Specific Research Programs and Resource Sharing

Medulloblastoma    
Primitive Neuroectodermal Tumors
Infant and Toddler Brain Tumors
Ependymoma
Glioma and Brainstem Glioma 
Brain Tumor Resource Laboratory - Novel mouse models and cancer stem cell lines
Tumor Paint 
Optides
Combination cancer therapy: Novel technology for multiplexed comparisons

 

Medulloblastoma    

We recently completed a study that identified a drug (IPI-926) that increases survival of medulloblastoma mice 5-fold in the absence of chemotherapy or radiation.  We further showed that medulloblastoma cells do not develop resistance to this drug the mechanism by which resistance develops to other drugs that target the same pathway.  Using patient-derived models, we learned that drugs that inhibit the sonic hedgehog pathway have no activity against tumors driven by other molecular drivers.  Taken together, the data shows that the 15-20% of medulloblastoma patients with mutations in the sonic hedgehog pathway should be considered for sonic hedgehog inhibitor trials in the future and that patients without sonic hedgehog pathway mutations would unlikely benefit from hedgehog pathway inhibitors.

Our laboratory generated the Smo/Smo mouse model of medulloblastoma, which is now being used in over 50 laboratories worldwide to identify and prioritize candidate new therapies for medulloblastoma patients.  A related mouse model, the ND2:SmoA2 mouse, provided insight into two aspects of medulloblastoma biology that were previously unrecognized.  These mice, which develop tumors because of a point mutation in the transgenic smoothened gene, also develop extremely severe cerebellar neuronal disorganization.  This is in stark contrast to mice with another point mutation nearby in the same gene, which develop medulloblastoma tumors, but have otherwise normal brain development.  These comparisons are providing insight into the developmental roles of the sonic hedgehog pathway and into the relationship between cerebellar organization and neurologic function.  Studies in these mice also led to the identification of a new and unexpected tumor suppressor gene.  Details will be published in 2012.

Dr. Olson currently leads the Phase III Children’s Oncology Group clinical trial ACNS0332, which will determine whether high risk medulloblastoma patients benefit from carboplatin radiosensitization or 13-cis retinoic acid (Accutane) in combination with cisplatin-based chemotherapy.

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Primitive Neuroectodermal Tumors (PNETs)   

PNET patients have traditionally been “lumped” with medulloblastoma patients for clinical trials, based solely on histopathologic similarities of these tumors.  PNET patients have not fully realized the improvements in survival that have been gained for medulloblastoma patients.  We have shown that PNETs are biologically distinct and respond uniquely to therapeutics. The supratentorial PNET specimens from the Children’s Oncology Group (COG) ACNS0332 clinical trial undergo gene expression and copy number variation studies.  Several surgical specimens have successfully generated cancer stem cell lines that were used for screening all FDA approved drugs, kinases, and kinome siRNA.  We have identified standard of care drugs that have no activity in PNET cells and patient-derived orthotopic xenograft mice and also identified FDA approved oncology drugs that are highly effective in non-clinical PNET models.  We are rapidly and collaboratively generating data on targeted therapies and traditional therapeutics that will likely serve as the foundation for the next national COG trial.  Importantly, the genomics and kinome screens are revealing important signaling data that provides trainees with insight into the biology of these tumors that have never been studied at the molecular level.

 

Dr. Olson currently leads the Phase III Children’s Oncology Group clinical trial ACNS0332, which will determine whether PNET patients benefit from carboplatin radiosensitization or 13-cis retinoic acid (Accutane) in combination with cisplatin-based chemotherapy.

 

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Infant and Toddler Brain Tumors   

Because the developing brain is easily damaged by radiation, causing severe learning and thinking effects, oncologists have dramatically reduced use of radiation in this age group.  Unfortunately, in the absence of radiation, survival is reduced to unacceptably low levels.  Previous work on effective combination targeted therapies in the Olson lab led to the current national clinical trial for infants and toddlers with non-desmoplastic medulloblastoma or primitive neuroectodermal tumors through the Pediatric Brain Tumor Consortium (PBTC). This clinical trial is led by Dr. Russ Geyer, a world-renowned expert on infant and toddler brain tumors, who leads our pediatric neuro-oncology clinical program.  The National Cancer Institute recently provided a 5 year grant to Dr. Olson’s laboratory that enables generation of patient-specific models of brain cancer, high throughput functional genomic screening, in vivo prioritization of candidate therapies, and ultimately the promotion of candidate therapies into clinical trials for infants and toddlers with brain cancer.

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Ependymoma   

We generated high quality patient-derived ependymoma mouse models and stem cell cultures that are suitable for high throughput screening.  We recently completed a screen of candidate targets for which drugs currently exist and are in or near human clinical trials.  In this screen, which looked at over 700 possible targets, the top 7 were all pathways for which drugs exist.  These candidates are now being advanced to mouse studies and drug combination studies. We believe that the findings will be able to advance to human clinical trials for children within a few years if progress continues at the current pace.

 

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Glioblastoma   

Children with Glioblastoma Multiforme (GBM) have a 5 year survival rate of less than 10%.  To identify new therapeutic targets, we collaborate with Patrick Paddison, who discovered a method for evaluating whether each gene in the genome specifically kills cancer cells while sparing normal neural stem cells.  We have discovered two entirely novel targets that, when inhibited, cause GBM cells to rapidly die while sparing normal neural stem cells.  We are collaborating with the National Institutes of Health, colleagues at St. Judes, two pharmaceutical companies, and three other labs around the world to identify and prioritize potential drugs that hit the targets that we identified.

In a separate study, the Olson lab is collaborating with Drs. Rostomily, Shendure, Nickerson, Paddison, and Waterston to identify the impact of tumor heterogeneity on treatment response and emergence of drug resistance in glioblastoma patients.

Brainstem Glioma

Whereas long term survival for children with various malignancies has improved from about 10% in the 1960s to over 76% currently, there has been virtually no progress on brainstem gliomas during that period.  A key reason is that the location of these tumors in the brainstem precludes surgical resection, so tumor removal is impossible and there have not been specimens available for laboratory research.  We have now generated patient-derived resources from brainstem glioma patients and are initiating studies on these.  We share these resources with other scientists and also contributed to a landmark study that will be published next month that describes the genetic mutations and abnormalities that contribute to this disease.

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Brain Tumor Resource Laboratory   

In the late 1990s, when Dr. Olson’s laboratory was beginning, the Washington Women’s Foundation provided a grant that enabled our laboratory to serve as a National Brain Tumor Resource Laboratory (BTRL).  Our BTRL generated resources from patient surgical samples and made panels that could be shared freely with any investigator around the world.  We established practices that reduced barriers to collaboration and promoted advanced molecular studies that led to the incredible understanding of pediatric brain tumor biology that has evolved in the subsequent decade.  With continued support from Seattle Children’s Hospital Guilds, we expanded services to the generation and sharing of mouse medulloblastoma models.  Our models are now used in over 50 labs world-wide and provided the scientific basis for four national clinical trials.

In 2009, a generous gift launched a new program focused on generating patient-specific cell lines for drug screening and mouse models for drug prioritization.  We challenged our team to imagine the day when a surgical sample from a child could generate cell lines and mice that would rapidly generate data that could guide clinical decisions for that particular patient.  Prior to achieving this goal, we reasoned that the data generated with these resources could shape the next generation of national clinical trials. 

We have now generated models for rare and under-studied types of pediatric brain cancer. In the past year, the Olson Laboratory generated 24 new mouse models that carry human brain tumors derived from our patient’s surgical specimens.  The same specimens are used to generate patient-derived cell lines that are useful for drug screening and prioritization.  About half the patient samples come from Seattle Children’s Hospital and the remainder from Children’s Oncology Group sites across America.   Because of the generosity of donors, we are able to share these resources with no strings attached to any laboratory around the world that wishes to study pediatric brain tumors.  Importantly, all of the resources are being molecularly defined, so that future therapies can be directed specifically toward the children who are likely to benefit – and so that children who are unlikely to benefit from a treatment are spared exposure to it and treated with more promising agents.

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Tumor Paint    

Dr. Olson’s lab, in collaboration with Dr. Ellenbogen, discovered Tumor Paint, which lights up cancer cells in a manner that will hopefully enable surgeons to clearly distinguish cancer foci from normal tissue in real time during cancer operations.  Dr. Olson’s laboratory has taken this technology as far as it can go in an academic laboratory.  It will now be brought to the FDA and patient clinical trials through Blaze Bioscience: The Tumor Paint Company.  The first meeting with the FDA is planned in late 2012.  The technology is being licensed to Blaze Bioscience in exchange for royalty and milestone payments that will fuel future cancer research in Seattle.

Time Magazine article »
 
Center news release »

 

 

 

 

 

 

 

 

 

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Optides   

Development of less damaging, more precisely targeted cancer therapies is essential in order to relieve patients’ suffering and improve treatment success. But even after decades of research, scientists still struggle to identify therapeutic compounds with the right mix of medicinal and cancer-targeting properties.

In collaboration with a number of internationally recognized cancer researchers at the Fred Hutchinson Cancer Research Center, our team is developing a fundamentally new class of anti-cancer compounds — molecules engineered to specifically attack cancerous cells while leaving healthy cells untouched. Our scientists are letting Nature guide their efforts, working with naturally occurring molecules that already possess ideal medicinal properties: small size, stability and exquisite specificity for their chemical targets. Using these natural compounds as templates, our team is engineering new, cancer-specific variants, called “Optides,” that promise to not only improve on traditional chemotherapies, but to do it more rapidly and more effectively than other next-generation approaches.

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Combination Drug Therapies   

The Olson laboratory invented a new technology platform that is revolutionizing cancer drug development.  This porous needle array technology allows investigators to inject multiple drugs into a single solid tumor and compare efficacy.  The technology, which is licensed to Presage Biosciences, is now used by top pharmaceutical companies to identify drugs that are more effective in combination than individually. Dr. Olson’s lab continues to use this technology to identify and prioritize drug combinations for pediatric brain tumor patients.

 

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