Calls Now Open
2027 Scholar-Innovator and ADDF-Harrington
Oncology, Inflammation, Musculoskeletal, Rare/Orphan
A Novel Humanized Antibody Inhibiting NOTCH3 Stem Cells in Meningioma
2024 Harrington Scholar-Innovator
Despite being the most common primary intracranial tumors and a significant source of neurological morbidity and mortality, meningiomas—tumors that arise from the lining of the brain and spinal cord—remain poorly understood. There are no standard-of-care medical therapies for these tumors (standard treatments are restricted to surgery or radiotherapy) and recent trials of molecular or biologic treatments have failed to improve outcomes for meningioma patients.
“On a very fundamental level, we don't understand the cellular origin of meningiomas,” Dr. Raleigh says. “So our project started off trying to understand the cellular architecture of meningioma evolution, and in doing so we were able to find a new therapeutic target and build a drug to hit that target.”
The target Dr. Raleigh cites is NOTCH3, a receptor protein that plays a significant role in the maintenance and function of stem cells by regulating their self-renewal and differentiation.
Unfortunately, NOTCH3 also drives meningioma initiating capacity, meningioma cell proliferation, meningioma angiogenesis, and meningioma resistance to radiotherapy—all of which increase meningioma growth and reduce patient survival.
Dr. Raleigh and his team identified a selective mouse antibody, aNRR3, that blocks NOTCH3-induced meningioma formation and sensitizes meningiomas to radiotherapy, reducing tumor growth and improving survival in preclinical models. They humanized and optimized 16 novel aNRR3 antibodies and then reduced that number to two for a window of opportunity clinical trial in patients with recurrent meningiomas.
Dr. Raleigh notes that in addition to intracranial tumors, NOTCH3 has been implicated in lung, colon, and breast cancer stem cells, and in arthritis pathology.
“Successful completion of this proposal sets the stage for clinical translation to myriad oncologic and inflammatory conditions,” he says.
"A large part of our progress has been enabled by Harrington Discovery Institute. This organization is a truly unique and wonderful effort to address what's often referred to as the translational 'Valley of Death' for new cancer therapies."