Frederick National Laboratory Advisory Committee Welcomes New FNL, NCI Leaders

By Chris Worthington, Staff Writer; contributed images
Dr. Doug Lowy, former acting NCI director, speaks at a Frederick National Laboratory Advisory Committee meeting.

The Frederick National Laboratory Advisory Committee (FNLAC) recently met to discuss the future of several high-profile Frederick National Lab initiatives in a meeting that included a chance to meet the new NCI and FNLCR leaders. Here is a look at a few of the highlights from the last of the 2017 FNLAC meetings.

New Faces at FNLAC

The committee was introduced to Dr. Norman (“Ned”) Sharpless, the new director of NCI, and Dr. Ethan Dmitrovsky, who has since replaced Dr. David Heimbrook as the president of Leidos Biomedical Research, Inc., which manages the Frederick National Lab.

Both offered brief comments to the committee. Sharpless said that he “spoke to every living former director of the NCI, and … asked all of them about” the Frederick National Lab, which has given him a better idea of the scope and the mission of the project—though he also believes that it’s an entity that remains poorly understood. He said he is eager to learn more and was looking forward to hearing from the committee.

Following the meeting, he tweeted: “Pleased to have met FNLAC members; appreciate your commitment. Look forward to cont'd excellence of #FredNatLab.”

Dmitrovsky thanked Heimbrook, saying “David has given his all to FNL and is an example of servant leadership.” Dmitrovsky also gave a brief history of his career, which began in Building 10 on NIH’s Bethesda campus but later shifted to academic institutions. He once promised Dr. Doug Lowy, former acting NCI director, that he’d eventually return to NCI and has now fulfilled that promise.

Lowy then thanked Heimbrook for overseeing the Frederick National Lab during a period of considerable change. FNL’s substantial improvement in recent years, Lowy said, is thanks in no small measure to Heimbrook’s leadership, especially in the development of the RAS initiative and initiatives related to the Cancer Moonshot.

“I could go on, but Dave has been a wonderful colleague for NCI, not just for Leidos,” said Lowy. “We have been able to interact in a very collegial way to try to make our communications and interactions between NCI and Leidos better than I think they have been in the past.”

Uncertainty Shrouds Budget Forecasts

Lowy spoke briefly about the fiscal 2018 NCI budget, which remains in flux. Each of the NCI budget appropriations proposed by the House, Senate, and executive branch vary greatly. The 2017 appropriation was $5.389 billion with an additional $300 million from the Cancer Moonshot for a total budget of $5.689 billion. The president’s proposed 2018 budget represents a decrease of 22.5% compared to 2017 funding, while both the Senate and House proposed increases of 3.1% and 1.5%, respectively.

ATOM Consortium Officially Launches

Heimbook then gave an update on the Accelerating Therapeutics for Opportunities in Medicine (ATOM) Consortium, which is seeking to transform the way cancer drugs are discovered by creating an open and sharable platform that integrates high-performance computing, shared biological data from public and industry sources, and emerging biotechnologies to dramatically accelerate the discovery of effective cancer therapies.

ATOM, which comprises the Frederick National Lab, the Department of Energy’s Lawrence Livermore National Laboratory, GlaxoSmithKline, and the University of California, San Francisco, launched on October 27.

The goal of the consortium, Heimbrook explained, is to create a new paradigm of drug discovery that would reduce the time from an identified drug target to clinical candidate from the current timeline (approximately six years) to just 12 months by using supercomputers to simultaneously pretest many molecules for safety and efficacy.

Within three years, the consortium hopes to develop workstreams and capabilities and ultimately create a proof-of-concept to demonstrate that its ambitious goal can be achieved.

The consortium’s research could lead to substantial cost savings, since much of the cost of a new drug—somewhere between $1 billion and $1.5 billion—is spent in the preclinical space, according to Heimbrook.

NCEF Is Fully Operational

Conversation then shifted to the National Cryo-Electron Microscopy Facility (NCEF) at NCI, which launched on May 15 under the guidance of Dr. Sriram Subramaniam, senior investigator, Laboratory of Cell Biology, who provided an update on the facility.

Though cryo-electron microscopy (cryo-EM) is not a new field, excitement has been building recently, culminating with Nature Methods naming cryo-EM its “Method of the Year” in the January 2016 issue.

Several months prior, in September 2015, the FNLAC unanimously approved a proposal for an NCI-funded national cryo-EM user facility at the Frederick National Lab. The proposal set a budget of $5 million per year for four years. Now that it has launched, NCEF will provide a no-cost service that gives researchers around the country access to high-resolution structural analysis.

According to Subramaniam, an FEI Titan Krios microscope is installed and operational in Gaithersburg, MD—though construction of a new microscope facility at the Advanced Technology Research Facility (ATRF) is slated to be finished by June 2018, at which point the first Krios microscope will be relocated to the ATRF.

A second Krios microscope will be added to the new facility beginning in July 2018, and a third may be added in 2019 depending on demand and continued funding. In addition, the NCEF may add one or two additional personnel if demand continues to grow. Currently, the wait time is one month for new projects, and that number is growing as the facility receives more requests. Users from 11 institutions have taken advantage of the service, and 40 projects have been imaged since the facility opened.

RAS Initiative Rolls On

After lunch, Dr. Frank McCormick talked about the RAS initiative, the current goals of which include directly targeting KRAS, understanding the biology of KRAS in the context of the plasma membrane, working with the Department of Energy to bridge experimental gaps using computation, and continuing to screen further leads.

McCormick then described several current RAS projects, including:

  • Targeting the C-terminal of the RAS protein to inhibit farnesyltransferase and geranylgeranyltransferase;
  • Developing compounds to knock down KRAS in cells;
  • Specifically targeting C185 and H95, which may be KRAS-selective; and
  • Collaborating with Dr. Subramaniam to use cryo-EM to image the RAF dimer.

Finally, McCormick announced that the second annual RAS symposium will be held from December 6–8 at the ATRF. More than 500 people are expected to attend or watch via webcast.

Dr. Doroshow Discusses the Chemical Biology Consortium

Dr. James Doroshow, deputy director, Clinical and Translational Research, and director, Division of Cancer Treatment and Diagnosis, discussed the Chemical Biology Consortium (CBC), a project that was conceived as the front end of the NCI Experimental Therapeutics (NeXT) program and is meant to engage the academic community to gather data and resources for high-risk projects, with a focus on the drug discovery pipeline.

Projects come in every four months, said Doroshow, and submissions are reviewed by a special interest panel to determine whether they are worth pursuing.

The consortium is currently involved in several projects: assisting in the development and advancement of a potential anti-apoptosis therapy targeting the Mcl-1 protein; epigenetic-based therapy through three projects, the Histone Demethylases KDM5A and 5B, disruption of the WDR5-MLL1 complex, and inhibition of Taspase1; a cancer metabolism project, LDHA; a proteasome inhibitor alternative, the p97 ATPase; and a novel endonuclease target. 

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