With new multimillion-dollar grants, UCLA scientists take stem cell research to patients

UCLA Health article
Scientists from UCLA are now bringing their groundbreaking stem cell science directly to patients in two exciting new clinical trials scheduled to begin in early 2014, thanks to funding from California's stem cell agency.
The new grants to researchers at UCLA's Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, which total nearly $21 million, were announced Dec. 12 at a meeting of the California Institute of Regenerative Medicine (CIRM) Citizen's Oversight Committee. They are apart of the state agency's Disease Team Therapy Development III initiative.
A team led by UCLA's Dr. Dennis Slamon and Dr. Zev Wainberg was awarded nearly $7 million for a clinical trial that will test a new drug targeting cancer stem cells, and UCLA's Dr. Donald Kohn received almost $14 million for a clinical trial that will focus on stem-cell gene therapy for sickle cell disease.
"The CIRM support demonstrates that our multidisciplinary center is at the forefront of translating basic scientific research into new drug and cellular therapies that will revolutionize medicine," said Dr. Owen Witte, director of the UCLA Broad Stem Cell Research Center.
Dennis Slamon and Zev Wainberg: Targeting solid tumor stem cells
This clinical trial builds on Slamon's previous work, partially funded by CIRM, with Wainberg and Dr. Tak Mak, director of the Campbell Family Institute at the University Health Network in Toronto, aimed at developing a drug that targets those stem cells thought to initiate solid cancer tumors.
The American–Canadian collaborative team will lead this first in-human Phase 1 trial testing their new therapy, which has received investigational new-drug approval from the U.S. Food and Drug Administration and Health Canada, Canada's therapeutic regulatory agency. The project has been approved to begin enrolling patients in both the U.S. and Canada.
"We are delighted to receive this CIRM grant that will drive our translational research from the laboratory to the clinic and allow us to test our targeted drug in a Phase I clinical trial," said Slamon, director of clinical and translational research at UCLA's Jonsson Comprehensive Cancer Center and professor, chief and executive vice chair of research in the division of hematology–oncology. Slamon is renowned for his research leading to the development of Herceptin, the first FDA–approved targeted therapy for breast cancer.
The trial is based on the evidence built over the last decade for what has become known as the "cancer stem-cell hypothesis," which holds that cancer stem cells are the main drivers of tumor growth and are resistant to standard cancer treatments. One view is that cancer stem cells inhabit a "niche" that prevents cancer drugs from reaching them; another is that tumors can become resistant to therapy through a process known as "cell-fate decision," in which some tumor cells are killed by therapy while others become cancer stem cells. These resulting stem cells are believed to be capable of self-renewal and repopulation of tumor cells, resulting in the recurrence of cancer.
The target of the team's new drug is an enzyme in cancer stem cells and tumor cells called Polo-like kinase 4, which was selected because blocking it has been found to negatively affect the cell-fate decisions associated with cancer stem-cell renewal and tumor cell growth, thus stopping tumor growth.
"Our goal is to test this novel agent in patients in order to establish safety and then to proceed quickly to rapid clinical development," said Wainberg, an assistant professor of hematology–oncology at UCLA. "We are excited to continue this academic collaboration with our Canadian colleagues to test this drug in humans for the first time."
Slamon, Wainberg, Mak and their colleagues will also look for biological indications called biomarkers that researchers can use to tell if and how the drug is working.
Donald Kohn: Stem-cell gene therapy for sickle cell disease
Kohn, a professor of pediatrics and of microbiology, immunology and molecular genetics in the UCLA College of Letters and Science, and his colleagues successfully established the foundation for using hematopoietic (blood-producing) stem cells from the bone marrow of patients with sickle cell disease to treat the disease itself.
This approach provides a revolutionary alternative to current treatments, as it creates self-renewing, normal blood cells by inserting a gene with anti-sickling properties into hematopoietic stem cells. With this technique, there is no need to identify a matched donor, so patients avoid the risk of their bodies rejecting donor cells.
During the clinical trial, the anti-sickling hematopoietic stem cells will be transplanted back into patients' bone marrow to increase the population of "corrected" cells that make red blood cells that don't sickle. Kohn will begin enrolling patients in the trial within three months. The first subject will be enrolled and observed for safety for six months. The second subject will then be enrolled and observed for safety for three months. If evaluations show that no problems have arisen, the study will continue with two more subjects and another evaluation, until six total subjects have been enrolled.
Sickle cell disease, which affects more than 90,000 individuals in the U.S., is seen primarily in people of sub-Saharan African descent. It is caused by an inherited mutation in the beta-globin gene that transforms normal-shaped red blood cells, which are round and pliable, into rigid, sickle-shaped cells. While normal red blood cells are able to pass easily through the tiniest blood vessels, called capillaries, carrying oxygen to organs like the lungs, liver and kidneys, sickled cells get stuck in the capillaries, depriving the organs of oxygen, which can lead to organ dysfunction and failure.
Current treatments include transplanting patients with hematopoietic stem cells from a donor. This is is a potential cure for the disease, but due to the serious risks of rejection, only a small number of patients have undergone this procedure, and it is usually restricted to children with severe symptoms.
"Patients with sickle cell disease have had few therapeutic options," Kohn said. "With this award, we will initiate a clinical trial that we hope will become a treatment for patients with this devastating disease."
CIRM Disease Team III Awards
The purpose of the CIRM Disease Team Therapy Development III initiative is to advance early clinical development of novel therapies derived from or targeting stem cells. These novel therapies may offer unique benefits with well-considered risk to those with diseases or serious injuries. The CIRM grants only support programs that include a clinical study that can be completed and analyzed within a four-year period.
The Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA was launched in 2005 with a UCLA commitment of $20 million over five years. A $20 million gift from the Eli and Edythe Broad Foundation in 2007 resulted in the renaming of the center. With more than 200 members, the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research is committed to a multi-disciplinary, integrated collaboration of scientific, academic and medical disciplines for the purpose of understanding adult and human embryonic stem cells. The center supports innovation, excellence and the highest ethical standards focused on stem cell research with the intent of facilitating basic scientific inquiry directed towards future clinical applications to treat disease. The center is a collaboration of the David Geffen School of Medicine, UCLA's Jonsson Comprehensive Cancer Center, the Henry Samueli School of Engineering and Applied Science and the UCLA College of Letters and Science.
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