What determines whether cancer treatment will be successful? Effectiveness is largely dictated by the genetic makeup of the cancer cells. A typical pre-clinical evaluation of a candidate anti-cancer drug will examine its impact on 10-15 samples of cancer cells. However, the genetic characteristics of human cancers are so diverse that such a narrow investigation can miss much information that would be valuable in identifying how and where potential medicines would be effective.

The Center for Molecular Therapeutics at Massachusetts General Hospital Cancer Center is pioneering a radically different approach. To capture the range of diversity inherent in cancers, Dr. Settleman’s laboratory developed new technologies and methods that enable a potential medicine to be quickly tested against cells from more than 1000 tumors representing many types of human cancer.

This approach permits early identification of which cancer cell characteristics will underlie sensitivity to the compound being examined. The resulting cell information may enable clinical trials to be more effectively targeted and thus increase the likelihood of success. Dr. Settleman is one of the researchers in the SWCRF Institute Without Walls. Using this high-volume test platform is the initial step in the SWCRF Drug Discovery Program.

It took 2 years to set up this innovative research platform - to culture hundreds of cell lines (long lived tumor-derived cells that maintain the cellular characteristics of the original cancer in the laboratory); to develop the robotic technology to permit high volumes of test results to be collected and analyzed; and to develop reliable machine-readable tests. Early tests produced some very interesting results that highlight the value of this approach.

• In addition to showing that the array correctly identified the cancers expected to be responsive to known tested compounds, this approach also identified some cell lines of other cancers which were also very sensitive – for example, a HER2 inhibitor was effective against breast cancer cell lines that had overactive HER2 genes, as expected; and, it was equally effective against other cancers (non-small cell lung cancer, ovarian cancer and esophageal cancer) in small subgroups that also had overactive HER2 genes. This indicates that, in addition to treating breast cancer, a HER2 inhibitor, like Herceptin, could provide an important treatment in a subset of other cancers, whose susceptibility would be identified by genetically testing tumors.


• 7% of all cancers and 70-80% of all melanomas show a mutation in the BRAF gene, so this is a target of significant research interest. Patient trials of a touted BRAF inhibitor showed unexpectedly little response, suggesting that BRAF inhibition might not be a fruitful avenue of attack. Tests in the high volume array replicated that lack of response. However, a different BRAF inhibitor compound still in an early stage of development demonstrated a remarkable effect. A detailed understanding of the characteristics of each cell line enabled the lab to explain how the two apparently similar BRAF inhibitor compounds worked through entirely different mechanisms, explaining why one was effective when the other was not.


• One potential medicine, now in phase 1 clinical trials, was also tested in the array. By comparing its profile of responsive cell lines to the profiles generated by known compounds, the lab revealed that the newer compound worked by inhibiting the growth of a particular protein. This kind of information would enable clinical trials to be more precisely targeted to those cancers that will, in fact, be vulnerable to the potential medicine being studied.

Since this research was done, the high volume array has been further expanded so it now contains 1,200 cell lines from many kinds of human cancers.


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