APRs in CTCs
FLEMINGTON, N.J.óArno Therapeutics Inc., a four-person clinical-stage biopharmaceutical company focused on the development of oncology therapeutics, has signed an agreement with Veridex LLC, a Johnson & Johnson company, to develop a diagnostic test to detect the presence of activated progesterone receptors (APRs) as a potential biomarker of anti-progestin activity in circulating tumor cells (CTCs). The diagnostic will help identify patients who could potentially benefit from treatment with anti-progestins including onapristone, an orally administered, investigational type 1 progestin receptor antagonist being developed by Arno.
CTCs are cancer cells that have detached from a solid tumor in the body and are found in the bloodstream. The collaboration will allow Arno to utilize Veridex's proprietary technology, CELLSEARCH, which uses microfluidic separation integrated with magnetic sorting, to isolate CTCs and further analyze the cells for the presence of APR. The CELLSEARCH CTC system is the first and only standardized, FDA-cleared, semi- automated system that captures, isolates and counts CTCs with a high level of sensitivity and specificity, says Dr. Alexander Zukiwski, vice president and chief medical officer at Arno.
Both Zukiwski and Arno CEO Glenn Mattes once worked at Johnson & Johnson and were familiar with Veridex and CELLSEARCH. Zukiwski notes that the system is approved and reimbursed and is already running on a commercial basis. Arno will continue to explore other CTC technologies, he adds.
"Systems under development may allow us to archive and store samples on a long-term basis and/or address multiple biomarkers in a single sample. The goal is to allow us to maximize the information from each and every patient," he says.
"We are pleased to work with Veridex as we believe its pioneering technology for isolating circulating tumor cells will serve as an important tool for the continued development and study of onapristone," Mattes adds. "By taking blood samples from patients rather than obtaining tissue samples, we hope to create a simplified and less invasive process for identifying patients that are most likely to benefit from treatment with onapristone."
The diagnostic test will be used in future clinical studies of onapristone, which the company is planning to begin in the second half of 2013.
In preclinical studies, the presence of APR has shown to be predictive of onapristone activity. Onapristone is believed to work by binding to progesterone receptor proteins, thereby inhibiting dimerization, phosphorylation and DNA transcription activity. Progesterone receptors (PRs) are found in particular cells including those of the female reproductive tissue and some cancers. The hormone progesterone binds to the receptors and may cause the cells to grow. Preclinical studies have shown that PRs can play a role as drivers of malignant cell growth in certain cancers.
"These data add to the growing body of knowledge indicating the potential of the compound to fill a high unmet medical need, and we plan to pursue a global orphan drug designation in endometrial cancer," says Mattes.
Arno has exclusive worldwide rights to develop and market three other anticancer product candidates. AR-42 is an orally available, broad-spectrum inhibitor of both histone and non-histone deacetylation proteins (a "pan-DAC"), that is currently enrolling patients in a Phase I clinical study. Preclinical data showed that AR-42 potently and selectively inhibits leukemic stem cells in acute myeloid leukemia (AML).
AR-12 is an orally available inhibitor of the PI3K/Akt pathway that causes cell death through the induction of endoplasmic reticulum stress. A Phase I clinical trial is currently enrolling patients with solid tumors or lymphoma. Both AR-42 and AR-12 were in-licensed from the Ohio State University.
AR-67 is a novel, third-generation camptothecin analogue that inhibits topoisomerase I activity. Arno is currently enrolling patients in a Phase II clinical study of AR-67 in patients with glioblastoma multiforme (GBM), a highly aggressive form of brain cancer. AR-67 was in- licensed from the University of Kentucky and University of Pittsburgh, which were co-developers.