Research Projects

This SCOR uses a multifaceted approach to develop and utilize targeted therapies in HR ALL biological subsets. Projects have been selected based on their ability to bring targeted therapy to the clinic. The projects are complimentary to one another in that each explores discrete targets but the therapy that emerges from each project can be deployed together. It is likely that multiple pathways need to be targeted to provide truly curative therapy in these high risk subsets. The Projects build on extensive basic and pre-clinical work of childhood ALL from the SCOR investigators, particularly high throughput genomic and NextGen sequencing studies.

Project I: Identification and Treatment of Ph-like ALL Cases with Variant ABL1 and PDGFRB Fusions

Project Co-Leaders:

Stephen P. Hunger, MD
Ergen Family Chair in Pediatric Cancer
Director, Center for Cancer and Blood Disorders
Children’s Hospital Colorado
Professor of Pediatrics
Chief, Section of Hematology, Oncology & BMT
University of Colorado School of Medicine

Charles Mullighan, MBBS, MSc, MD
Associate Member, Department of Pathology
Co-Leader, Hematological Malignancies Program
St. Jude Children’s Research Hospital

Project I will builds on TARGET findings of tyrosine kinase gene alterations in the Ph-like subset of high risk ALL and preclinical studies and case reports showing that ABL1 and PDGFRB fusions can be targeted by ABL1 class TKIs. The core of this Project will be implementation of a clinical trial designed to determine whether addition of dasatinb to chemotherapy improves outcome of Ph-like ALL patients with ABL1 and PDGRB fusions. In parallel, this Project will develop and utilize pre-clinical models to test new therapeutic strategies for novel TK gene fusions, focusing particularly on ABL2, CSF1R, EPOR and JAK2 fusions.


Project II: Targeting In Vivo Resistance in Relapsed Pediatric Acute Lymphoblastic Leukemia

Project Leader:

William L. Carroll, MD
Julie & Edward J. Minskoff Professor of Pediatrics
Professor of Pathology
Director, Perlmutter Cancer Center

Project II aims to build on their discovery of relapse-specific mutations in NT5C2 and MSH6 that correlate with early relapse and resistance to thiopurines. The mechanism of resistance will be explored further using in vitro and in vivo models. The underlying hypothesis is that these clones likely exist at very low levels in all cases at diagnosis and emerge under the selective pressure of chemotherapy at a time when dependence on thiopurines is greatest (e.g. maintenance). Thus experiments are designed to track the emergence of these clones during maintenance and once detected alter therapy to include an intensive non-thiopurine backbone. This approach will be modeled in experimental animals. The availability of remission samples during maintenance from patients who eventually relapse with MSH6 or NT5C2 mutations allows for testing the feasibility of using NextGen sequencing to detect clonal emergence before clinical relapse. Finally as proof of principle for targeted therapy inhibitors of both normal and mutant NT5C2 will be developed.


Project III: Pharmacologic Targeting of Cell Cycle Progression in Acute Lymphocytic Leukemia

Project Co-Leaders:

Ioannis Aifantis, PhD
Associate Professor, Department of Pathology
Perlmutter Cancer Center

Elizabeth A. Raetz, MD
Professor of Pediatrics
Medical Director, High Risk Leukemia and Lymphoma Program
Huntsman Cancer Institute
University of Utah

Project III originates from compelling work from the Aifantis lab showing the dependence of T-ALL leukemogenesis and progression on D type cyclin/CDK4/6 complexes. The dependence on D cyclin has been demonstrated in animal models and the investigators will determine the relative contribution of CDK4/6 in an innovative Ccnd3/CDK4/6 inducible knock out model. Importantly the availability of a highly selective CDK inhibitor PD-0332991 (Pfizer) already in phase II trials makes targeting this pathway a reality. Investigators have already showed promising activity in T cell lines and xenograft models but they now plan to test this compound integrated into a backbone of chemotherapy first in preclinical animal models and then in a phase 1 trial in children, adolescents and young adults with relapsed T-ALL, a highly refractory subgroup.


Project IV: Targeted Nanotherapeutics for ALL Therapy

Project Co-Leaders:

Jeffrey Brinker, PhD
UNM Distinguished UNM Regent’s Professor of Chemical and Nuclear Engineering and Molecular Genetics and Microbiology
Fellow, Sandia National Laboratories

Stephan Grupp, MD, PhD
Medical Director, Stem Cell Laboratory
Associate Professor of Pediatrics
University of Pennsylvania School of Medicine
The Children’s Hospital of Philadelphia

Cheryl Willman, MD
The Maurice & Marguerite Liberman Distinguished Chair in Cancer Research
Professor of Pathology and Medicine
Director & CEO, University of New Mexico Cancer Research & Treatment Center

Project IV co-leaders have worked together with Jeffrey Brinker, PhD’s team at Sandia National Laboratory (Center for Integrative Technologies) and the UNM College of Engineering for the past two years to develop a novel therapeutic strategy for the treatment of BCP ALL: an ALL-targeted “nanocarrier” termed the “protocell.” By wrapping a functionalized fluid lipid bilayer membrane containing a targeting peptide or single chain antibody around a high surface area mesoporous silica core with tremendous cargo (drug) carrying capacity, the protocell has overcome several of the limitations of existing nanocarriers currently in clinical use. This team of investigators has recently demonstrated the efficacy of targeted protocells for the treatment of hepatocellular carcinoma and for the targeted delivery of small inhibitory RNAs (siRNAs) directly to cancer cells. In the context of this SCOR, they are now optimizing the design of targeted protocells (using CD19 and CRLF2) for ALL therapy and will undertake studies of protocell stability, bio-distribution and uptake in normal and leukemic cells and tissues, pharmacologic dose range, toxicology, and therapeutic efficacy in ALL xenograft models in vivo, laying the foundation for larger scale FDA-reviewed IND-directed toxicology studies which are the human endpoint of this SCOR project.