosine kinase inhibitor used to treat leukemia has shown promise against a rare and aggressive type of ovarian cancer—small cell carcinoma of the ovary hypercalcemic type (SCCOHT)—that strikes young women and girls, according to a study led by the Translational Genomics Research Institute (TGen).
Ponatinib (Iclusig) was found in drug screens and preclinical studies to significantly delay tumor growth and reduce tumor volume in SCCOHT, according to the study published by Lang et al in Clinical Cancer Research. The findings suggest that ponatinib should be tested for use in SCCOHT patients in clinical trials.
SCCOHT has been diagnosed in women as old as 47 years and as young as 14 months, with a median diagnosis of only 24 years of age. It has a 2-year survival rate of less than 35%.
“Current treatment for this devastating cancer has such poor response rates and extreme toxicity that we must find better therapeutics,” said Jeffrey Trent, PhD, FACMG, TGen President and Research Director and senior author of the study. “Our work identifies a new treatment strategy that could provide these young women with improved patient benefit.”
SMARCA4
An international research team led by TGen, an affiliate of City of Hope, first discovered that a mutation in the gene SMARCA4 was the genetic cause of SCCOHT, according to a 2014 study published by Jelinic et al in Nature Genetics. The SMARCA4 gene—previously associated with lung, brain, and pancreatic cancer—was the only recurrently mutated gene in the study's samples.
In the most recent study, TGen laboratory researchers found that SCCOHT tumors, driven by the inactivation of the SMARCA4 gene, are reliant on receptor tyrosine kinase (RTK) cellular pathways. Researchers identified these pathways from screens of drugs already approved by the FDA that might be effective against this cancer.
“We identified ponatinib as the most effective clinically approved RTK inhibitor,” said Jessica Lang, PhD, a TGen postdoctoral fellow and co-lead author of the study. “It holds the potential for rapidly improving outcomes for these young patients.”
In laboratory models, ponatinib delayed tumor-doubling time by fourfold, while reducing tumor volumes in models by as much as 58.6%.
“Evaluation of a panel of selective RTK inhibitors highlighted ponatinib as the most potent tested agent in SCCOHT cell lines,” said William Hendricks, PhD, Assistant Professor in TGen's Integrated Cancer Genomics Division, and the other co-lead author of the study. “Clinical investigation of this FDA-approved oncology drug is warranted in SCCOHT.”
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
