The CCIA’s Daniel Carter, PhD, Glenn Marshall, MD, and co-authors report that they have identified and validated a new molecular target in a highly aggressive and usually fatal subtype of neuroblastoma, a cancer of nerve cells that is one of the most frequent solid tumors in children. They observe that CBL0137, a drug candidate developed by the biotech company Incuron in collaboration with scientists from RPCI, demonstrated significant antitumor activity in preclinical models of neuroblastoma. The researchers provide evidence that the protein complex FACT (facilitates chromatin transcription) represents a new and promising biomarker candidate for treatment of this aggressive, treatment-resistant disease, and suggest a variety of possible clinical applications for the FACT-targeting drug CBL0137.
CBL0137 is a small molecule that belongs to a class of agents called curaxins, which were invented by a group that included paper co-author Andrei Gudkov, PhD, DSci, Senior Vice President for Basic Science at Roswell Park and founder and Chief Scientific Officer of Incuron.
“This work, which beautifully demonstrates the power of international collaboration of oncology researchers working both at academic centers and private enterprises, gives us hope that we will see improved cure rates and long-term outcomes for children afflicted with this aggressive disease,” says Dr. Gudkov. “We hope to soon be able to extend the opportunity to participate in clinical studies of curaxin CBL0137 to children with neuroblastoma, a prospect we eagerly await given the limited treatment options available currently.”
While another target for this subtype of neuroblastoma, the MYC oncogene, exists, efforts to effectively reach this target by pharmacological agents have so far proven unsuccessful. The study in Science Translational Medicine for the first time demonstrates that MYC activity in these tumors depends on the presence of FACT and that inactivation of FACT effectively neutralizes MYC, resulting in the death of neuroblastoma cells.
“The presence of FACT in this type of tumor is as bad a prognostic marker as excessive activity of MYC is,” notes paper co-author Katerina Gurova, MD, PhD, of the Roswell Park Department of Cell Stress Biology, who led efforts to decipher the mechanisms of activity through which curaxins successfully target FACT, as documented in earlier published research.
As distinct from many of the drugs currently used to treat neuroblastoma, curaxins appear to kill cancer cells without causing DNA damage, the major source of cancer treatment side effects. The safety, pharmacokinetics and pharmacodynamics of oral and intravenous formulations of CBL0137 are currently being investigated in two ongoing Phase 1 clinical studies in adults with advanced metastatic solid tumors cancers and lymphomas. To date, no dose-limiting toxicities have been observed with either oral or intravenous administration through the highest CBL0137 dose levels tested.
The paper, “Therapeutic targeting of the MYC signal by inhibition of histone chaperone FACT in neuroblastoma,” is available online at stm.sciencemag.org.