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Robert J. Canter, MD from the University of California, Davis will study inhaled canine IL-15 to maximize immunotherapy responses in dogs with metastatic osteosarcoma.
Survival rates for osteosarcoma (OSA) have been stagnant for 40 years with poor survival rates for patients with stage IV disease. Therefore, our overarching goal is to advance immunotherapy in OSA and translate this to better survival for patients. Although cytokine therapy (like IL-15) can powerfully stimulate the immune system to attack cancer, results in human clinical trials have been modest, in part because of the risk of severe side effects. We have piloted the use of inhaled human IL-15 via nebulizer treatments in dogs with OSA lung metastases and observed exciting results in an early-stage trial. This novel delivery appears to improve the dose/ toxicity relationship since the drug is delivered directly to the lungs where lung metastases are present while limiting exposure to the rest of the body. These data were particularly exciting since we gave only 14 days of inhaled IL-15 given the risk of neutralizing antibody formation when using human drugs in dogs. Given the potential for delayed responses with immunotherapy, here we will evaluate prolonged duration inhaled canine IL-15, hypothesizing more responders and a longer duration of response with prolonged inhaled canine IL-15 therapy. IL-15 is the prototypical stimulator of natural killer (NK) cells, a key arm of the immune system against viruses and cancer. As there is increasing evidence for the concept of NK "priming" to increase cytotoxicity and persistence, we hypothesize that in vivo priming of endogenous NK cells with inhaled canine IL-15 at the site where lung metastases are present is an exciting approach for enhanced NK anti-tumor effects, decreased systemic toxicity, and improved clinical outcomes in OSA. In Aim 1, we will perform a phase II trial using a Simon 2-stage design to evaluate safety and efficacy with response rate as the endpoint in dogs with OSA. In Aim 2, we will evaluate circulating NK, T, and myeloid-derived suppressor cells as predictors of response/ non-response to therapy.
Osteosarcoma (OSA) is the most common form of bone cancer. It affects approximately 3,000 people in the United States every year. Although surgery and chemotherapy are effective for many patients, the cancer spreads to the lungs in approximately 50% of patients . Unfortunately, the prognosis for patients with metastatic OSAS is poor (approximately 25% 5-year survival), and novel therapies are urgently needed. Few new treatments have been successful for OSA over the last 40 years, and immunotherapy (which has revolutionized the treatment of other cancers) has had limited if any benefits in OSA to date. Dogs are also commonly afflicted by OSA. Although statistics are not as robust in dogs, some estimates have suggested that there are between 20,000 – 50,000 cases of dog OSA per year in the United States. OSA in dogs is highly similar to human, including the genetics, the patterns of spread, and the response to surgery and chemotherapy. Like people, dogs with OSA need new therapies for their aggressive cancer, and we as humans can gain important insights into cancer biology, immune responses, and novel treatments by studying new cancer therapies in dogs with OSA. Our research proposal is anticipated to provide near-term impact in both canine and human oncology by evaluating a novel delivery of IL-15 directly to the tumor environment. Human IL-15 is available for human clinical use, so clinical trials in humans can be developed quickly using inhaled IL-15 if our results are exciting. If successful, we expect a first-in-human study within three years of completing this project. To facilitate this, we purposefully included pre-IND enabling studies using our canine model. For human trials, we will formulate rhIL-15 into an aerosol delivery system, and we plan to submit an Investigational New Drug (IND) application to the FDA to test this approach in human OSA trials. We also have exciting correlative studies embedded in the trial to dissect novel mechanisms of response.
Shahab Asgharzadeh, MD from Children’s Hospital Los Angeles will study the Identification of circulating immune signature as a biomarker of disease response and resistance in patients with relapsed osteosarcoma treated with nivolumab and regorafenib.
Osteosarcoma (OS) is the most common bone malignancy in children and young adults; a devastating cancer for which outcomes have not improved for decades. Recently, two clinical trials demonstrated that a drug called regorafenib had some benefit in adult patients with OS whose tumor was not responding to treatment (refractory) or had returned (recurrent). One of the ways that regorafenib works is by shutting down signals in the cancer cell that cause it to grow. Immunotherapy is a treatment that allows the body’s own immune system to fight diseases such as cancer. Immunotherapy drugs that specifically target the immune system (e.g. nivolumab) have not been very successful in OS. In certain types of other cancers, immunotherapy has a better effect if it is given with a drug like regorafenib. We are conducting a multi-site pediatric and young adults trial (SARC038) through the Sarcoma Alliance for Research Through Collaboration testing a novel combination of nivolumab plus regorafenib to see if it will work better than regorafenib alone in patients with refractory/recurrent osteosarcoma. SARC038 trial has several correlative biology studies to better understand reasons why a patient does or does not respond to the therapy. One of the biology objectives requires collection of blood samples before, during and after treatment to perform a detailed analysis of immune cell components and immune-related gene expression profiles, which is akin to understanding the immune cells programming and instruction set. The analysis of these samples in the 23 patients enrolled in the first stage of the trial is the subject of this research proposal. To our knowledge, this type of comprehensive analysis of the peripheral immune profiling in patients with osteosarcoma has not been previously reported and will set the groundwork for future childhood immunotherapy trials in OS as well as have the potential to predict who is likely to benefit from combination nivolumab and regorafenib.
Osteosarcoma (OS) is the most common bone cancer in children and young adults. With current treatments, we are unable to cure about 40% of patients with OS. Novel therapies are desperately needed. Recently, immunotherapy, a treatment that allows the body’s own immune system to fight diseases such as cancer, has shown benefit in several cancer types. However, the benefit of immunotherapy in patients with OS has yet to be realized. We will perform a comprehensive assessment of different types of immune cells and their programming/instruction set (called gene expression profiling) using state of the art techniques. Assays will be conducted on blood samples from children and young adults enrolled on the SARC038 clinical trial and treated with nivolumab (drug that enhances immune cell function) and regorafenib (drug that shuts down growth promoting signals in the cancer cells). Using serial peripheral blood samples prospectively collected from patients prior to, during, and after therapy, we will gain a better understanding of disease response and resistance in patients with relapsed/refractory OS which will allow us to better tailor therapies for children treated on future immunotherapy trials. Importantly, we will also establish a benchmark for correlative studies of the activity and types of circulating immune cells for future research and immunotherapy trials in OS, as well as generate new hypotheses to improve the impact of existing immunotherapies for not only patients with osteosarcoma, but also for those with other difficult to cure pediatric cancers.
Heather Gardner, DVM, PhD, DACVIM (Oncology) from Tufts University was awarded an OutSmarting Osteosarcoma grant Because of Annaleigh and in collaboration with Fishin' for the Cure and will study liquid biopsy platforms to support early detection of metastasis and inform future interventions in osteosarcoma.
Standard liquid biopsy approaches that detect copy number changes and point mutations in circulating cell-free DNA (cfDNA) hold promise for early detection of cancer but are limited in sensitivity. Moreover, these liquid biopsy tests rely on the ability to distinguish tumor-derived and normal cell-derived cfDNA and assess specific genetic changes in cfDNA that are often static over the course of disease (i.e., copy number changes). Therefore, dynamic alterations in methylation and gene-expression associated with cancer treatment and response to therapy are not adequately captured. The objective of this research is to validate and improve a comprehensive multi-parameter liquid biopsy approach to identify early signatures of treatment resistance, prior to the development of clinically detectable metastatic disease. This work will provide the requisite computational structure necessary for prospective studies confirming the impact of early detection of drug resistance signatures using liquid biopsy. Importantly, we will generate a blueprint for future prospective studies designed to test the utility of this tool for preventing metastatic progression through liquid biopsy guided early intervention as new treatment options become available.
A major challenge towards improving outcomes for osteosarcoma (OS) patients is the development of multi-drug resistant metastatic disease. The lack of sensitive biomarkers of response to treatment is a critical barrier to progress in preventing metastatic disease. This work seeks to improve upon existing liquid biopsy approaches by evaluating multiple parameters in cell-free DNA (cfDNA) and cell-free RNA (cfRNA). We will first optimize and then validate a multi-parameter liquid biopsy method for early identification of treatment resistance in tumors with a structurally complex tumor genome, such as OS. This species and sarcoma subtype agnostic approach represents a paradigm shift in monitoring response to treatment in OS by incorporating temporal characterization of biomarker signatures.
Ryan D. Roberts, MD, PhD from The Abigail Wexner Research Institute at Nationwide Children's Hospital was awarded an OutSmarting Osteosarcoma grant in collaboration with Fishin' for the Cure and will study combination therapies targeting heterogeneity and lung environment in metastatic osteosarcoma.
Lung metastasis remains the deadliest complication for patients with osteosarcoma. Metastatic disease develops quite differently from primary tumors. Interventions targeting the mechanisms that drive lung colonization and growth could succeed where other efforts, including current conventional therapies, have failed. Our previous work has identified specific interactions that occur between lung cells and certain subsets of osteosarcoma cells that cause the lung to react as if it has been wounded. This physiologically abnormal wound response causes the lungs to undergo whole-scale restructuring of the surrounding lung, altering the types of cells present and producing a rigid network of fibrotic scar tissue. This creates a local environment that is dramatically different from normal lung, changing it in ways that appear important for supporting the emergence and/or recruitment of tumor cells that proliferate rapidly, leading to recurrence, resistance, and, in far too many cases, death. This proposal aims to leverage our newfound understanding of this biology to identify novel therapeutic combination strategies, focusing on interventions that can be rapidly translated to clinical trials, strategically pairing agents in ways that lessen the side effects of treatment.
An intervention that prevents lung metastases from occurring or that renders lung metastases treatable could revolutionize the care of patients with osteosarcoma. Such an intervention would be even more impactful if it combines treatments in a way where patients will actually feel better than they would otherwise—an opportunity never before realized in this disease. These impacts would only be greater if they utilize agents with well-established safety profiles in children and are already widely prescribed in chronic pediatric diseases, minimizing barriers to translation. Our increased understanding of the biology of metastatic colonization of the lung has led us to combinations that could achieve exactly that. Our preliminary pilot studies have been quite positive. We propose here to expand our work into larger preclinical studies in additional models of metastatic osteosarcoma to see if these predictions hold true and to establish rationale supporting the development of a clinical trial.
Sam Volchenboum, MD, PhD from the University of Chicago was awarded an OutSmarting Osteosarcoma grant Because of Annaleigh and will develop a data commons to support new treatments for osteosarcoma.
Despite decades of progress in curing pediatric cancer, bone tumors are among the most deadly pediatric malignancies. Of children with non-metastatic osteosarcoma, the survival rate is 69%, while cure rates for tumors that have spread to distant areas is a dismal 27%. In an era of high-resolution gene sequencing and personalized medicine, it is tragic that most children with bone tumors are treated with decades-old chemotherapy regimens. The field is ripe for progress, and the key to innovation is more and better-connected data. The Pediatric Cancer Data Commons at the University of Chicago is dedicated to lowering barriers to cancer research. The PCDC creates universal data standards for pediatric malignancies, transforms data into this new standard, and offers up those data to researchers. Over the past eight years, the PCDC has developed advanced international data dictionaries for eleven pediatric tumor types and is ingesting data from tens of thousands of children. The PCDC team has also developed GEARBOx (Genomic Eligibility Algorithm at Relapse for Better Outcomes), a tool to assist clinicians in quickly and efficiently finding clinical trial matches for patients. The PCDC has formed HIBiSCus (Harmonization International Bone Sarcoma Consortium), with members from the nine countries, and created a harmonized international data dictionary. Here we propose to launch the HIBiSCus data commons, with clinical and genomic biomarker data from thousands of children with osteosarcoma from all over the world, harmonized to a common standard, and available to researchers through an advanced cohort discovery tool and rigorous governance for data sharing. This resource will transform research for these deadly tumors, allowing researchers unprecedented access to data and enabling discovery of mechanisms of disease and novel therapies.
The therapy for most cancers is determined by the clinical and biological subtype at the time of diagnosis. These subtypes are usually associated with treatment response and resistance. Though fundamental to many other cancers, this work has not been sufficiently performed for osteosarcoma. No cancer is a singular biologic disease, and osteosarcoma is no exception to this paradigm. Currently, osteosarcoma patients are grouped according to the tumor’s behavior (e.g., metastatic disease or poor necrosis), but this tells us little about the underlying causes and provides no new insights into novel therapeutic options. The key to discovery is to aggregate large amounts of data from multiple sources, all harmonized to a single standard. Here, we proposed to bring together thousands of patients’ data harmonized to the balloted consensus standard defined by the HIBiSCus consortium. Once these data are available for query, researchers can interrogate the data and develop novel hypotheses about clinical and biologic subtypes and how to mitigate their outcomes. Additionally, the inclusion of molecular data in the PCDC dictionary (and commons) will drive research and facilitate the development of better technologies for matching kids to clinical trials. The PCDC will expand the osteosarcoma data dictionary to include relevant molecular markers and will work to include these data in initial and subsequent versions of the data commons. Further, these data can be used to power the GEARBOx clinical trials matching platform. The design and widespread deployment of this platform to aid clinicians in their quest to find appropriate precision treatment for their patients with osteosarcoma has the potential to be transformative for treatment and cure.
Amanda Marinoff, MD from the University of California, San Francisco was awarded an OutSmarting Osteosarcoma Young Investigator grant Because of Charlotte and will study novel molecular biomarkers for risk stratification in pediatric osteosarcoma.
The objective of this proposal is to develop and improve risk stratification in osteosarcoma -- that is, our ability to predict which patients will respond to standard therapy and which patients need different treatment that matches their disease biology in order to prevent relapse. Currently, all patients with osteosarcoma receive the same treatment at diagnosis, regardless of how likely their disease is to respond to that therapy. By developing a new targeted gene expression test using a platform called Nanostring that will incorporates a novel predictive gene signature that will classify patients into a high risk and standard risk group at diagnosis, this project paves the way for precision medicine clinical trials that offer different treatments to patients with different disease biologies and different likelihoods of cure.
Treatment strategies for children, adolescents, and young adults (AYA) with osteosarcoma (OS) have not changed in over 40 years, and survival for those who have disease that has spread to other parts of the body or comes back after standard treatment is dismal. At the same time, the approach to risk stratification — that is predicting who will respond to standard treatment and who needs different treatment that matches their disease biology — remains imprecise, does not incorporate any molecular features (such as the genetic changes that drive each individual’s tumor), and has not helped to improve treatment strategies. Furthermore, the current one-size-fits all treatment approach for all newly diagnosed patients does not reflect the many different subtypes of the disease at the genetic level. Preliminary studies from our lab show that OS can be classified into two risk groups that have different biologies and are associated with different clinical outcomes. In this project, I will develop a new tool, called a targeted gene expression test, to classify OS into these two risk groups. If validated, this test can be translated into new precision medicine clinical trials that incorporate new treatment strategies for OS and that test different treatments in different subtypes of the disease. By improving risk stratification in OS, the overall goal of these efforts is to improve survival and minimize treatment-related toxicities for children and AYA with osteosarcoma.
Marta Roman Moreno, PhD from the University of California, San Francisco was awarded an OutSmarting Osteosarcoma Young Investigator grant Because of Sydney and will study CRISPRi screening to identify vulnerabilities in metastatic osteosarcoma.
Scientific objective: The major goal of this proposal is to understand the connection between intratumor heterogeneity and metastatic capacity, as well as the role of specific oncogenic alterations in these processes. Through this research plan we will try to identify novel drivers of metastatic spread in pediatric OS, to understand the molecular mechanisms of these drivers, and to find new therapies to target these mechanisms to prevent the progression of metastatic disease. Long term, my objective is to contribute to the identification of new therapeutic targets that can lead to clinical trials and ultimately improvement in patient outcomes for metastatic osteosarcoma. Hypothesis: Metastatic ability in OS is due to the presence of a subset of cells within the tumor that have intrinsic capacity to survive in the metastatic niche (mainly lungs) during chemotherapy due to persistence in a pro-metastatic gene state. Rationale: Most osteosarcoma patients have micrometastasis at diagnosis. MAP therapy is effective for some patients, but others relapse due to persistence of metastatic cells resistant to therapy. I hypothesize that focused loss-of-function CRISPRi screening coupled to DNA sequencing in vivo will identify genes driving metastasis when paired with functional studies. These studies will be carried out in a panel of well- characterized cell lines with distinct metastatic capacity and for which there is extensive clinical annotation. My goal is to define new vulnerabilities to treat OS patients, establishing a link between basic discovery and translation, both of which are urgently needed in OS.
The goal of this proposal is to improve our mechanistic understanding of the process of lung metastasis. I use OS as a model system since this tumor type frequently metastasizes to the lung. However, the mechanisms that drive this process are mostly unknown. Using our own gene expression data and public datasets, I identified candidate metastasis-associated genes in OS. I then designed a custom pooled CRISPRi library to identify potential gene vulnerabilities for metastatic OS. The main aim is to use this library to understand the mechanisms that allow metastatic competence to identify new potential therapies which I will test in vivo using orthotopic models of metastatic OS. I will be mentored by Dr. Alejandro Sweet-Cordero, Chief of the Division of Pediatric Oncology and Benioff Professor of Children’s Health at the University of California San Francisco (UCSF). Dr Sweet-Cordero is a senior investigator with broad experience in genomics, cancer biology and translational therapeutics relevant to this application. Together with Dr. Sweet-Cordero, we have developed a comprehensive training plan for me that will increase my expertise in metastasis biology, sarcoma biology, functional genomics, and in vivo mouse studies. I plan to use these interdisciplinary approaches to solve critical clinical problems in sarcoma research. There is a clear need for newer effective agents for patients with OS, specifically for patients who are afflicted with metastatic and recurrent tumors. Throughout this work, new therapeutic vulnerabilities will be identified in the context of metastatic OS, which should contribute to our understanding of OS biology and help translate this knowledge to better therapies in the field of childhood cancer. By harnessing sophisticated model systems focused on metastatic OS and innovative technologies, we will “move the needle” for a disease with little improvement in therapy over the last 30 years.
