Cancer therapeutics found in translation | May 23, 2016 Issue - Vol. 94 Issue 21 | Chemical & Engineering News
Volume 94 Issue 21 | pp. 30-35
Issue Date: May 23, 2016

Cover Story

Cancer therapeutics found in translation

Interdisciplinary teams at leading cancer centers work with 
outside partners to translate their basic research into medical practice
Department: Business
Keywords: oncology, translational research, collaboration, outsourcing, cancer
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MD Anderson’s main site consists of more than a dozen buildings just south of downtown Houston.
Credit: MD Anderson
 Aerial view of the University of Texas MD Anderson Cancer Center’s main site south of downtown Houston.
 
MD Anderson’s main site consists of more than a dozen buildings just south of downtown Houston.
Credit: MD Anderson

The 135,000 patients who pass through the University of Texas MD Anderson Cancer Center every year must navigate a vast maze of buildings. During long visits in Houston, they move from waiting areas, labs, and imaging centers to therapy suites, hospital rooms, and doctors’ offices. For these patients, the experience is daunting not only in its scale but also because the most ill among them may be seeking their last chance at treatment.

In brief

Scientists at National Cancer Institute-designated comprehensive cancer centers work at the forefront of oncology research and clinical science. Their unparalleled access to patients helps them identify disease targets and position potential therapies. Looking to translate their basic knowledge and clinical expertise into cancer therapies, several centers have established in-house drug development initiatives. By advancing potential drug candidates to the proof-of-concept stage, they hope to attract pharmaceutical industry collaborators to move new therapies through development and eventually to the market.

Read on to learn how the centers’ new approach to cancer therapy development is reshaping the way drug companies and academic researchers interact.

MD Anderson is one of the National Cancer Institute’s (NCI) 45 comprehensive cancer centers. Over many decades, these centers have built strong bases in patient care and clinical research.

But they are also wellsprings of basic science supported by annual research budgets in the hundreds of millions of dollars apiece. In labs and classrooms extending beyond the hospital complexes, they are home to prominent researchers, many of whom helped advance the science behind generations of cancer drugs, including today’s breakthrough immunotherapies.

At the centers, researchers and other staffers are driven by a desire to help patients, yet this feeling can be compounded with frustration. They want to be more effective in translating their special combination of research knowledge, clinical expertise, and medical insight into new therapies.

Increasingly, researchers and other officials at the NCI centers see the answer in mixing in-house R&D with industry partnerships. But when it comes to striking a deal, they can find that big pharma, despite its desire for new sources of innovation, isn’t interested in betting on basic research discoveries.

As a result, such centers are “taking things in their own hands,” says Bernard Munos, founder of the InnoThink Center for Research in Biomedical Innovation. “They have found out that their breakthrough discoveries can sit on the shelf, despite their promise, because of the conservativeness of the pharma industry.” With newfound do-it-yourself attitudes, these centers are building interdisciplinary programs grounded in deep understanding of disease biology to discover new therapies and move them toward clinical development.

It’s unlikely that the centers will try taking a drug all the way to market, Munos says. “They realize that this is expensive and, frankly, also a little bit boring. The early part of the translational research process is still pretty close to their core competencies.” Even by beginning the process, they can reduce the risk, increase the value of their therapeutics assets, and spark interest from pharma.

Extracting value is important. Declining government grant money has made industry sources critical to keeping research going. National cancer centers support their research through federal and local grants, philanthropic and foundational funding, sponsored-research and industry support, and investments and royalties. External sources often account for more than half of the money many centers spend on research.

At MD Anderson, one vehicle for tapping outside partners is the Institute for Applied Cancer Science (IACS), which opened in 2012 to discover small-molecule cancer drugs. A similar program, Oncology Research for Biologics & Immunotherapy Translation, targets biologics.

“An institution the size of ours needs to be providing its patients additional options,” IACS Executive Director Philip Jones says. “The ultimate goal here is to get some of our projects onto pharmacy shelves and one day have some of the medicines we develop change patients’ lives.”

The IACS team consists of about 75 researchers recruited primarily from the pharmaceutical industry. The institute has amassed capabilities including assay development, screening, pharmacology, and biomarker discovery. It also has structural biology and medicinal and computational chemistry capabilities.

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Cross-country
The National Cancer Institute has designated 45 sites across the U.S. as comprehensive cancer centers recognized for the depth and breadth of their research in basic, clinical, and/or population sciences. Most centers are affiliated with university medical centers.
Credit: National Cancer Institute
US map showing the 45 National Cancer Institute-designated comprehensive cancer centers. Fact boxes highlighting MD Anderson, Dana-Farber, Fred Hutchinson, Memorial Sloan Kettering, and Mayo Clinic.
 
Cross-country
The National Cancer Institute has designated 45 sites across the U.S. as comprehensive cancer centers recognized for the depth and breadth of their research in basic, clinical, and/or population sciences. Most centers are affiliated with university medical centers.
Credit: National Cancer Institute

1 Dana-Farber Cancer Institute

Founded: 1947
Main site: Boston
Faculty principal investigators/instructors: 373
Total revenues: $1.2 billion
Research spending: $348 million
Company partners: Array BioPharma, AstraZeneca, Bristol-Myers Squibb, Eli Lilly & Co., Evotec, Janssen
Start-up connections:
Acetylon Pharmaceuticals, Checkpoint Therapeutics, C4 Therapeutics, Neon Therapeutics, Tensha Therapeutics, Tizona Therapeutics

2 Fred Hutchinson Cancer Research Center

Founded: 1975
Main site: Seattle
Faculty: 215
Total revenues: $486 million
Research spending: $338 million
Company partners: GlaxoSmithKline, Juno Therapeutics, Merck & Co., Roche
Start-up connections: Adaptive Biotechnologies, Juno Therapeutics, Nohla Therapeutics, Presage Biosciences

3 University of Texas MD Anderson Cancer Center

Founded: 1941
Main site: Houston
Faculty: 1,714
Total revenues: $4.5 billion
Research spending: $781 million
Company partners: AbbVie, Amgen, Astellas Pharma, AstraZeneca, Boehringer Ingelheim, CytomX, GlaxoSmithKline, Intrexon/Ziopharm Oncology, Merck & Co., Tesaro
Start-up connections: ACF Pharmaceuticals, Codiak BioSciences, Immatics US, OncoResponse

4 Mayo Clinic Cancer Center

Founded: 1864
Main site: Rochester, Minn
Research physicians/faculty: 759
Total revenues: $10.3 billion
Research spending: $663 million
Company partners: Baxalta, Helix, Velocity Pharmaceutical Development
Start-up connections: Anexon, Vitesse Biologics, Vitruvian Networks

SOURCE: National Cancer Institute
NOTE: All total revenues and research spending numbers are for 2015.

“It’s everything that you have in a medium-sized biotech operation,” says Jones, who spent 15 years at Merck & Co. before moving to Dana-Farber Cancer Institute and then to MD Anderson. In contrast with what he experienced in industry, Jones says IACS researchers can interact quickly with other scientists who can help position therapies in different cancers and in the right patients because they are colleagues already within MD Anderson.

“We really have the best of both worlds,” Jones says. By “embedding a drug discovery operation here within the cancer center, we have the ability to identify novel targets and then move industry-quality molecules into development and proof-of-concept studies.”

IACS is advancing at least three discovery programs intended to deliver clinical candidates within the next 24 months. Its lead candidate, IACS-10759, is an inhibitor of oxidative phosphorylation for treating acute myeloid leukemia. With support from a soon-to-be-named foundation partner, it should move into a Phase I study this year.

Housed in new lab and initially backed with funds from MD Anderson, IACS is expected to become self-sustaining. Its intellectual property and collaborations should generate licensing fees, milestone payments, and royalties.

Indeed, this is already happening. In March, IACS announced a collaboration with Waltham, Mass.-based Tesaro, which will fund R&D in return for exclusive rights to develop and commercialize any resulting small-molecule candidates.

The match between IACS and Tesaro seems to be good. The six-year-old biotech firm’s business plan has been to acquire and develop existing drug candidates. Now “we want to bring more innovation into our pipeline through external discovery activities,” says Tesaro’s chief scientific officer, Jeffrey Hanke.

“They convinced us they had assembled an industry-level team that could really do creative drug discovery,” Hanke says of IACS. The partners quickly found that their desired drug targets overlap. “What drew us to IACS is a common philosophy of how we think about new targets and how we go after them from a drug discovery perspective,” he adds.

In fact, many of the researchers at IACS and Tesaro have known each other for years. Jones is among the inventors of niraparib, a poly(ADP-ribose) polymerase (PARP) inhibitor that Tesaro licensed from Merck in 2012. The drug is in Phase III trials for ovarian and breast cancers. Now the deal has opened new connections to even more investigators, Hanke says. “You can move pretty quickly within a broad institutional network like MD Anderson.”

Although the partners communicate often, “these guys know how to innovate, so we are not going to be too much in their way,” Hanke says. And they move aggressively because “they are motivated to make a difference,” he adds. Tesaro hopes to move the first candidate from the collaboration into development in early 2017.

Other centers are seeing drug companies with similar goals. “More and more, big pharma and biotech are looking to externalize innovation,” says Gary Sclar, interim chief research business development officer at Dana-Farber. Sclar’s office helps researchers move discoveries from the lab to the clinic and through to commercialization. Along with evaluating technologies, it handles patenting, licensing, collaboration setup, and start-up creation.

Increasingly, Sclar says, deals are shifting from the traditional sponsored-research model, involving one company and one investigator, to collaborations that might span preclinical and clinical studies and involve a dozen or more scientists. Dana-Farber is well-positioned to take advantage of this trend because its activities are split about equally between basic and clinical research, he adds.

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In addition to his presidential duties at MD Anderson, Ronald DePinho remains an active scientist within MD Anderson’s Institute for Applied Cancer Science.
Credit: University of Texas MD Anderson
MD Anderson President Ronald DePinho in an Institute for Applied Cancer Science lab.
 
In addition to his presidential duties at MD Anderson, Ronald DePinho remains an active scientist within MD Anderson’s Institute for Applied Cancer Science.
Credit: University of Texas MD Anderson

To help facilitate collaborations, Dana-Farber forms integrative research centers. One example is the Robert & Renée Belfer Center for Applied Cancer Science, an industry-inspired, self-sustaining center within the institute that is trying to discover and advance cancer therapies. Its founding director is Ronald DePinho, who is now MD Anderson’s president.

In February, Dana-Farber also joined four other NCI centers as part of Bristol-Myers Squibb’s (BMS) nine-month-old Immuno-Oncology Rare Population Malignancy (I-O RPM) program. The program focuses on the clinical investigation of immuno-oncology therapeutics for patients with high-risk, poor-prognosis cancers.

The I-O RPM partners will test drugs from the BMS pipeline. In 2011, BMS received approval for using the anti-CTLA-4 antibody Yervoy to treat melanoma. In 2014, its anti-PD-1 antibody Opdivo also was approved for melanoma, followed by lung and kidney cancer approvals in 2015. Much of the basic research and clinical work on these checkpoint inhibitors occurred at NCI centers. BMS acquired both of them with its 2009 acquisition of the biotech firm Medarex.

In the past, a big pharma firm might have contracted with a cancer center only to conduct a clinical trial and not much else. Thanks to motivations on both sides, new relationships between drug companies and clinical centers are becoming more collaborative from the start.

For example, rare cancers present particular challenges that led BMS to work with the cancer centers. These institutions have groups specializing in rare diseases and therefore see the most cases. Without access to specialized patient populations, developing new drugs or simply testing existing therapies would be impractical, if not impossible.

“We can go to the experts who really know these very, very small subgroups and design the right clinical trials,” explains Fouad Namouni, BMS’s medical head. But it doesn’t stop there. “It is really a very focused partnership in terms of clinical development and very good quality translational science,” he says.

Mayo Clinic Cancer Center took another approach about a year ago when it joined forces with the biopharmaceutical firm Baxalta and drug developer Velocity Pharmaceutical Development to create a drug R&D venture called Vitesse Biologics.

Baxalta was looking for creative ways to fund outside opportunities, says Geeta Vemuri, who heads the company’s investment arm. Drawing on the partners’ expertise and networks, Vitesse can find innovations anywhere as long as they align with Baxalta’s interest in hematology, oncology, and immunology.

Velocity is responsible for target identification, early-stage candidate selection, and the design and execution of preclinical and clinical protocols. Mayo researchers bring basic science and clinical expertise to these areas as well and will run early-stage clinical trials. Baxalta will provide antibody and protein development, manufacturing, and commercialization capabilities.

When projects become ready to move into the clinic, Vitesse will create spin-off subsidiaries. At least three projects have been identified, and the first spin-off is expected to be announced soon. If results of Phase I trials are promising, Baxalta has the option to acquire the drug candidates for further development.

For Mayo, Vitesse represents a new approach to working with outside partners. “In the past, the interaction between Mayo researchers and biotech and pharma companies occurred on an ad hoc basis, and those interactions led to a very mixed series of results,” says Andrew Badley, who directs Mayo’s Office of Translation to Practice within its Center for Clinical & Translational Science.

“About five years ago, some research faculty expressed the desire for Mayo to become involved in a more systematic way with drug discovery,” Badley says. Although the idea came from researchers, the institution was quick to adopt it. “Our leadership believes that it is in the best interest of our patients for Mayo researchers to be able to translate their basic science and discoveries into new therapies,” he explains.

Established only a few years ago, Badley’s office helps set up and oversee collaborations with outside partners. It also shapes internal project and translation teams. To help handle these tasks, he recruited two individuals with experience in drug and product development. The office also works closely with Mayo’s tech transfer department.

Compared with the tech transfer office, “we are more heavily involved in the selection of projects to move into partnerships, project management, and problem solving,” Badley says. “We define and make sure that our projects meet certain milestones, and if we are funding projects, which sometimes we do, then our funding is based upon the accomplishment of milestones.”

To provide its researchers with the resources required to foster drug discovery and development, Mayo has, for example, built and staffed small research and services groups at Mayo sites in Arizona and Florida. It also has connected with partners to provide drug discovery tools. Through these connections, Mayo researchers can now access high-throughput screening, assay methods, hit-to-lead optimization, medicinal chemistry, toxicology, and manufacturing.

Those involved in academic drug discovery efforts such as these may realize “that they can do the work cheaper than pharma because they are doing it virtually and outsourcing tasks when needed,” InnoThink’s Munos says. They may also enjoy more flexibility than do large pharma companies in being able to start and kill projects.

“Historically, the shorter the connection between the biomedical scientists and the patient, the better things have worked,” Munos says. “The ability for the scientist to gather feedback from patients and make patient observations directly has been a significant driver of innovation.”

As the number of collaborations rise, both sides are learning to work together. “We typically will create pilot projects with companies just to learn what it is like to interact,” Mayo’s Badley says. “Those with whom the relationship is good, deadlines are met, there’s no miscommunication, and things work smoothly tend to be ones that we continue to work with long term.”

Ferran Prat, vice president for strategic industry ventures at MD Anderson, contends that shaping collaborations becomes straightforward once there is alignment among senior managers. “If you have a shared philosophy of what the two parties can do together, then it is relatively easy to implement things on the logistics and capital sides.” Trained as both a chemist and lawyer, Prat spent nearly 15 years in industry before moving to the cancer center.

His 15-person office was set up about three years ago to manage tech transfer and commercialization in addition to collaborations. Before then, he says, the center’s relationship with industry was limited largely to enrolling patients for clinical trials. MD Anderson was not geared toward creating assets that, at the very least, could be “lobbed to the pharmaceutical industry or, even better, that we could actually codevelop,” he adds.

Not all companies are receptive to close collaboration with the cancer centers. “There are companies that still look at us as just providers of patients, like a pair of hired hands,” Prat says. “We just choose not to work with those companies, and that’s okay.” But overall, he’s been pleased with the number of companies that do want to work with the centers. And he sees a need for it.

“We believe that the drug development process, as it is now, is broken,” Prat says. “We are trying to change it to be a lot more collaborative and avoid the syndrome of a relay race.” Handoffs during the many stages of drug discovery and development are “very inefficient, and a lot of intellectual input is lost on both sides. It is not good for anybody but certainly not good for patients,” he says.

Researchers at the cancer centers are adapting to the changed relationship with industry, tech development managers say. Most have been receptive to looking outside their organizations and being able to advance their research.

“There is so much pent-up demand for something like this that we’ve just unleashed,” says Nicole Robinson, Fred Hutchinson Cancer Research Center’s vice president for industry relations and business development.

Hired less than a year ago to head the center’s Industry Relations & Technology Transfer Office, Robinson runs a roughly 12-person team that is focused on outreach, both internal and external. Internally, it has been working with faculty to explore opportunities for patenting, licensing, collaborating, and creating spin-offs.

Externally, Robinson wants to increase interactions with partners. Part of this process, she says, is “shopping our wares” and making companies, venture investors, and even other institutions aware of what the center has to offer in terms of its science and specialized research tools.

“These partnerships can be all different shapes and sizes,” Robinson says. Not only are there opportunities for different collaborative experiences, but there’s also good potential for increasing the diversity of funding coming into the center. “We want to make sure we have a sustainable funding base,” Robinson says.

Mirroring efforts at other NCI cancer centers, Fred Hutchinson plans to use existing funds to launch an initiative supporting proof-of-concept development work, Robinson says.

“All of this is an investment that the Hutch is making—hopefully with the promise of a really nice return,” she says. “And for us, the return is on the dollar investment but also on the mission investment. We want a return on our investment so that we can continue to pump revenues back into the organization to continue the discovery cycle.”


Cancer centers create wealth of start-up companies

Fred Hutchinson Cancer Research Center has a cell-processing facility in which it can manufacture therapies for early-stage clinical testing by its start-up companies.
Credit: Fred Hutchinson Cancer Research Center

Collaborations with industry partners are just one means by which many National Cancer Institute centers move their discoveries into commerce. They and their scientists created some of the first biotech firms and now are forming some of the most investment-popular start-ups in today’s hot area of immuno-oncology.

In 1981, former scientists from Fred Hutchinson Cancer Research Center founded biotech pioneer Immunex, which was later sold to the biotech giant Amgen. In 2013, Fred Hutchinson joined Memorial Sloan Kettering Cancer Center, Seattle Children’s Research Institute, and prominent venture capitalists who contributed $120 million to launch Juno Therapeutics, a leader in engineering T cells to fight cancer.

“We have a really entrepreneurial faculty here at the Hutch,” says Nicole Robinson, vice president for industry relations and business development. She says the center gets approached constantly by venture firms wanting to learn more about its technologies. “Many companies have started simply because the researchers have had connectivity to the venture community,” she says.

Since 1987, the University of Texas MD Anderson Cancer Center has created more than a dozen start-ups. A recent one is exosome-focused Codiak Biosciences, backed by $80 million from some of the same firms that invested in Juno. Similarly, Dana-Farber Cancer Institute has ties to numerous start-ups. Many were launched by former institute scientists Jay Bradner, who founded firms including Tensha Therapeutics and C4 Therapeutics, and Gregory Verdine, creator of Warp Drive Bio and Wave Life Sciences.

Establishing a start-up makes sense when scientists discover a platform for discovery or target validation rather than a single drug candidate, according to Ferran Prat, MD Anderson’s vice president for strategic industry ventures. An early-stage technology “needs organizational structure, managerial skill, and boatloads of capital to make it into something big,” he adds.

Although technology development of any sort calls for patience, industry collaborations around drug candidates typically generate some early returns for the centers in up-front fees and research support. In contrast, “most of the start-up opportunities are back-ended,” says Gary Sclar, interim chief research business development officer at Dana-Farber.

Setting up a new company incurs costs, and most of the return won’t come until the firm launches a product, goes public, or gets acquired. “So it is an investment in the future—start-ups aren’t going to pay your bills today,” he says.

With this in mind, most cancer centers hold equity investments in their spin-off companies. For example, both Fred Hutchinson and Memorial Sloan Kettering have stakes in Juno and are in the position to receive milestone payments on licensed products as well as royalties. Juno also is obligated to make “success payments” to both centers in cash or stock worth tens of millions of dollars each.

Juno itself has leveraged these strong connections. As it builds its own production facility, the company has used Fred Hutchinson’s in-house facility to produce materials for some early-stage clinical trials. And both Fred Hutchinson and Memorial Sloan Kettering have worked with Juno to run clinical trials.

“They are great partners and phenomenal colleagues, and we continue to do deals with them,” Robinson says. In February, Juno and the center announced a new immuno-oncology clinical trials unit. The University of Washington and Seattle Cancer Care Alliance are also investing. As part of the deal, Juno will provide research funds to Fred Hutchinson to support cancer immunotherapy research.

 
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