The University of Chicago Comer Children's Hospital Archives

2018

Scholar Grant

James Labelle

Chicago, IL

Targeting the BCL-2 Family and p53 Pathway in Diffuse Large B-Cell Lymphoma Using Combination Peptide Amphiphiles

“Evasion of cell death is integral to malignant transformation and therapeutic resistance. The overall goals of this proposal are to overcome therapeutic resistance in pediatric B-cell lymphomas by simultaneously activating two related, but distinct cell death pathways in malignant B cells. Using diffuse large B-cell lymphoma (DLBCL) as a model system, the project aims to first understand the mechanism(s) of how activating apoptosis (cell death) through targeting the BCL-2 family of apoptotic proteins and reactivating the p53 tumor suppressor pathway will overcome cell death blockade. Secondly, we aim to target peptide-laden nanoparticles specifically to B cells to maximize DLBCL killing and minimize off-target side effects.

The technical innovation of this proposal relies on the development and application of unique cancer chemical biology research tools based on the native biological structure of biofunctional a-helices. The conceptual innovation of the proposal derives from our ability to harness the BCL-2 family and p53 biologic peptides to explore the mechanism and hierarchy of dual-targeted apoptotic pathway therapy on the induction of cell death in highly resistant human B-cell lymphoma. The potential impact of multi-targeted therapy of a malignant cell would not only limit off-target side effects but could revolutionize our approach to cancer treatment in patients with refractory, heterogeneous, or multi-clonal diseases. To test this, future preclinical testing of these compounds in pre-clinical models of human DLBCL will be performed. Such proof-of-concept testing would lay the groundwork for true future clinical translation in pediatric patients where DLBCL represents up to 20% of pediatric and young adult lymphomas and where therapeutic resistance leads to particularly dismal outcomes.

• Upregulation of the BCL-2 family of proteins and inactivation of the p53 pathway are two major mechanisms by which B-cell lymphomas evade cell death.
• Activation of cell death by targeting the BCL-2 family and reactivation of p53 signaling are tremendous therapeutic goals. Unfortunately, targeting these pathways individually leads to clinical therapeutic resistance.
• Our goal is to simultaneously reactivate cell death in refractory diffuse large B-cell lymphoma (DLBCL) through the targeted intracellular delivery of novel therapeutic peptides designed to specifically activate BCL-2 family-mediated cell death and release p53 from oncogenic sequestration allowing for normal p53 signaling.
• Therapeutic peptides will be delivered to diseased cells using peptide amphiphile nanoparticles specific for B-cells in an effort to maximize malignant cell death and minimize off-target effects.
• This therapeutic strategy can be extended to a host of pediatric cancers independent of their genetic makeup. “

2017

Scholar Grant

Dr. Susan Cohn

Chicago, IL

MELK, A New Therapeutic Target for Neuroblastoma

Less than 50% of high-risk neuroblastoma patients achieve long-term survival, and survivors are at risk for serious treatment-related adverse events. Thus, there is a desperate need for more effective, less toxic treatments. Maternal Embryonic Leucine Zipper Kinase (MELK) drives aggressive tumor growth in several adult malignancies, and increases resistance to DNA-damaging drugs and radiation. The MELK inhibitor OTS167, developed by our co-investigator Dr. Nakamura, potently suppresses tumorigenicity in several adult preclinical models. These promising results have led to a first-in-human Phase I trial at the University ofChicago for adult patients. Our preliminary data demonstrate that MELK expression is associated with clinically aggressive neuroblastoma, poor survival, and resistance to radiotherapy. We hypothesize that MELK is a therapeutic target for neuroblastoma, and thatMELK inhibition with OTS167 will sensitize tumors to DNA damaging-treatments and be effective therapy for children with neuroblastoma. To test this hypothesis we will: 1) characterize the effects of MELK on neuroblastoma phenotype using cells with genetic and pharmacologic MELK inhibition; 2) determine the mechanisms by which MELK mediates resistance to radiation in neuroblastoma; and 3) test the anti-neuroblastoma activity of OTS167 with and without radiation in preclinical models. Ultimately, we hope these studies will lead to the development of effective, MELK-targeted treatment strategies that will improve the outcome of children with neuroblastoma.

GOALS

To investigate how MELK promotes aggressive neuroblastoma tumor growth and
To evaluate the anti-neuroblastoma activity of the MELK inhibitor OTS167 in animal resistance to radiotherapy.
models.

To investigate if OTS167 will increase sensitivity to radiation therapy To obtain the data needed to design early phase clinical trials testing OTS167 in children with neuroblastoma refractory to current therapies.

The long-term goal is to develop new, effective treatment strategies that target MELK
and lead to improved outcome for children with neuroblastoma.

2014

Impact Grant

Dr. Natasha Pillay Smiley

Chicago, IL

In the United States, approximately 3,500 children and adolescents are diagnosed with a brain tumor each year. Recent advances in treatment and technology have extended the average survival rates for more children. Subsequently, the long-term health of survivors has gained attention in recent years. Dr. Pillay Smiley, a fourth year neuro-oncology fellow at Lurie Children’s who will join the neuro-oncology team as a full time faculty member at the completion of her fellowship, believes that quality of life is an area of utmost importance for current clinical and research efforts in pediatric neuro-oncology. One of her primary goals is to positively impact both the survival and quality of life of brain tumor survivors as well as those who are at-risk of brain tumors through the development of two novel programs:

– A clinical service focused on the late-effects of treatment and quality of life issues that impact young brain tumor patients.
– A clinic for patients with genetic predispositions to central nervous system tumor development

Funding from the Hyundai Young Investigator Clinical Grant award would allow Dr. Pillay Smiley to develop the infrastructure needed to launch and sustain these important additions to our comprehensive clinical program during the first year of operations. Moreover, it would provide a foundation for her to expand the current knowledge base surrounding quality of life and survivorship issues through ongoing clinical research. Hyundai’s gift would play a critical role in allowing her to achieve these goals.