What is Translational Research? Explaining the “Valley of Death’”

research2In our last post, we explored the different phases of cancer research. One of these phases—translational research—is sometimes referred to as the “Valley of Death.”

Translational research got this reputation because the process of translating early discoveries into effective treatments for patients is time-consuming, costly, and often unsuccessful. A discovery in basic science—for instance, a new way of monitoring how a certain tumor spreads through the body—must be followed by years of additional work before it becomes a treatment.  One recent article estimated that the rate of success in translational science is less than 1%. This means that if 5,000-10,000 compounds are tested, only about 5 will end up in Phase 1 studies, and only a single drug is likely to survive to become approved by the FDA.

If we follow the tumor discovery down the drug pipeline, we begin with researchers trying to figure out what proteins, enzymes, or other targets will accompany the tumor they can now track, and which of them might be susceptible to treatment. Perhaps after much testing, researchers discover that a single protein is instrumental to the growth of the tumor. The next step is to find compounds that will inhibit this protein, thus inhibiting the spread of the tumor. They might test hundreds or even thousands of compounds to see which ones work to inhibit this protein. Then, they need a good model of the tumor to test these potential compounds. Once they have narrowed down the compounds to the hundred or more most effective drugs, they will test them on animal models.  Both tumor models and animal models take time and expertise to develop to ensure they are accurate and behave like a tumor in a human.

The handful of potential treatments that make it through these initial phases and through pre-clinical testing may go on to Phase I studies in humans, the next stage of the research pipeline. If researchers are incredibly lucky, one of these treatments will be effective in treating the disease and patients will be able to tolerate it. After several more rounds of clinical trials, the drug can move on to the expensive and lengthy process of receiving FDA approval for wider use.

Although translational research is a crucial step for discovering new cancer treatments, it is an under-funded research area, in part because the risk of failure is so high. While a discovery in basic science has the potential to impact hundreds of disease areas, translational research is the crucial bridge between the laboratory and improving outcomes for patients today. In addition, because early research is so often funded by government and clinical trials are often funded by pharmaceutical companies, it can be difficult to move between these different environments and funding models. You can find more information about translational research here, here, or here.

The Challenging Road to New Childhood Cancer Therapies

research1Even though cancer is responsible for more deaths in children than all other diseases combined, the road to developing new treatments for pediatric cancer is long and slow. There are roughly four phases in the development of new therapies: basic research, translational research, clinical trials, and FDA review and approval.

Basic research is motivated by scientific curiosity without a specific end goal or product in mind. In contrast to applied research, which focuses on the practical use of scientific discoveries, basic research is undertaken for the advance of scientific knowledge and often serves as a foundation for the applied work that follows. One example of basic research is the development of recombinant-DNA techniques in the laboratory. This discovery has allowed scientists to study human genetics in much greater detail, so that scientists can now understand the precise coding of cancer mutations.

The second phase of research, translational research, takes discoveries in basic science and tries to apply them to treating and preventing diseases. This phase of research has been nicknamed the “valley of death” because it is incredibly difficult to move a discovery successfully from basic science to clinical application. Sometimes, researchers will test a compound unsuccessfully on one disease and find years later that this same compound is effective for treating a completely different disease.  This is true for raloxifene, a drug developed for osteoporosis that is actually more effective at breast cancer prevention. Translational research includes identifying cancer biomarkers and targets, and developing early testing in animal models. Even though translational research is often not successful, it is the crucial bridge between early discoveries and new drugs for patients.

Once researchers have found compounds that work on animal models, they move into the third phase of research: clinical trials. Clinical trials test new treatments on human patients. Clinical trials also have phases, which you can read more about here. Once a new treatment has gone through clinical trials, it must also go through FDA review and approval, another lengthy process in which the FDA determines whether the treatment is effective and safe for all patients.

The funding model for the current pipeline is piecemeal, contributing to the slow pace of drug development. The early stages of the pipeline are primarily funded by public sources like the National Institute of Health, while the latter stages of clinical development and FDA review are chiefly funded by for-profit industry like pharmaceuticals. Translational research is often a mix of government funding, private funding, and pharmaceutical development. CureSearch works to accelerate this process by funding research that is moving into clinical development to speed the translation of promising discoveries into potential new therapies to treat children’s cancers. By providing flexible, large-scale funding for researchers with project support and firm research deadlines, CureSearch tries to move translational discoveries into clinical application faster.

Meet the Children: Wesley Zablocki

Wesley was diagnosed with osteosarcoma (bone cancer) on March 29, 2011, after a chance fall and lucky x-ray. He was immediately thrust into the world of hospitals, doctors and the unknown. His parents had no idea what to expect with the treatments, how he would react or what they would do to their otherwise healthy son. After nine months of chemo treatments and a really-really long limb salvage surgery he was pronounced “No Evidence of Disease” for nine months. Then in October of 2012 there was a recurrence of thecancer in his lungs. Immediately they were again thrown into a life they did not choose.

Wesley had six more months of chemo and surgery on his lungs. His first set of post treatment scans, in April 2013, showed one small spot on his right lung that was too small to do anything about so the doctors just watched it for six months until it grew some and they could remove it. Another lung surgery. In the meantime it was discovered that his leg had not completely healed as they thought and in January of 2014 he had another lengthy surgery on his leg to fix the issues. Just when the family thought there might be a break in the action his scans in February displayed more cancer in his left lung. A third lung surgery.

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Six Young Investigator Grants Now Available!

$1.3 million in research funding to be provided by CureSearch
CureSearch for Children’s Cancer is now accepting applications for six (6) Young Investigator Grants. These “Young Investigator Pathway to Independence Grants” are funded at $225,000 each over three years and will be available in the areas of neuroblastoma, palliative care, rhabdomyosarcoma, and three “open” areas. “Open” applications may be in disease or discipline areas of pediatric oncology and will be based on the merits of the research proposed, the productivity of the applicant, mentorship, and environment.

Awards will be announced in October, 2014 and funding will begin in January, 2015.

For those interested in applying, RFAs are available on proposalCENTRAL.altum.com.

Why Even ‘Failure’ Is Important

Most of us probably learned about the scientific method in grade school: ask a question, do research, construct a hypothesis, test it to see if it works, analyze results, and communicate the conclusion. We also probably learned that even when your experiment doesn’t turn out the way you expected, the results are still important!

This is also true in academic medicine. When researchers work to develop an effective new treatment, they often start by testing out specific chemical compounds and their effects on cancer cells. Researchers have to rule out hundreds or even thousands of compounds before they find one that works. This is a very long process, and from the outside, it can sometimes seem like nothing is getting done. However, the process of elimination is crucial to discovering new treatments! Every compound crossed off the list gets researchers one step closer to their ultimate goal: finding effective, safe treatments for childhood cancer.

One example is the discovery of All-Trans-Retinoic-Acid (ATRA), which is used to treat Acute Promyelocytic Leukemia (APL), which is a unique subtype of Acute Myeloid Leukemia (AML). In the 1970’s, children diagnosed with APL were considered very high-risk cases. Only about 50% made it to complete remission, and many relapsed or suffered significant side effects. Researchers who were studying the cellular structure of APL discovered that APL had a high number of “immature” cells, meaning they replicated very quickly. They realized that certain compounds might be able to make these cells “differentiate,” or mature, so they behaved more like normal cells. After testing hundreds of compounds like butryrate, hypoxanthine, and dimethyl sulfoxide, they landed on ATRA. ATRA was a vitamin-A derivative that caused APL cells to “differentiate,” dramatically reducing the spread of the cancer. ATRA has far fewer side effects than conventional chemotherapy, and it was nearly miraculous in treating the disease. Adding ATRA to standard treatment increased the remission rate from about 50% to almost 90%.

In order to find ATRA, researchers first had to eliminate hundreds of other compounds that failed to work with APL. Researchers could have considered these other compounds “failures,” but we prefer to think of them as necessary steps along the way toward the development of a new treatment. At CureSearch, we know that the road to a life-saving discovery is paved with these failures.

Sources:

Breitman, T. R., Stuart E. Selonick, and Steven J. Collins. “Induction of differentiation of the human promyelocytic leukemia cell line (HL-60) by retinoic acid.” Proceedings of the National Academy of Sciences 77.5 (1980): 2936-2940.

Breitman, T. R., Steven J. Collins, and B. R. Keene. “Terminal differentiation of human promyelocytic leukemic cells in primary culture in response to retinoic acid.” Blood 57.6 (1981): 1000-1004.

CureSearch Hosts Second Annual Research Symposium!

Topics will focus on emerging themes in laboratory science
Symposium

On October 17-18, CureSearch will host its second annual research symposium in Washington DC. This year’s Symposium, entitled “Translational Oncology: Emerging Targets in Childhood Cancer” will focus on emerging themes in laboratory science with potential for early implementation. Featured speakers include Malcolm Smith, James Bradner, and John Maris.

The Symposium offers special networking opportunities for young investigators seeking careers in clinical or translational oncology. For more information about the event, including registration and hotel information, please visit www.curesearch.org/Symposium. We hope to see you there!

Meet the Children: Cora Johnson

Cora JohnsonIn seventh grade, Cora found a lump in her breast. She and her mother Martha went to the doctor to see what was causing the lump. Cora’s doctors performed an ultrasound, but the results were inconclusive. After another ultrasound her team of doctors determined that she had a tumor. They weren’t sure what type of cancer Cora had, but they knew that they had to remove it.

Cora had surgery at Children’s Hospitals and Clinics of Minnesota, where doctors discovered that she had a rare form a skin cancer called Dermafibrosarcoma Puterberan. Another surgery was needed to ensure that clear margins were obtained. Since then Cora continues to be monitored by her oncologist and surgeon.

While they were at the hospital, Cora saw a poster for the CureSearch Walk and told her mom that she wanted to get involved. They formed a team – Cora’s Pink Posse – and started fundraising right away. Cora has taken the lead on organizing events and motivating her teammates to continue fundraising. Helping other children with cancer has become her passion. “We love seeing people come together to support survivors and those who have lost their battles,” says Martha. “Seeing people come together is really moving. The CureSearch Walk has become a great community.”

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