Inside CRI: Spring 2015

By March 3, 2015Inside CRI
Hope vs. hype: Stem cell research and treatments

 Sean J. Morrison, Ph.D., Director of the Children’s Research Institute

Earlier this year there was widespread media coverage about a medical procedure in which renowned hockey great Gordie Howe was said to have received stem cells in Mexico, reportedly improving the 87-year-old’s health following a stroke he suffered last year.

The news reports about this episode shined a spotlight on several issues that have revolved around stem cell research and related treatments for more than ten years.

Specifically, what is the realistic promise that stem cells and regenerative medicine hold for treating currently untreatable conditions? How quickly should potential treatments be made available for those suffering from these diseases? And how can we strike a balance between the rigorous requirements for scientific evidence and the hopes of desperate patients for a cure?

In fact, the stem cell research being conducted today is leading to new therapies, including therapies for currently incurable diseases. The research is surging forward much more quickly than I had expected, and there is an enormous amount of promising data. New treatments are starting to emerge for a variety of diseases and conditions.

But most people don’t understand how much research is required to transform even the best ideas into new therapies and to deliver them safely and effectively to patients.

In 1955, the first clinical trial of bone marrow transplants among unrelated patients was performed. Although the rationale underlying this procedure proved to be correct, and similar transplants now save thousands of lives per year, all seven patients in the first trial died. What they didn’t know at the time was that a successful transplant required the immune systems of the donor and recipient to be genetically matched. It took another 14 years of research before Donnell Thomas figured out how to do this and the first successful bone marrow transplant between an unrelated donor and recipient could take place.

The point is that even when the idea underlying the new therapy is right, and the therapy will ultimately succeed on a large scale, it can take a long time to learn how to do it safely and effectively. In my lab, we have been working for more than five years on a novel drug combination to treat melanoma, and are just now in a phase 1 clinical trial to test if the therapy is safe in patients.

We first studied the responses of melanoma cells to the drugs in a laboratory dish, and when that proved successful we moved on to treating mice that were implanted with human melanomas, a process that took several years to complete. Even in the hopeful event that we have positive results from the current trial, we will still need years of additional testing before significant numbers of people would benefit from the therapy.

In the United States, the Food and Drug Administration requires that new therapies be proven safe and effective before they can be marketed to patients. But some try to circumvent those requirements, either by trying to evade FDA regulation in the U.S. or by setting up a clinic outside the country to offer unproven therapies.

Meanwhile, the FDA is between a rock and a hard place. They get criticized both for making the approval process too rigorous and lengthy to enable new treatments to be brought quickly to market, and for not being careful enough when treatments turn out to have unanticipated safety problems after approval.

When you talk to reputable companies going through the FDA process to get a new treatment approved, there is widespread respect for the process. These are the companies that are spending millions, sometimes billions, of dollars to get approval.

Those companies know that the FDA is what allows experts to assess whether a particular treatment is safe and effective, something that individual patients or physicians rarely have the time or expertise to do on their own. Thus, despite all the criticism, Americans are much better off for having an FDA, because it’s the FDA that protects us from well-meaning ideas that just don’t work and from snake oil salesmen.

There are current efforts both on national and state levels to truncate the regulatory process for getting new treatments to patients. In Japan, a new law allows a stem cell therapy to be marketed to patients for a limited period of time if it has been shown to be safe in early clinical trials, but not yet shown to be effective in later clinical trials. And in the U.S., a growing number of states have passed or are considering so-called “Right to Try” laws that allow terminally ill patients to gain access to treatments that have appeared to be safe in early clinical trials, even if they have not yet proven effective.

These are troubling developments that are likely to have negative consequences for patients. First, without phase II and III clinical trials we cannot know whether a new therapy is safe or effective. This means that patients and doctors who take advantage of these accelerated paths to therapies will be forced to make decisions about which “therapies” to try, without any the information required to assess whether they are likely to benefit.

Beyond this risk to individual patients, there is a larger cost to our health care system. We could end up deploying a substantial amount of health care resources and personal financial resources for therapies that do not even work. This recently happened in Italy, where the country’s health care system was briefly overwhelmed by patient demands for a “stem cell therapy” that turned out to be bogus.

It’s important to remember that clinical trials are not just for the people enrolled in the trials, but also for all the other people in the world who are suffering or who will suffer in the future from the same disease. Many enrollees in clinical trials say they want to at least see progress toward curing the disease, even if they do not benefit personally. For that to happen, we have to systematically study potential new therapies in clinical trials that collect and share data on outcomes. Foreign clinics that sell unproven therapies to patient don’t do that.

Thus, when patients go outside the system of clinical trials to seek an unproven treatment, not only is their own response in doubt, but it also slows efforts to systematically collect the data required to improve treatments for future patients.

Cancer gene discovery stirs hope for future treatment

Each year in the United States, 700 children are newly diagnosed with neuroblastoma, 500 with Wilms’ tumor and 100 with hepatoblastoma.

Dr. Hao Zhu of the Children’s Medical Center Research Institute at UT Southwestern and his team have identified a gene known as Lin28 that contributes to the development of those childhood cancers, in a study conducted with mice designed to model the cancers. If the findings prove to be applicable to humans, the research could lead to new strategies for targeting certain pediatric cancers at a molecular level.

The next step for Dr. Zhu and his team is to establish whether genes related to Lin28 have similar effects on the development of cancer, and to determine if those genes might be more effective targets for potential therapies

CRI awarded for creating culture of innovation

When the Children’s Medical Center Research Institute at UT Southwestern (CRI) officially opened its doors in 2012, one of the ways it wanted to distinguish its efforts in biomedical research was by relentlessly pursuing discoveries that would change the direction of science and medicine. CRI’s early success in breaking new ground is reflected not only in the number of discoveries published in the highest impact scientific journals — 23 and counting — but also in the recognition its scientists and the institute itself are receiving for the work being done.

Recently CRI was named an Innovation Catalyst by the Greater Dallas Chamber for strengthening the region’s capacity for innovation. The award reflects the culture at CRI that encourages bold risk-taking in pursuit of significant findings toward the treatments of tomorrow. CRI’s discoveries are already leading to clinical trials to test new therapies for incurable diseases, including a Phase 1B clinical trial that is now underway to assess a novel drug combination in stage IV melanoma patients.

CRI also has established an innovative Genetic and Metabolic Disease Program in collaboration with Children’s Medical Center Dallas and the UT Southwestern Department of Pediatrics (see A quest to pinpoint and treat unidentified diseases in this issue of Inside CRI). The goal of the program is to improve the diagnosis and treatment of children who suffer from inborn errors of metabolism by applying cutting edge genomic and metabolomic technologies to identify the genetic defects in undiagnosed children, and to understand their consequence for metabolic pathways.

In addition to the significant work being done in the lab and in the clinic, CRI researchers have been exceptionally successful at leveraging philanthropic investments with extramural grant funding from the Cancer Prevention and Research Institute of Texas, the National Institutes of Health, the Howard Hughes Medical Institute, and other medical research organizations.

Overall since its inception, CRI has attracted $41 million in extramural grant funding, an exceptional figure for a new institute.

A quest to pinpoint and treat unidentified diseases

In late 2013, the Children’s Research Institute at UT Southwestern (CRI) launched its Genetic and Metabolic Disease Program, led by Dr. Ralph DeBerardinis. The program focuses on identifying mutations in genes that are causing previously unidentified metabolic problems in children who present at Children’s Medical Center Dallas, and to use that information to develop new therapies.

The clinical side of the program currently has five physicians who see patients — with plans to grow to eight physicians — along with support personnel including genetic counselors and dieticians. On the research side of the program, scientists at CRI are using the information gathered in the clinic to investigate the molecular basis of genetic diseases that are currently not understood, and then find ways to reverse the metabolic process and treat those diseases.

The program has already identified new disease mutations in two different families. In one family, identification of the mutation led directly to new strategies to attempt to treat the patient. The next development for the program is to begin generating a large, de-identified database of metabolite levels in children with genetic diseases as well as those who are disease-free — a resource that does not currently exist anywhere in the world — which will greatly improve the ability to recognize metabolic abnormalities in those children who have unidentified diseases.