Filter Used to Elucidate Cellular Interactions and Improve Cancer Drug Discovery

Researchers have identified two genes that, when simultaneously activated, cause the most deadly form of glioblastoma, an aggressive brain tumor.

Therasis cofounder, Andrea Califano, Ph.D., and Wei Keat Lim, Ph.D., head of Computational Systems Biology at Therasis, Inc. (New York, NY, USA), along with a team of scientists from Columbia University (New York, NY, USA), have reported on the discovery in an advanced online edition of the journal Nature on December 23, 2009.

The genes were identified by reverse-engineering a map of the intricate molecular interactions that occur within the actual tumor cells, also known as a cellular network, using sophisticated cancer systems biology algorithms. These computational methods and algorithms were developed in the laboratory of Dr. Califano, who is also the director of the Joint Centers for Systems Biology and associate director of the Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center.

The team used one of the algorithms (ARACNe [Algorithm for the Reconstruction of Accurate Cellular Networks]) to reconstruct the cellular network that controls the behavior of these tumors. Then, a second algorithm (MARINa) was used to identify the master regulators of the worst prognosis in glioblastoma from this network. This analysis pinpointed two genes, with no known prior association with brain cancer, as playing a major, synergistic role in determining the most aggressive properties of glioblastoma, including invasion of normal surrounding tissue and angiogenesis. ARACNe and several other algorithms are exclusively licensed to Therasis from Columbia University. Together, they form the computational foundation of the company's drug discovery platform, known as the Therasis filter.

The computational findings were confirmed by a follow-up validation study, in which the expression of these genes was found to be strongly correlated with increased mortality. Furthermore, the tumor network and genes' functions were validated both in cell lines and in mouse models. Expression of the two genes in neural stem cells caused them to display all the hallmarks of the most aggressive glioblastoma. Conversely, silencing these genes in aggressive human glioma cells, which are normally highly tumorigenic when transplanted in mice, completely blocked their ability to form tumors.

"This study validates the potential of the Therasis filter to transform oncology drug discovery and development by enabling a comprehensive understanding of the inner regulatory interactions in actual tumor cells to guide target identification,” commented Dr. Califano. "These findings of two new synergistic glioblastoma targets support our technology platform and will guide new approaches to combination therapy and associated diagnosis through targets and biomarkers that are causally, rather than statistically, associated with the tumors.”

Rather than identifying therapies based solely on cytotoxicity, or ability to kill cancer cells, the Therasis filter enables a more informed approach to drug development by determining key molecular targets and uncovering synergistic interactions within a cellular network. The subsequent reverse mapping of the effects of a single agent or combination on these cellular activities affords a better determination of the mode of action and specific toxicity of new treatments, as well as biomarkers of activity.

Therasis was recently founded by Dr. Riccardo Dalla Favera, Dr. Owen O'Connor, and Dr. Andrea Califano, leaders in basic, translational, and clinical oncology research. The company is developing an internal pipeline of oncology drug candidates and forming drug discovery partnerships with other pharmaceutical and biotechnology companies.

The Therasis filter enables the identification of disease-specific alterations in the networks of molecular interactions that regulate cellular processes, allowing the rapid identification of new chemical entities and synergistic combinations that target these alterations. Beginning with high throughput screening of compound libraries, the Therasis filter first collects a large number of molecular profiles of chemically perturbed cells. These profiles are used to reconstruct accurate maps of molecular interactions, also known as "interactomes.” The latter are experimentally confirmed and analyzed to identify disease-specific alterations in tumor-derived tissues, compounds targeting these alterations and biomarkers complementing clinical development. Interactomes are also effective in characterizing drug mechanisms of action, supporting both drug rescuing and drug repositioning efforts.

Therasis is a new drug discovery company developing oncology therapeutics for use as single agents or in combination therapy. The company's proprietary technology, the Therasis filter, represents a paradigm shift in the ability to discover therapeutic targets, their chemical inhibitors, and associated biomarkers. This platform integrates expertise in high throughput screening, systems biology, cancer genetics, and clinical research. Therasis plans to utilize its discovery engine to identify new chemical entities for internal development and to forge collaborations with pharmaceutical and biotechnology companies on drug repositioning. Therasis' technology platform was developed at Columbia University by specialists in cancer genetics, cancer systems biology, and cancer therapeutic development.

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