Violet. A bright, spirited, laughter-filled 11-year-old girl who bravely fought brain cancer. Her wish, like the wish of many children with incurable cancers, is to give back to science and help other kids like herself. Her spirit, and the spirits of others like her, is the inspiration behind Project Violet.
Now the Fred Hutch scientists are spearheading an ambitious program to develop optides that target some of the most treatment-resistant malignancies: brain cancer, melanoma, breast cancer, and tumors of the neck and throat. These molecules are poised to spark a radical leap forward in cancer medicine. You can make a difference by adopting a drug today.
A team of scientists at Fred Hutchinson Cancer Research Center including Drs. Jim Olson, Roland Strong, Patrick Paddison, and Eduardo Mendez are developing a fundamentally new class of anti-cancer compounds: molecules engineered to attack cancer cells without harming the healthy cells around them. These new compounds, called optides, could dramatically improve on traditional chemotherapies. And their approach is potentially less expensive and more powerful than other next-generation techniques. Optides address one of cancer treatment's most vexing problems: chemotherapies usually destroy healthy tissue alongside the cancerous cells they target. This can exact a heavy toll on patients, with many suffering such severe side effects that they must limit their chemotherapy dosage or stop treatment early. In contrast, optide molecules can be better instructed to bind to particular kinds of cancer cells, disabling only those cells. Optides can also be attached to chemotherapy drugs, transforming them into precision therapies that ignore healthy cells.
This innovative research uses nature as its guide. Many organisms produce tiny proteins, called peptides, that are small enough, stable enough and specific enough to deliver cancer drugs. The team of scientists modify these molecules to generate versions that zero in on cancer cells.
Olson pioneered the clinical use of optides when he teamed up with researchers at Seattle Children's and the University of Washington to develop an innovative "tumor paint" — a drug that attaches to cancer cells and illuminates them, helping surgeons identify where cancers begin and end.
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.
We 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.
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.
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.
Using patient-derived xenografts, our lab recently identified two drugs that show excellent efficacy in infant and toddler brain tumors including atypical teratoid rhabdoid tumor (ATRT) and medulloblastoma. Based in part on our work, one of these drugs is now in clinical trial for children with brain cancer and a clinical trial is planned for the other.
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.
We generated high quality patient-derived ependymoma mouse models and stem cell cultures that are suitable for high throughput screening. Some interesting candidates have emerged in our pre-clinical studies. Much more work needs to be done as we advance these candidates toward human clinical trials.
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 described the genetic mutations and abnormalities that contribute to this disease.
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.
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. Since 2009, the Olson Laboratory generated over 30 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.
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. Tumor Paint is derived from a peptide that originally was isolated from scorpions – the variant that we plan to use in human clinical trials preferentially binds to cancer cells rather than normal cells. We use this targeting molecule to deliver a fluorescent molecule specifically to cancer cells. Tumor Paint is now being advanced to human clinical trials through Blaze Bioscience
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 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. More information about Optides can be found at ProjectViolet.org.
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.
Click the image above for more information on the CIVO platform: