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2019 SEBASTIANSTRONG DISCOVERY SCIENCE AWARDS
Targeting the Tumor Microenvironment of Metastasis to Treat Metastatic Ewing Sarcoma
PI: David M. Loeb, MD, PhD, Albert Einstein College of Medicine
Ewing sarcoma is the second most common bone tumor in adolescents and young adults. Over the years, a series of clinical trials has dramatically improved the survival of children diagnosed with Ewing sarcoma that has not spread – from 20% in the 1970’s to over 75% today. During this timeframe, outcomes for patients who either present with metastatic tumors (tumors that have spread from their primary site) or who suffer a metastatic relapse have not improved at all. Currently, treatment of these patients includes intensive (and very toxic) chemotherapy, surgery, radiation, and sometimes bone marrow transplantation. Thus, there is an urgent need to understand the biology of Ewing sarcoma metastasis and to develop new, less toxic, treatments based on this understanding. Our group has developed a clinically relevant mouse model of Ewing sarcoma metastasis that we have used to study this process in the lab. We discovered that a drug that blocks the Wnt signaling pathway in Ewing sarcoma cells prolongs survival of these mice. Our collaborators have discovered a new mechanism of cancer metastasis, dubbed Tumor Microenvironment of Metastasis, or TMEM, that can be inhibited by other relatively nontoxic drugs. We have preliminary evidence that TMEM functions in Ewing sarcoma, and plan to explore ways to interfere with TMEM in our mouse models to develop novel, less toxic treatments to prevent Ewing sarcoma metastasis in patients. We will approach this problem in three ways. First, we will perform tests designed to confirm that TMEM in Ewing sarcoma functions in the same way as has been described in breast and pancreatic cancer. Next, we will use a panel of targeted therapies to determine which can interfere with TMEM function in Ewing sarcoma. These will include inhibitors of a variety of signaling pathways, all of which have been implicated in TMEM function. Each inhibitor being tested is available for administration in clinical trials. Our third step will be to test drugs that individually inhibit TMEM function in combinations to see which are able to prevent metastasis in our mouse models. Effective combinations will then be tested in clinical trials with the expectation that they will provide a relatively well-tolerated, less toxic treatment to prevent metastasis and improve survival.
Re-purposing HIV Nucleoside Reverse Transcriptase Inhibitors for High-Risk Neuroblastoma Therapy
PI: Daniel Weiser, MD; Co-I: Brad Rybinski, BS; Albert Einstein College of Medicine
Neuroblastoma is a pediatric cancer of the developing nervous system that arises from early nerve cells called neuroblasts. Neuroblastoma accounts for one of six childhood cancer deaths, and half of children with aggressive, high-risk neuroblastoma succumb to disease within five years, suggesting that some children have a form of “ultra-high risk” (UHR) neuroblastoma that still lacks effective therapies. Therefore, new strategies to identify and treat children with UHR neuroblastoma are urgently needed. Recent research has demonstrated an association between UHR neuroblastoma and high levels of telomerase. Telomerase is an enzyme that allows cancer cells to keep proliferating without dying, suggesting that inhibiting telomerase would be an effective therapy for UHR neuroblastoma. No effective telomerase inhibitor has yet been developed. However, the crucial component of the telomerase enzyme that allows it to function is a reverse transcriptase, and reverse transcriptase inhibitors (RTIs) have been used as HIV medications for decades. Therefore, we hypothesize that the RTI tenofovir will inhibit telomerase in neuroblastoma cells and enhance the efficacy of conventional chemotherapy. Our project is designed to “re-purpose” tenofovir as novel telomerase inhibitor for patients with neuroblastoma. We have preliminary data that demonstrates activity of tenofovir against neuroblastoma cells directly and, to a greater extent, when combined with chemotherapy. We will expand this testing in the laboratory, as well as in mouse models of neuroblastoma. We anticipate that neuroblastoma with high levels of telomerase and associated poor prognosis will respond most remarkably to tenofovir, resulting in improved survival. Re-purposing of an FDA approved drug like tenofovir as a telomerase inhibitor for properly selected patients with neuroblastoma will allow swift translation of novel combination therapy concepts into the clinic. Therefore, successful completion of our research plan has the potential to lead to a rapid breakthrough for patients with UHR neuroblastoma by shifting it from a fatal diagnosis to one that is both identifiable and treatable.
2019 OUTSMARTING OSTEOSARCOMA AWARD (grant made through MIB Agents)
New Immune-mediated Therapies for Lung Osteosarcoma
PI: Alex Y. Huang, M.D., Ph.D., Case Western Reserve University / Angie Fowler AYA Cancer Institute
Osteosarcoma (OS) is a highly aggressive malignant primary bone cancer with a high propensity for lung metastasis. OS frequently originates from primitive mesenchymal bone-forming cells in the long bones during periods of rapid bone growth. Consequently, OS represents the most prevalent bone cancers affecting children and adolescent and young adults (AYA), with ~400-600 cases a year and accounts roughly half of all new cases of OS diagnosed in the United States. Despite aggressive combination chemotherapy and surgery, the outcome for metastatic OS remains dismal, and the overall survival in children and AYA patients with metastatic OS has not improved significantly over the past 3 decades. A high proportion of OS patients develop metastatic disease at distant sites either at the time of diagnosis or after initiation of multimodal therapy including combination chemotherapy and surgery. The lung accounts for >80% of all OS metastatic sites. Unfortunately, almost all of the patients who develop surgically unresectable pulmonary metastatic OS (pOS) invariably succumb to this devastating disease. Therefore, pOS represent a disease with urgent unmet needs. Dr. Huang’s research aims to achieve meaningful, immunotherapy clinical trial-enabling pre-clinical studies in 3 areas: 1) Perform in vivo treatment efficacy validation and complete safety and toxicity profiling studies using BG34-200 in 2 other pOS mouse models to establish generalizability of this approach as well as to gather data for IND filing with the FDA. 2) Gather in vivo efficacy data of treating pre-clinical pOS model using TGFbR1 inhibitor, Vactosertib, with either immune checkpoint blockade or NK cell therapy. These results will inform the creation of another clinical trial design, submission for PRMC approval and IND filing with the FDA in the next 8-12 months; and 3) Investigate anti-tumor efficacy and immune reactivation in pOS by treating pre clinical pOS models with CA IX-specific inhibitor VD11-4-4 in the next 12 months in order to provide strong scientific rationale for future 3rd OS clinical trial. Our ongoing multi-pronged approach to finding novel therapeutic options for pOS is based on strong scientific rationales, demonstrated efficacy data, and unique opportunities to leverage existing ready-to-go pharmacologic agents and engaging industry partners. Coupled these factors with institutional knowledge in immuno-oncology translational research pipeline and infrastructure at Angie Fowler AYA Cancer Institute and Case Comprehensive Cancer Center, we are uniquely poised to quickly evaluate and offer these therapies for pediatric and AYA OS patients in the very near future.
2018 YOUNG INVESTIGATOR GRANTS
Augmenting Chimeric Antigen Receptor T Cell Induced Epitope Spreading for Pediatric Solid Tumors
PI: Michael Leibowitz, MD/PhD, Children’s Hospital of Philadelphia
Dr. Leibowitz’s study will look at the potential of an immunotherapy for solid tumors. Immunotherapy has been successful in certain pediatric blood cancers but is hard to replicate in non-blood cancers, like solid tumors. His project investigates a process called “epitope spreading” where cellular immunotherapy induces non-targeted cancer cells to die and triggers the immune system to react against cells that express different bio-markers. His project hopes to expand epitope spreading induced by reprogrammed immune cells in pediatric solid tumors, so that cellular immunotherapy may become a viable treatment option.
UPDATE 1: “With the support of SebastianStrong Foundation, I was able to hire a technician in the lab, which has been very helpful in advancing our project. We are currently performing in vivo mouse experiments to determine whether modification of our CAR T cells to secrete FLT3 ligand enhances killing of solid tumors through epitope spreading. I am excited to see what the data will show.”
UPDATE 2: “Recently, we found that combining an antibody that activates the immune system, used in combination with CAR T cell therapy, augmented epitope spreading and solid tumor regression in mice. I’m in the process of alienating this finding in other tumor models and other strains of mice. I hope to have the experiments complete and ready for publication within the next 6-12 months.
Targeting Glutamine Metabolism in MYC Driven Atypical Teratoid Rhabdoid Tumors
PI: Jeffrey Rubens, MD, Johns Hopkins University School of Medicine
Dr. Rubens’ project aims to target changes in tumor metabolism (how tumor cells generate energy) in an effort to improve survival rates in children with brain tumors. Cancer cells are more dependent on glutamine to generate energy to support their rapid growth while normal cells are more dependent on glucose for these metabolic needs. This difference in metabolism allows his lab to specifically target tumor cells with a medication called DON that blocks this glutamine metabolism. This medication has previously been used in humans and has been shown to be safe and well tolerated but has never been used to treat childhood brain tumors. The project aims to prove the preclinical efficacy of DON therapy with a plan to develop a new clinical trial at the completion of this research that will improve treatment for children suffering from brain tumors.
UPDATE 1: “We continue to be very excited about the progress we have made in our SebastianStrong Foundation funded research. We continue to develop the pre-clinical data that will support a future clinical trial aimed at improving survival in atypical teratoid rhabdoid tumors (AT/RT). We have found that the glutamine metabolic inhibitor, 6-diazo-5- oxo-L-norleucine (DON) combines synergistically with carboplatin to extend survival in orthotopic mouse models of AT/RT. We aim to submit our findings for publication this month, & continue to work toward developing the first clinical trial utilizing DON therapy to target aggressive, MYC- expressing tumors.”
UPDATE 2: “We continue to be excited by the progress we have made. We submitted our findings that the glutamine metabolic inhibitor 6-diazo-5-oxo-L-norleucine (DON) combines synergistically with chemotherapy to extend survival in AT/RT for publication in the journal Clinical Cancer Research. Our manuscript was reviewed favorably and we are currently working on revisions before sending the manuscript back for publication. We are also working toward translating these findings into a new clinical trial to treat AT/RT. Finally, we have teamed up with the Drug Discovery Program at Johns Hopkins University to test the efficacy of novel DON pro-drugs that are able to better cross the blood-brain-barrier and achieve higher concentrations in brain tumors. These pro-drugs hold great promise to further improve therapies in AT/RT while reducing side effects associated with the medications.”
2018 SEBASTIANSTRONG RESEARCH GRANT
Clinical Trial of Disulfram to Overcome Chemotherapy Resistance In Sarcomas
PI: Matteo Trucco, MD, University of Miami’s Sylvester Comprehensive Cancer Center
SebastianStrong Foundation’s grant to Dr. Matteo Trucco will test the safety and ability of adding disulfiram to chemotherapy to overcome the resistance to chemotherapy seen in relapsed sarcomas. Metastasis and relapse are the major cause of death from pediatric bone and muscle tumors (sarcomas). Current chemotherapy can kill the majority of sarcoma cells, but often some are able to survive the chemotherapy and give rise to new cancers (relapse) or spread throughout the body (metastasis). We have been using the same chemotherapy for pediatric sarcomas for decades. Sarcoma cells that express high levels of an enzyme called Aldehyde Dehydrogenase (ALDH) have proven to be resistant to chemotherapy. The drug disulfiram, used safely for over 50 years for the treatment of alcoholism, blocks ALDH and laboratory tests have shown that it makes sarcoma cells more sensitive to chemotherapy. This is the first step in developing disulfiram as a way to make current treatment more effective against pediatric sarcoma.
UPDATE 1: “With the support of the SebastianStrong Foundation combined with support from similar foundations, we secured the funding necessary to conduct a clinical trial testing the ability of a drug called disulfiram (Antabuse) to overcome the resistance to chemotherapy seen in several sarcomas. Disulfiram blocks an enzyme called Aldehyde Dehydrogenase. This enzyme has been found to make cancer cells resistant to many of the chemotherapy drugs used to treat pediatric sarcomas. By blocking this enzyme, we hope to make chemotherapy more effective in treating those cancers, and in time potentially enable doses to be reduced leading to less toxic treatments. With all the necessary funding secured, we are in the process of obtaining approval by the University and the FDA to conduct the trial and contract with laboratories to perform the drug and enzyme measurements necessary to assure we are hitting the target.”
UPDATE 2: “Our clinical trial adding the alcoholism drug disulfiram (Antabuse) to chemotherapy to target the cells that are resistant to the chemotherapy is in development. We have secured funding from other organizations which, combined with the award from the SebastianStrong Foundation, will allow us to purchase the drugs and cover the costs of conducting the trial and necessary laboratory testing to better understand how the disulfiram is working and which patients are likely to benefit. We are about to submit a Letter of Interest (LOI) to the National Pediatric Cancer Foundation (NPCF) to consider opening the trial through the Sunshine Project Consortium which includes 20 of the top Pediatric Cancer Centers in the country. Opening the trial through this consortium would make this treatment available to more patients and help complete the trial more quickly. The trial was presented at the annual NPCF summit in February, was well received and we were invited to submit the LOI for consideration. We have also partnered with Dr. Kurt Weiss, whose laboratory is leading the studying of disulfiram in sarcomas, to perform the necessary experiments testing the response to the disulfiram treatment in tumor samples. Independently, disulfiram was found to be one of the most active drugs in 2 of 3 pediatric sarcomas screened against 215 FDA-approved drugs. While the process of developing a clinical trial is frustratingly slow, we continue to make progress and anticipate opening the trial either locally or nationally in the near future.”