May 12, 2017, by James H. Doroshow, M.D., and Jerry Collins, Ph.D.
If you ask most cancer researchers how we can achieve greater therapeutic gains for patients, they will almost certainly cite the need to find effective combinations of treatments. Indeed, combination therapies are viewed as a central way to overcome one of the most vexing issues in cancer therapy: treatment resistance.
Now, NCI has released a new, easy-to-use resource to help researchers identify potentially promising combinations of cancer drugs. This resource, called the NCI ALMANAC, provides data showing how well pairs of Food and Drug Administration-approved cancer drugs performed in killing tumor cells from the NCI-60 Human Tumor Cell Lines, a library of cancer cell lines maintained by NCI.
The data in the NCI ALMANAC are a starting point for future studies and are by no means definitive. With this new resource, we’ve done some heavy lifting for the research community, performing a resource-intensive, robust drug screen to generate data that can provide researchers with new hypotheses to advance to the next stage of investigation.
Indeed, as our group at NCI reported April 27 in Cancer Research, this new database has already borne fruit. Using the NCI ALMANAC, we identified several different drug combinations that have never before been tested together in humans but that nevertheless had powerful cell-killing effects in a number of the NCI-60 cell lines.
Based on what’s known about how the individual drugs in these combinations work, it’s highly unlikely that many of these combinations would have ever been subject to investigations without the NCI ALMANAC data. Yet, based on further mechanistic and animal model studies for two of these combinations, NCI investigators have launched two phase I clinical trials to test these respective drug pairs in patients with advanced cancer.
A New Use for a Well-Tested Resource
The NCI-60, which includes cell lines from a diverse array of cancer types, was established more than 25 years ago. Since that time, it’s been a valuable resource for researchers from academia and the private sector.
Although it has limitations, the NCI-60 is the most robust molecularly characterized cell line panel in existence. For each cell line in the NCI-60, we have data on RNA expression, protein levels, enzyme activity, and much more. So, when a novel compound is tested against cell lines in the NCI-60, it’s possible to determine not just whether it kills the cells, but how it affects the molecular machinery of a cancer cell—information that is critical for understanding how a drug works.
The idea behind the NCI ALMANAC is simple: use the NCI-60 to determine whether specific drugs are more effective when used together in combination than when used alone. In practice, however, developing this new resource was anything but simple.
The NCI ALMANAC includes data on more than 5,000 pairs of FDA-approved drugs that were tested against the NCI-60—a total of 300,000 experiments. And each drug in each pair was tested at different doses, producing nearly 3 million data points.
From Hypothesis to Clinical Trial
The report from our NCI group in Cancer Research provides an ideal case report of what the NCI ALMANAC results might mean for advancing new drug combinations into human trials.
We began by conducting follow-up experiments on a subset of drug pairs identified in the database that exhibited potent cell-killing effects. From this work, we selected two drug pairs for more extensive follow up: nilotinib (Tasigna®) and paclitaxel (Taxol®), as well as bortezomib (Velcade®) and clofarabine. These combinations were tested for their antitumor activity in several mouse models of human tumors, and additional experiments were performed to investigate the mechanisms by which these combinations kill tumor cells.
The results from this work were convincing enough that we launched phase I clinical trials of both drug combinations at the NIH Clinical Center. The nilotinib/paclitaxel and bortezomib/clofarabine trials are ongoing and still recruiting patients.
From Heatmap to Phase I Trial
The screening results captured in the NCI ALMANAC can be viewed in multiple formats, from heatmaps, which provide a way to quickly and easily visualize results, to dose-response graphs, which allow for deeper dives into the data.
Data in the NCI ALMANAC showed that the combination of nilotinib and paclitaxel had robust cell-killing effects in blood cancer and triple-negative breast cancer cell lines. Based on these data, the NCI researchers conducted more in-depth analyses of this combination, including testing in different triple-negative breast cancer mouse models and performing molecular analyses of tumor samples from treated mice.
The experiments confirmed that in many models, each drug on its own had either no effect on tumors or inadequate activity. But, together, they effectively killed cancer cells and shrank tumors. In one model, in fact, the treatment completely eradicated tumors and prevented them from returning for the duration of the experiment.
Additional analyses of tumor samples and cell lines suggested a mechanism for this drug pair’s enhanced cell-killing, but the NCI team noted that further studies are needed to better understand how the combination works.
Building on a Public Resource
The research effort that produced the NCI ALMANAC began in 2009, with an infusion of funds from the American Recovery and Reinvestment Act. As a result, the database doesn’t include many of the newer drugs approved by FDA over the past several years. Nevertheless, this publicly available tool should help to generate scientific ideas that may also apply to more recently approved therapies.
Of course, the community is transitioning from standard cancer cell lines to newer, more advanced models of cancer—a transition that NCI is actively working to advance. With the NCI ALMANAC, however, we’ve used tried-and-true models to provide a new resource for identifying and developing potentially effective new therapies. [To allow investigators to conduct similar studies more easily in their own model systems, NCI offers an updated set of FDA-approved anticancer drugs in plated formats. More information is available on the Developmental Therapeutics Program website.]
Because all the drugs included in the NCI ALMANAC are FDA approved, it should be easier to address the regulatory requirements for testing any promising NCI ALMANAC drug combinations in humans, greatly expediting the ability to move these drug pairs into clinical trials.
We encourage the research community to investigate the NCI ALMANAC and are hopeful that, as a result, we’ll see additional clinical trials that identify effective combination therapies for our patients.