Our Platform
For decades, the standard preclinical model for testing the efficacy of oncology drug candidates has been the human tumor xenograft. However, well known challenges with these models include the artificial nature of the implanted tumor cells, which have adapted for growth in culture as opposed to an in vivo environment that would more closely mimic tumor activity in humans. Despite the low success rate of oncology products in clinical development – in part due to the high rate of false positives associated with this method of testing – xenografts are used broadly throughout the industry.
AVEO’s Human Response Platform™ is based on the company’s proprietary, genetically defined mouse models of human cancer, in which each model is engineered to contain signature genetic mutations that are present in human disease. Beyond these cancer-initiating engineered mutations, the resultant tumors acquire common and distinct spontaneous mutations during tumor progression. These mutations provide additional natural genetic variation more akin to the range of genetic heterogeneity encountered across different primary human tumors.
AVEO’s platform helps address three key issues in cancer drug discovery and clinical development:
- Target Identification and Validation: Identifying and validating which of the many candidate cancer causing genes are most important to tumor growth.
- Drug Discovery: Enabling the development of tumor models driven by the target gene of interest to facilitate the evaluation of drug candidates directed against the target, and the selection of the most promising candidate.
- Biomarker Identification: Enabling the identification of genetic markers, or biomarkers that may help identify patients more likely to be responsive or resistant to such drugs by leveraging the naturally occurring genetic variation in the AVEO cancer models and their divergent sensitivity to anti-cancer drugs.
AVEO is using its capabilities to develop its own pipeline of oncology therapeutics and has engaged in partnerships with leading biotechnology and pharmaceutical companies to leverage its platform.
AVEO was founded with the goal of developing a fundamentally new kind of cancer model designed to overcome many of the limitations of traditional xenograft models, and thereby improve the probability of success in developing new cancer drugs. AVEO utilizes these novel models to identify and validate target genes that drive tumor growth, to identify drugs that can block the function of these targets, and to identify patients most likely to respond favorably to treatment with such drugs.
AVEO has used these models to advance drugs in its own pipeline and in collaboration with strategic partners such as Merck, OSI Pharmaceuticals (a wholly-owned subsidiary of Astellas US Holding), Schering-Plough (now Merck) and Biogen Idec. The company’s cancer models, together with the various techniques developed in-house to use these models to aid in the discovery and development of new cancer drugs, are collectively referred to as the Human Response Platform (HRP). Key components of the HRP are covered by issued patents or pending patent applications.
The power and versatility of AVEO’s mouse model platform is greatly enhanced by its patented method of making chimeric mouse models. In addition to this method of creating novel tumor models, the company has also developed a model of human breast cancer in which many of these same features have been applied to genetically modified human breast tissue.
This human-in-mouse (HIM) model is created by first isolating normal human breast tissue from surgical specimens, genetically modifying it to express oncogenes, and then introducing the modified tissue into specially engineered mice. The modified breast tissue first grows into normal breast tissue, but then rapidly develops into human breast tumors while growing in the mouse breast tissue.
In a proprietary method called the Mammalian Second Site Suppressor (MaSS) screen technology, AVEO turns off the inducible oncogene driving the growth of the tumors in the models. Other genes are then activated in the tumor cells to see if the tumor cells grow with the driving oncogene turned off. This allows screening for genes capable of replacing the function of a known oncogene. Such genes are potential new targets for anti-cancer drugs. The MaSS screen technique is protected by issued patents exclusively licensed to AVEO by the Dana-Farber Cancer Institute.
AVEO has conducted MaSS screens in multiple tumor models developed in different tumor types with different genetic backgrounds. These screens identified many genes important in tumor formation. The most common pathway identified using the AVEO screens has been the HGF/c-Met pathway, and this observation triggered the initiation of the company’s program to develop antibodies against HGF (the AV-299 program). Numerous other pathways have also been identified, including ErbB3, Notch and FGF, all of which are now the basis of ongoing antibody discovery programs.
The data from all of the screens performed to date are routinely re-evaluated and compared with data coming from other sources, such as mutations identified in the human Cancer Genome Sequencing project. Many target genes originally identified in the screen are poorly understood — these targets become more interesting as targets as new data about their function become available. This large data set provided the basis of the company’s target discovery strategic partnerships with both Merck and OSI Pharmaceuticals (a wholly-owned subsidiary of Astellas US Holding). In the case of OSI, scientists from AVEO and OSI have reevaluated the AVEO target data base with a goal of finding novel targets possibly involved in the transition of a tumor cell to a more aggressive phase, where the original epithelial tumor cell becomes more mesenchymal like — more invasive and able to survive passage through the blood stream — the so-called epithelial-mesenchymal transition.
Candidate genes identified in AVEO’s genetic screens go through extensive validation protocols. Key validation steps include:
- Assessment of tractability based on cell surface expression or secretion
- Oncogenic gain of function in patented Directed Complementation models
- Determination of human relevance based on publicly available and proprietary human expression, mutation and amplification data
- Examination of intellectual property landscape
- Generation, characterization and testing of proof of principle antibodies in human cancer xenografts and proprietary AVEO cancer models.