Targeting EGFR with Aveo’s Genetically Engineered Mice

By Malorye Allison

Cancer researchers complain a lot about the xenograft models that are currently a mainstay of preclinical oncology research, but little has been done to improve the situation until now. Aveo Pharmaceuticals scientists have found a way to genetically engineer mice that will grow their own cancers containing the very mutations seen in specific human forms of the disease, including lung, colon, and breast tumors. One of the first targets for the company’s own pipeline is the epidermal growth factor receptor (EGFR), which is known to be a particularly tricky one. 

Aveo’s scientists hope their new models will give them an advantage. With xenografts, cancerous cells or tissue are embedded into an immunosuppressed mouse. “The tissues from xenografts have gone through so many passages in culture they bear little resemblance to a primary tumor, and the context is very different too,” says Tuan Ha-Ngoc, Aveo’s president and chief executive officer. 

He believes the company’s models better mimic how the receptor works in humans and how different mutations influence it. “We can put in particular oncogenes and tumor suppressor genes,” says Ha-Ngoc. Gene expression studies are done to characterize the tumors and their response to particular drugs. That data can be compared with results from patient samples so the scientists can see just how close to the “real thing” their models are.

One advantage of these models is that the tumors grown also pick up additional mutations, replicating the type of variation seen in real patients’ malignancies. But there are other advantages as well. “The key is to be able to have a model in which you can induce tumor formation in an adult animal with a full immune system and in the full genetic context,” says Ha-Ngoc. “Cancer is a disease not just of the cell, but of the whole system.” 

Aveo’s key intellectual property is a patent covering use of a couple of approaches to create inducible tumors, which they call the Human Response Prediction Platform. “To our knowledge, no one else has such flexible models, where you can insert a different gene and in a matter of months create a new model,” says Ha-Ngoc.

EGFR is a difficult cancer target, because the mutations are just beginning to be understood, but it is one that many companies are eyeing now. Erlotinib (Genentech/Roche/OSI’s Tarceva), gefitinib (AstraZeneca’s Iressa), and cetuximab (ImClone’s Erbitux) are all aimed at this family of receptors. Coming up fast are a pack of new monoclonal antibodies, as well as dual, multiple, and irreversible EGFR inhibitors. All these approaches have different purported advantages.

Non small-cell lung cancer is a disease in which EGFR plays a key role, and Aveo is testing its own EGFR inhibitor (AV-412) for this condition. The drug is a small molecule that also targets HER-2. Earlier trials of similar small molecules, including gefitinib and erlotinib, showed that sensitivity and resistance are linked to certain mutations. To better understand these relationships, Aveo scientists have done extensive testing with a variety of mutations seen in non-small cell lung cancer. 

Gefitinib was the first EGFR-inhibitor approved for lung cancer, but it's use was dramatically curtailed after a large trial showed the drug did not improve survival. By that time, erlotinib was available and was deemed the better choice. Both of these drugs were highly anticipated, and there has been a lot of research into how they work. Intriguing data suggests gefitinib is effective in subsets of patients, but it is not clear why or how to select the best candidates for the drug. Meanwhile, resistance to erlotonib is a problem for some patients.

Published studies suggest that tumors with the EGFR L858R mutation are less likely to respond to either erlotinib or gefitinib. The double mutant EGFR L858R/T790M, meanwhile, is thought to account for about half of all resistance to these drugs. Patients with these particular mutations are thus at a serious disadvantage. 

Aveo recently released data showing that in its genetically engineered models, AV-412 is ten times as active as erlotinib against tumors with L858R mutations. The drug is also active against the L858R/T790 mutation. 

The drug is currently in Phase I, and once Aveo scientists determine the optimal dose to use, they will do some smaller proof-of-concept trials in erlotinib-resistant patients. They’ll be able to use the gene expression data generated from the animal models to confirm they are hitting the same target and getting similar effects.

Ha-Ngoc sees this approach as the new paradigm. “We used to see the Velcro approach, where people threw things just to see what would stick. Now, if the genetic profile in the mice resembles what we see in humans, we can be more directed,” he says.

Additional Reading:

Albanell J, Fascon P. “Small molecules with EGFR-TK inhibitor activity.” Current Drug Targets. 2005;6:259–274.

Burris HA. “Dual kinase inhibition in the treatment of breast cancer: initial experience with the EGFR/ErbB-2 inhibitor lapatinib.” The Oncologist. 2004;9 (suppl. 3):10–15.

Engelman JA et al. “MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling.” Science Express. April 26, 2007. Science DOI: 10.1126/science.1141478

Heymach JV et al. “Epidermal growth factor receptor inhibitors in development for the treatment of non-small cell lung cancer.” Clinical Cancer Research. 2006;12 (14 suppl.):4441s–4445s.

Kwak EL et al. “Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib.” PNAS. 2005;102:7665–7670.

Shigematsu H, Gazdar AF. “Somatic mutations of epidermal growth factor receptor signaling pathway in lung cancers.” International Journal of Cancer. 2006;118:257–262.

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