New Models and High-Throughput Screening for Glioblastoma Therapies

Tom Mikkelsen, MD, FRCP(C)

Tom Mikkelson
Co-Director, Hermelin Brain Center
Henry Ford Hospital

Brent Stockwell, PhD

Brent Stockwell
Stockwell Lab
Columbia University

Title: Combination Drug Screening Program
Investigators: Tom Mikkelsen, Brent Stockwell
Grantees: Novartis, Henry Ford Hospital, Columbia

Long before brain cancer drugs enter human clinical trials, they undergo testing in preclinical laboratory models to determine if they might effectively fight brain cancer.  Because existing preclinical models do not reflect the striking differences between brain tumors from different people, preclinical testing can be slow, inefficient, and inaccurate – exactly what we can’t afford in the search for a brain cancer cure.

To combat this problem, ABC2 recently brought together a collaboration between glioblastoma experts at Novartis, Henry Ford Hospital, and The Howard Hughes Medical Institute at Columbia University.  The goal of this new collaboration is two-fold: first, to create publicly available, state-of-the-art glioblastoma models that reflect the true biology and heterogeneity of human brain tumors; and second, to use these new models to predict drugs or drug combinations to which specific human glioblastomas should respond.

The ABC2-funded collaboration has already made great strides toward the first goal.  Teams at each institution have transplanted human tumors – which retain their widely varying genetic characteristics – into mice to create a panel of tumor-laden mice that reflects the variability of actual human brain tumors.  The teams have also developed an analogous panel of glioblastoma cells that, when grown in laboratory dishes, reproduce important aspects of glioblastoma biology while simultaneously permitting high-throughput drug screening to identify potential new therapies.

With this new arsenal of tools in hand, the teams are moving toward their second goal of identifying therapies to which specific glioblastomas should respond.  They have assembled a broad library of existing drugs to screen – both as individual compounds and in rational combinations – in the new laboratory models.  Some of the drugs in this library are already approved by the FDA for use in other indications, meaning that they could quickly move into the clinic if they are effective.  Preliminary results from the first round of drug screening are encouraging, and they have revealed vastly different drug sensitivities for different tumors as well as several classes of drugs worthy of further exploration as potential glioblastoma treatments.  Given these discoveries, the teams are expanding their screen to include more drugs and expanding their laboratory models to include an even greater variety of human tumors – thereby increasing the value of this resource for the entire glioblastoma community.

With ABC2’s help, this collaboration has brought to bear the clinical and research expertise of Henry Ford Hospital and Columbia and the resources of Novartis – the world’s largest pharmaceutical research and development enterprise.  The newly developed laboratory models have already filled a significant gap in brain cancer research technology, and the high-throughput screening they allow will speed progress toward identifying tumor-specific glioblastoma therapies.