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doi: 10.1097/01.COT.0000444900.19117.bf
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James Doroshow on How NCI is Facilitating Drug-Discovery Combinations/Collaborations

Keller, Daniel M. PhD

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PHILADELPHIA—Public and private partnerships are taking an important role in drug discovery and development, and the International Meeting of the Society for Melanoma Research featured a session exploring ideas for how these partnerships may speed drug identification, testing, and approval.

James Doroshow, MD, Deputy Director of Clinical and Translational Research and Senior Investigator in the National Cancer Institute's Laboratory of Molecular Pharmacology, noting that the NCI is one of the largest public sector players in this endeavor, informed the audience of assembled melanoma investigators how the institute can facilitate the testing of small-molecule combinations for cancer therapy and foster collaborations.

In the past, he explained, cytotoxic chemotherapies used drugs that were active against a tumor, each with a different mechanism of action to minimize the development of resistance. Different toxicities allowed full-dose therapy.

Today, though, since modern targeted therapies use agents with activity against a particular molecular pathway, agents with complementary effects on the same or different targets in the pathway may be used together. Toxicities are related to the specific target inhibitions and may be moderate and different from those of cytotoxic drugs, allowing prolonged administration. Continuous administration or high doses may be chosen to effect maximal target inhibition.

Several challenges stand in the way of developing combination targeted therapies, he said. “The number one issue is that we still do not know nearly enough about the mechanisms of action and toxicity for a wide range of targeted agents.”

In addition, he said, a lack of biomarkers, assays, assay standardization, and imaging tools results in an inability to assess targeted effects.

“Another major issue is the lack of commercially available formulated agents for use in vitro or, I'd say, even in vivo,” he pointed out. “So, a couple of years ago we put together a panel of agents... We will send you all of the FDA-approved agents in DMSO [dimethyl sulfoxide]. They've all been QC'ed [quality control tested].” The compounds are provided free in “NCI COMBO Plates,” and more than 10,000 of these sets have been sent out so far to investigators around the world.

Drugs need to be tested in combination because growth inhibition is not predictable from the activity of single agents against a variety of cell lines, he continued. Experiments show that some two-drug combinations may be better than single agents whereas others may show a loss of benefit relative to best single-agent results.

The current Approved Oncology Drugs COMBO sets include 114 approved anti-cancer drugs in two microtiter plates per set. All proprietary agents in the sets have been obtained from commercial sources. The sets are shipped frozen on dry ice. For academic researchers, nonprofit organizations, and small businesses, there is no charge for the plates except for shipping costs. Cost-sharing arrangements can be worked out for large businesses.

Information for requesting the plates can be found at http://1.usa.gov/1g9kwsU. Required information includes a brief explanation of the research hypothesis and its relevance to cancer and a brief description of the screening process and characteristics of the assay. Data on the drugs in the plates and their arrangement on the plates are available in Excel format at the above link.

Doroshow also discussed the Cancer Immunotherapy Trials Network, funded through 2016, which was established to stimulate Phase I and II clinical trials to bring to the clinic novel immunotherapy agents, combinations, and approaches in a range of malignancies. The network now involves more than 25 institutions in the United States and Canada.

The NCI will produce reagents that lack a commercial sponsor, he said. A few of the agents with a high potential for cancer immunotherapy are interleukin (IL)-15, IL-7, and anti-CD-40. The first two are T cell growth factors and are being produced by the NCI. The NCI is supporting an academic effort for the development of anti-CD-40.

Finally, combination studies of anti-cancer agents can lead to questions and conflicts involving intellectual property. There may also be risks of adverse outcomes from the evaluation of investigational agents because of limited knowledge of their safety and efficacy.

Thus, he said, NCI has developed a system for negotiations between two or more companies and investigators and their institutions to work out non-exclusive royalty-free licenses to discover combinations of investigational agents in which NCI will “act as a middle man to make sure that these intellectual property [IP] requirements” are respected.

The system implements common data sharing and IP option agreement language. Collaborative and funding agreements now cover 105 trials combining investigational agents plus material transfer agreements covering 75 investigational agent combinations in non-clinical studies.

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iPad Extra!

In a video interview with Dan Keller on the iPad edition of this issue, James Doroshow elaborates on his remarks at the meeting, noting that the NCI wants to let cancer researchers know about the availability of resources.

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