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Pediatric Developmental Therapeutics Center of Excellence at UCSF

University of California San Francisco
Katherine Matthay, MD, Kieuhoa Vo, MD, - Scholars: Amit Sabnis, MD, Lena Winestone, MD/MSHP, Beth Winger, MD/PhD, Bo Qiu, MD/PhD
Grant Type: 
Center of Excellence Grants
Year Awarded: 
Type of Childhood Cancer: 
Leukemia, Neuroblastoma, General Pediatric Cancer
Project Description: 

UCSF has an active Pediatric Cancer Developmental Therapeutics Program. The goals of the program are:

  1. to translate promising laboratory findings into rational early phase trials of novel targeted therapies for children with cancer; and
  2. to train new researchers with an interest in developing and leading early phase clinical trials.

Our team has a long and outstanding track record for leading phase I and II clinical trials in pediatric oncology. The program benefits from the rich resources for clinical and translational research available at UCSF, one of the nation's preeminent health sciences institutions. Our pediatric research laboratories focus on a range of pediatric cancers including neuroblastoma, leukemia, sarcomas, and brain tumors. Findings from these laboratories have led to phase I trials of targeted therapy. Designation as a Center of Excellence will allow us to expand our program in several key ways. We will enhance coordination with our research laboratories to focus on the most promising new drug targets, expand the portfolio of clinical trials we are able to offer patients in the Western United States, improve our outreach efforts to increase clinical trial participation, and increase collaboration with other Alex’s Lemonade Stand Foundation Centers of Excellence. We will train new investigators with the aid of strong mentorship and formal structured course work in our Training in Clinical Research Master's degree program and our NIH-sponsored Clinical Pharmacology training program. The net impact of these efforts will be a self-sustaining premier pediatric cancer developmental therapeutics program that improves the treatment of children with cancer.

Project Update

Tiffany Chang, MD, a Developmental Therapeutic Scholar at UCSF's Center of Excellence (shown above), answered questions about the project (August 2014):

"It is truly an honor to have been chosen as an ALSF Scholar. The generosity of donors and volunteers makes necessary cutting-edge research in childhood cancer possible. It is because of this support that we may be able to offer kids and their families fighting JMML [juvenile myelomonocytic leukemia] hope for a cure in the future." - Dr. Tiffany Chang

Why did you choose to create a Center of Excellence (COE) at UCSF?
We were extremely fortunate to have the opportunity to apply for a Center of Excellence Award in Developmental Therapeutics. One of our strengths at UCSF is an emphasis on translational research, making it a natural choice to establish a COE here. UCSF is poised to train young investigators in developmental therapeutics by capitalizing on the ground-breaking laboratory research conducted here, and bringing novel agents targeting pediatric cancer into the clinic. Our developmental therapeutics program is growing rapidly, and the ALSF award is allowing us to continue expanding our efforts.

How long does it take to study a new therapeutic intervention?
It takes an average of 12 years (and millions of dollars) for a drug to move from the laboratory bench to the patient’s bedside. Furthermore, only 10% of the drugs that begin preclinical testing ever make it to human testing, and even fewer make it all the way to FDA approval. 

How many studies do you run concurrently for childhood cancer?
We currently have 30 Phase I/II clinical trials open at UCSF treating children with a variety of cancers including leukemia, brain tumors, neuroblastoma and sarcomas.
What obstacles/challenges do you face in bringing new treatments to children with cancer?
I think it is a truly exciting time in pediatric cancer research. New drugs are being discovered at a remarkable pace, but just when we are most poised to capitalize on all the prior years of investment, the current funding climate has placed potential life-saving discoveries in jeopardy. 

As I mentioned, the cost of developing a new drug is high, and childhood cancer as a whole, though significant, is too small a market to attract the attention of private industry. Furthermore, industry-sponsored studies of new agents in children typically lag far behind studies in adults. Only 4% of the National Cancer Institute’s budget is dedicated to childhood cancer. As such, foundations like ALSF play a critical role in bridging these funding gaps so that promising new treatments make it to the children who need them.

What has this grant from ALSF allowed you to do that you wouldn’t have been able to do otherwise? Describe your role as a Developmental Therapeutic Scholar. How are you being trained and what is the long term expectation for you in your field?
As an ALSF Scholar, I have been able to enroll in the Training in Clinical Research (TICR) Master’s Degree Program at UCSF, and am initiating my second year of study as of July 2014. This clinical research curriculum has complemented the laboratory training I have already received, and will allow me to most effectively translate my preclinical findings to benefit patients through the first MEK inhibitor clinical trial in children with leukemia. I have also completed a 2-year American Course on Drug Regulatory Sciences (ACDRS), which provided me with intensive training in the scientific and regulatory requirements needed to take a novel agent from the laboratory to first-in-man studies to FDA registration. 

Being an ALSF Scholar has leveraged further support for my research, which has been invaluable. Since becoming an ALSF Scholar, I have received the following awards:

  1. 2013 UCSF Melvin M. Grumbach Award for Excellence in Research: awarded to one pediatric fellow each year for excellence in research.
  2. St. Baldrick’s Fellow Award: one-year extension of grant supporting pediatric oncology research ($48,500) after completion of 2-year award.
  3. Leukemia & Lymphoma Society Special Fellow in Clinical Research Award: three-year grant supporting pediatric oncology research  ($65,000 per year).
  4. NIH Loan Repayment Program Renewal: One-year renewal after completion of prior 2-year award.
  5. Acceptance to the Translational Research Training in Hematology (TRTH) program.

This program provides junior researchers with a unique, year-long training and mentoring experience. The program is a joint effort of the European Hematology Association (EHA) and the American Society of Hematology (ASH) and is focused on helping early-career scientists build successful careers in hematologic translational research, including pathogenesis, diagnostics, and experimental treatment of hematological disorders. Twenty early-career scientists are selected each year to participate in this rigorous training program. TRTH faculty is made up of international leaders in hematology who cover biostatistics and biomarkers, genetics and molecular biology, ethics, and phase I clinical study design.  The TRTH program contains: a week-long spring course, a meeting at the EHA Annual Congress where trainees work on refining their research proposals, and a meeting at the ASH Annual Meeting where trainees make a final presentation on the status of their research.

Through the mentorship of Dr. Matthay and Dr. Dubois, I am also training to become a leader in the field of developmental therapeutics in high risk childhood leukemias. My long term goals would be to lead a Phase I/II Pediatric Cancer Center.

Has effectiveness been achieved for any of the therapeutics you are studying? What does this mean for children with cancer and their families?
I am excited to say that I have been able to successfully demonstrate preclinical efficacy of an experimental agent called a MEK inhibitor inmurine models of leukemia, and that these results have provided the rationale necessary to drive a Phase I/II clinical trial of a MEK inhibitor in children with leukemia.

Normal blood cells grow in response to various signaling pathways. These pathways are regulated by “on” and “off” switches. Some types of leukemia occur when these cells lose the “off” switch and grow out of control. I study a specifically aggressive type of leukemia called Juvenile Myelomonocytic Leukemia (JMML) for which the sole curative therapy is bone marrow transplant. Only half of the patients are cured, thus better treatment is desperately needed. 90% of patients with JMML have mutations that cause excessive signaling through a pathway called Ras, making this pathway the “Achilles heel” of JMML. We hypothesized that inhibiting the Ras pathway with a targeted agent (a MEK inhibitor called PD0325901) would lead to clinical improvement in a mouse model of JMML. Without treatment, these mice develop high white blood cell counts, progressive anemia, large spleens, and decreased survival.  Treatment with 901 resulted in significant clinical improvement, with normalization of white blood cell counts, correction of anemia, reduction of spleen size, and prolongation of survival. Our findings support the use of targeted therapies MEK inhibitors in patients with JMML and other Ras-driven cancers, and we are actively working to translate these findings into a Phase I/II clinical trial. I am utilizing the skills I obtained in the lab to design and optimize genetic and biochemical assays of patient samples, which will aim to answer important correlative biology questions in children enrolled on this study. I hope that this targeted therapy will provide children and their families with an alternative, less toxic treatment to hematopoietic stem cell transplant, and perhaps ultimately lead to a cure.

Chang T, Krisman K, et al. “Sustained MEK inhibition abrogates myeloproliferative disease in Nf1 mutant mice.” 123 (1) J Clin Invest. 2013; 123(1):335–339.

Chang T, Dvoark C, Loh, M. “Bedside to bench in juvenile myelomonocytic leukemia: insights into leukemogenesis from a rare pediatric leukemia.” Blood 2014, in press.

Co-funded by: 
I Care I Cure