Such drugs are designed to attack cancer cells’ ability to grow into larger tumors, but often they are met with resistance by a protein within non-Hodgkin’s lymphoma cells called CRM-1, or Exportin 1. CRM-1 shuttles tumor suppressor proteins out of the nucleus of the cell and into the cytoplasm, which surrounds the nucleus. Those suppressor proteins work only when they are inside the nucleus, so CRM-1 actions make the tumor-killing drugs less effective and allow tumors to continue growing.
Asfar Azmi, a research associate in the WSU School of Medicine’s department of pathology, is exploring how novel drug candidates developed by Karyopharm Therapeutics of Natick, Mass., prevent CRM-1 from moving tumor suppressor proteins out of the nuclei of non-Hodgkin’s lymphoma cells. When the drugs are added, the CRM-1 does not function, and the suppressors remain in the nucleus, preventing tumor growth.
The American Society of Hematology has deemed the finding significant enough to select it for an outstanding abstract achievement award, as well as the subject of an oral presentation at its annual meeting Monday. Azmi said he considers his selection an honor; because of the society’s rigorous review process, less than 15 percent of reviewed abstracts typically are selected for oral presentation at its annual meetings.
Azmi works in the laboratory of Ramzi Mohammad, professor of oncology at Wayne State and the Barbara Ann Karmanos Cancer Institute. Researchers in that laboratory are working with Karyopharm to develop a drug that can be used in clinical trials by the middle of next year.
Founded in 2008, Karyopharm Therapeutics is focused on the discovery and development of those novel CRM-1 inhibitors, which it calls “selective inhibitors of nuclear export,” or SINE. Those compounds target CRM-1 for the treatment of cancer, autoimmune diseases and HIV.
“All tumors develop resistance to anti-cancer drugs at least partly because their normal tumor suppressor proteins are kicked out of the nucleus by CRM-1, and this nuclear localization of the important tumor suppressor proteins is required for cell killing,” Azmi said. “Together with Karyopharm, we have characterized a new class of drugs that blocks the export machinery. This allows the important tumor suppressor proteins to stay in the right place and induce tumor cell killing.”
While some previous drugs aimed at inhibiting the shuttling function of CRM-1 have worked, they also have proven toxic to noncancerous cells, Azmi said. The set of inhibitors he has characterized has left noncancerous cells undamaged in mice; the new drugs also can be effective at much lower dosage levels. He has tested this latest set of SINE molecules in non-Hodgkin’s lymphoma tumors because they are particularly resistant to many anti-cancer agents. Azmi previously has used similar drugs to kill pancreatic tumors, which also are highly resistant to those inhibitors.
“Really these are very effective drugs,” he said. “They are killing resistant lymphoma cells at very low concentrations, or nanomolar range. Such tumors were developed in Mohammad’s lab from patients who did not respond to standard chemotherapy.”
Inhibitors being developed by Karyopharm and characterized in Mohammad’s laboratory constitute a global approach that can be used to combat many types of cancer, Azmi said, and can be used as single agents or added to standard chemotherapy.
“We are excited at the possibilities for applications of Dr. Azmi’s work,” said Sharon Shacham, one of Karyopharm’s founders and its chief scientific officer. “It marks the continuation of a successful partnership with Dr. Mohammad’s research team, and we look forward to the clinical trial process.”