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Outsmarting Osteosarcoma 2022



Michael Leibowitz, MD, PhD from the University of Colorado/Children’s Hospital Colorado will study altering the tumor microenvironment to increase epitope spreading and augment chimeric antigen receptor T cell therapy for metastatic osteosarcoma.

For Abstract

Altering the tumor microenvironment to increase epitope spreading and augment chimeric antigen receptor T cell therapy for metastatic osteosarcoma

Scientific objective and rationale

There is a new and effective treatment for pediatric blood cancers. The treatment involves reprograming a patient’s own cells to destroy their tumor cells, a process called cellular immunotherapy. Despite great effort to use cellular immunotherapy to treat “solid” tumors, which include tumors of the bones, muscles and other parts of the body, we have not been successful yet. One major reason is that the reprogrammed patient cells are designed to recognize a single marker on a cancer cell. In some blood cancers, all of the tumor cells express the same marker increasing the likelihood that cellular immunotherapy can cure the patient. Solid tumors are more heterogeneous than blood cancers, meaning each solid tumor cell may express a different marker. Therefore, cellular immunotherapy is less likely to destroy all solid tumor cells and the chances of achieving a cure is much more difficult. A potential solution is to trigger the body’s own immune system to destroy tumor cells that express many different markers, a process called “epitope spreading”. The focus of this project will be to test strategies to augment epitope spreading in osteosarcoma so that cellular immunotherapy may become an effective and viable treatment option in the future.


Osteosarcoma (OS) is the most common malignant bone tumor in children, adolescents and young adults. Roughly 30% of patients that present with localized disease die within 5 years due to metastatic disease. About 20% of newly diagnosed patients present with metastatic disease which portends a poor prognosis. The 5-year overall survival is less than 40% in patients with metastatic disease at presentation. Despite efforts to introduce novel therapies, cytotoxic chemotherapy and surgery remain the standard-of-care for the last 40 years. There are few salvage therapies and limited options for experimental therapies for osteosarcoma. In fact, the Children’s Oncology Group assembled a task force to prioritize novel agents for osteosarcoma. This proposal entails two separate and potentially complementary approaches to address a significant unmet medical need to facilitate new and targeted treatment opportunities for patients with metastatic and/or recurrent OS. Leveraging my lab’s expertise in CAR T cell immunology and my collaborator, Dr. Sid Mitra’s deep understanding of CD47 biology in solid tumors, these studies represent highly translational novel treatment paradigms. In fact, anti-CD47 therapies are already in Phase I clinical trials for solid tumors (NCT02367196). To our knowledge, this proposal represents the first pre-clinical study combining CD47 blockade with CAR T cells. Importantly, these studies will increase our understanding of how CAR T cells impact the solid tumor microenvironment. Ultimately, we hope that our data may provide the rationale for a clinical trial utilizing FLT3L secreting CAR T cells in combination with anti-CD47 to treat pediatric osteosarcoma in the future.

John Ligon, MD, from the University of Florida, was awarded the Outsmarting Osteosarcoma Because of Dylan Young Investigator Award and will study RNA-nanoparticle vaccines to overcome the immunosuppressive tumor microenvironment of canine osteosarcoma.

For Abstract

Using RNA-nanoparticle vaccines to overcome the immunosuppressive tumor microenvironment of canine osteosarcoma

Scientific objective and rationale

Recent advances have shown that it is possible to use a patient's own immune system to fight cancer. Osteosarcoma, the most common bone cancer in children and young adults, is one cancer type that has not responded to immune-based treatments. Most patients who relapse die when the osteosarcoma spreads to the lung, and it is critically important to design new treatments to prevent these young lives from being lost. Dr. Ligon's team analyzed osteosarcoma samples from human patients and found that while immune cells are present in osteosarcoma lung tumors , they are kept at the outside of the tumor because the tumor has several ways to "exclude" these immune cells. In collaboration with Dr. Sayour, Dr. Ligon's team proposes to use a new immune-based therapy called an RNA nanoparticle vaccine, which may be able to reprogram the tumor and allow immune cells to kill the cancer. In collaboration with Dr. Milner in the University of Florida College of Veterinary Medicine, Dr. Sayour and Dr. Ligon have already begun dog clinical trials of the RNA nanoparticle vaccine for pet-dogs with brain tumors and osteosarcoma. These studies have shown that RNA-nanoparticles are safe in dogs, and in some cases effective in treating dogs with cancer either by themselves or when combined with other treatments like radiation. Dr. Ligon proposes an expansion of the dog clinical trial to include dogs with osteosarcomas which cannot be removed by surgery. This will create two new opportunities: 1) to combine RNA nanoparticles with radiation therapy, and 2) to obtain a piece of the tumor after treatment with the RNA nanoparticle and see how the tumor has changed under the microscope. The ultimate objective is to generate evidence that RNA nanoparticles are safe, effective, and activate the body's immune system in a way that can destroy osteosarcoma and create the basis for expanding treatment with RNA nanoparticles into human clinical trials for patients with osteosarcoma.


The focus area to be studied is immunotherapy for children/adolescents and young adults with osteosarcoma, and specifically those whose cancer has either come back after previously being treated (recurrent disease) or which has spread to the lungs. These patients currently have no treatments available which can cure their cancer, so this study will hopefully lead to a new treatment (RNA nanoparticles) being offered in a future human clinical trial for patients with osteosarcoma. RNA nanoparticles are especially exciting because they are made from a patient's own tumor, allowing for a personalized treatment. While the risks of this new treatment are still unknown, any potential benefit from trying a new treatment for this difficult to treat cancer is worth pursuing. This study is important because, unlike models in the lab with mice that are used to study osteosarcoma, dog osteosarcoma is very similar to human osteosarcoma. If RNA nanoparticle vaccines are safe and effective in dogs, this would give us hope that these treatments would be safe and effective in humans. Furthermore, by treating dogs whose tumors cannot be removed by surgery, we will gain a rare opportunity to look at how the tumor changes after treatment with RNA nanoparticles which is very difficult to do in human patients. Importantly, RNA nanoparticles entered human clinical trials in early 2022 for patients with brain tumors. As RNA nanoparticles are already in clinical trials for another type of cancer, this means that it may be easier to get approved for osteosarcoma. A draft of a human clinical trial for patients with osteosarcoma has been discussed with the National Pediatric Cancer Foundation which runs the Sunshine Consortia, and would be willing to open a clinical trial with RNA nanoparticles for patients with osteosarcoma at multiple hospitals. These studies in dogs will provide strong evidence to begin a human clinical trial of RNA nanoparticles for osteosarcoma in the near future.

Dan Regan, DVM, PhD from Colorado State University will study Focal Adhesion Kinase (FAK) inhibition to improve losartan-sunitinib immunotherapy in metastatic osteosarcoma.

For Abstract

Focal Adhesion Kinase (FAK) inhibition to improve losartan-sunitinib immunotherapy in metastatic osteosarcoma

Scientific objective and rationale

The immune suppressive tumor microenvironment (TME) is recognized as a key barrier to generating effective immune responses against cancer, particularly in immunologically “cold” cancers such as osteosarcoma (OS). Our long-term goal is to disrupt this immune suppressive environment by depleting and/or functionally altering tumor associated macrophages, the dominant immune suppressive cell in the TME. We previously demonstrated that blockade of monocyte migration with an already FDA-approved repurposed drug (losartan), combined with a multi-kinase inhibitor (toceranib), resulted in significant clinical benefit (50% response rate) in dogs with metastatic OS. Based on this canine trial, this drug combination is currently being evaluated in a Phase I trial in pediatric OS (NCT03900793). The objective of this proposal is to improve the effectiveness of this losartan/toceranib protocol by addition of a complementary molecular-targeted therapy, and at the same time develop novel lung immune monitoring technologies to better assess OS patient treatment responses to anti-metastatic therapies. We hypothesize that addition of a focal adhesion kinase (FAK) inhibitor will significantly improve tumor responses when combined with our original losartan/toceranib immunotherapy protocol, and that immune monitoring via bronchoalveolar lavage samples obtained from the lungs will correlate with tumor responses. FAK signaling has recently been shown to drive an immune suppressive TME, in addition to its known direct effects of promoting cancer cell migration and proliferation. In support of this, our preliminary data indicate FAK is hyperactivated in both canine and human OS and that FAK inhibition results in direct anti-tumor effects including inhibition of cell proliferation, and significantly extended survival in an OS lung metastasis model. Further, genomic analysis of canine and human OS tumors link upregulated FAK signaling with an immune suppressive TME.


Osteosarcoma (OS) is the most common primary malignant bone tumor, yet overall survival for OS patients has not improved since the advent of multi-drug chemotherapy protocols in the 1980s. This clinical failure is directly attributable to our inability to treat the >30% of OS patients who develop tumor recurrence, nearly always in the form of lung metastasis. Currently, we have no effective clinical actions to take for these patients as chemotherapy dose-intensification, new molecularly targeted therapies, and immune checkpoint inhibitors have all failed to improve survival in metastatic OS patients. Thus, the current conundrum: Despite 1) discovery of intrinsic molecular drivers of OS progression, and 2) a relatively high degree of genomic instability in these tumors, this has not translated into clinical effectiveness of molecular and immune checkpoint targeted therapies in this disease, despite promising studies in rodent models demonstrating pre-clinical efficacy. Our prior work and the studies proposed here strive to re-write this blueprint by utilizing a comparative oncology approach in dogs with naturally occurring OS to improve translational predictability. These studies are innovative as they propose the use of complementary and readily implemented immunotherapy approaches to treat metastatic OS in a translationally relevant animal model, while also utilizing novel, technically advanced immune monitoring strategies to assess mechanisms underlying these interventions. Our prior work demonstrates a successful track record of rapidly translating canine OS clinical studies to human OS patients. Thus, the studies proposed here are likely to have high impact for patients with pulmonary metastatic OS as they build on our prior success of the losartan/toceranib immunotherapy (the basis for a currently ongoing pediatric OS trial- NCT03900793) by addition of a readily deployable pharmacologic (FAK inhibition) approach with proven activity in other tumor types.

Jason Yustein, MD, PhD, from Emory University will study combinatorial therapies to improve immune-mediated approaches for osteosarcoma.

For Abstract

Combinatorial therapies to improve immune-mediated approaches for osteosarcoma

Scientific objective and rationale

Overall survival rates for Osteosarcoma (OS) remain about 65-75% and are significantly worse for patients with advanced or relapsed disease, often with long-term outcomes of less than 30%. Therefore, alternative therapeutic approaches are needed. Using the patient’s immune system to help target and eliminate the tumor has been an active area of research for many cancers. Prior studies have reported the significance of a tumor microenvironment that inhibits the OS patient’s immune system from targeting the tumor. Unfortunately, there has been minimal success using immune alteration therapies for sarcomas. To effectively evaluate candidate immune altering approaches and compounds, it is essential to test on relevant models. Using novel genetically altered mice that our laboratory has developed to mimic osteosarcoma tumor initiation and development, we have been actively studying the biology of the tumor cells and non-tumor cells, including immune cells. Our mouse models also provide valuable tumor cell resources that allow us to perform studies evaluating the effects of immunotherapy, or small molecules that alter the immune system. The overall objectives are focused on (1) assessing the effects of combination immune altering drugs and targeted kinase inhibitors on osteosarcoma development and metastatic progression and; (2) to perform comprehensive molecular characterization of the effects the combination therapies have on the tumor environment. Specifically, we will test several small molecules targeting key tumor-promoting pathways in OS, including the kinase inhibitors Cabozantinib and the beta-catenin inhibitor Tegavivint. These drugs have recently shown anti-tumor activity for osteosarcoma as single agents. Besides targeting the tumor cells, these inhibitors alter the behavior of the immune cells in other cancers. Our studies will provide essential molecular insights and pre-clinical assessment of rational combination therapy that can lead to clinical trials.


While chemotherapy has been the standard of care, and the evaluation of targeted therapies, such as multi-tyrosine kinase inhibitors, have been used to treat pediatric sarcomas, these therapies have primarily focused on the primary tumor cell biology. More recently, there has been a tremendous focus on using the patient’s immune system to help target the tumor. Investigating the applications of immunotherapy to treat OS is an emerging field, as we are learning more about the OS tumor microenvironment. One class of small molecules includes immune checkpoint inhibitors (ICI). While ICIs have shown promise in some adult cancers, previous clinical trials using ICI as monotherapy have proven ineffective in OS. To effectively investigate the potential applications of immunotherapy to treat OS, it is essential to evaluate candidate immunotherapeutic approaches and compounds, including checkpoint inhibitors, on relevant, immune competent models. Our laboratory has developed and extensively characterized genetically engineered mouse models of OS, which mimic the molecular pathogenesis, development, and progression of the disease. Using our tremendous expertise and familiarity with our high-risk phenotypic and molecular syngeneic models, we will perform highly efficient combinatorial pre-clinical trials, so promising combinations are prioritized for subsequent trial consideration. In addition, our proposed spatial molecular studies will undoubtedly reveal proteo-transcriptomic insights into tumor evolution in response to single-agent and combinatorial therapy. Our studies can be transformative and provide rationale treatment regimens implementing immunotherapeutic approaches for high-risk OS patients, thus addressing an unmet need for a substantial patient cohort in dire demand for effective alternative therapies.

Eunice Lopez-Fuentes, PhD from the University of California, San Francisco was awarded the Outsmarting Osteosarcoma Because of Charlotte Young Investigator Award and will study two epigenetically distinct cellular states in osteosarcoma, defined by a cluster-specific set of pioneer transcription factors and show differential drug response.

For Abstract

Two epigenetically distinct cellular states in Osteosarcoma are defined by a cluster-specific set of pioneer transcription factors and show differential drug response

Scientific objective and rationale

Identical twins share the exact same DNA, but even twins who share the exact same DNA can differ substantially in their attributes. The same applies to your cells, every cell in your body contains the same DNA with ~ 20000 genes. Yet somehow, the DNA provides the basis for each cell’s individuality. This can be explained by epigenetics, which literally means “above the genes”. Epigenetics refers to external modifications to DNA that turn genes "ON" or "OFF." These modifications do not change the DNA sequence, but instead, affect how cells "read" genes. Epigenetics plays an important role in pediatric cancer since it can turn “OFF” a tumor suppressor or turn “ON” a tumor helper. My scientific goal is to define what are the epigenetic modifications to DNA in osteosarcoma cells and to understand how epigenetics may influence therapy response, resistance and metastasis. In my preliminary work I have identified two main subclasses in osteosarcoma defined by a type of epigenetic assay called ATACseq. I have also discovered that these subclasses correlate with differential response to targeted therapies. I want to uncover what are the key mechanisms that drive the existence of these distinct epigenetic subclasses and use this knowledge to find new informed strategies for treatment.


Despite recent advances, there has been little progress in the identification of clinically actionable vulnerabilities in osteosarcoma and in understanding what factors promote tumor cells survival. In current studies, there is an over-reliance on tumor cells that have been used for decades. I propose the identification of liabilities of osteosarcoma tumor cells using a unique set of samples, including the continuum of the disease, such as biopsy, resection and metastatic samples. All this samples were derived from patient tissues and can mimic osteosarcoma in mouse models. After the cells are injected in the mouse leg, cells can form a tumor in the paratibial and after weeks or months, the mouse shows liver and lung metastasis. I will study the epigenetic modifications in this diverse set of samples and how these modifications play a role in response to targeted therapies. From preliminary results, I identified two subclasses of osteosarcoma with different epigenetic modifications showing differential drug response. I want to evaluate this differential drug response in mouse models. I will use single and combinatorial drug therapy based in the vulnerabilities found per osteosarcoma subclass. I will use Barasertib and Trametinib alone or in combination with cisplatin (common chemotherapy) in mouse models to evaluate whether the tumor can shrink or whether metastasis is generated. Both drugs have been used in clinical trials for cancer. Barasertib has been used in 10 clinical trials, mostly for leukemia, only 2 are focused on solid tumors with no results posted. Trametinib has been used in 90 clinical trials in cancer in the past and 46 are active. From those, only 1 clinical trial was performed in pediatric cancer to investigate the safety and tolerability. The proposed studies will help to consider dividing osteosarcoma in subclasses to evaluate drug response and will lay the foundation for epigenetically-informed clinical trials.

Kristen VanHeyst from UH Rainbow Babies and Children’s Hospital was awarded the Outsmarting Osteosarcoma Because of Charlotte Young Investigator Award and will study modulating TGF-beta Signaling in the tumor microenvironment as an effective therapy for osteosarcoma.

For Abstract

Modulating TGF-beta Signaling in the Tumor Microenvironment as an Effective Therapy for Osteosarcoma

Scientific objective and rationale

Osteosarcoma (OS) is the most prevalent aggressive primary malignancy of the bone affecting children and young adults. Approximately 10% to 20% of patients have metastatic disease at initial presentation. The most common site for disease metastasis and recurrence is the lungs. Although overall survival in patients with OS has improved with advances in therapy, there have been no significant improvements in survival outcome in patients with pulmonary metastatic osteosarcoma (pOS) or recurrent/refractory osteosarcoma (rOS). Unfortunately, the prognosis is grim. Due to the complex genetic makeup of OS, molecular targeted therapy approaches are not feasible. For this reason, novel therapeutic approaches are desperately needed. Transforming Growth Factor-Beta (TGF-beta) is an abundant and potent immune suppressive molecule produced by OS cells and immune cells in the tumor microenvironment (TME). The presence of TGF-beta contributes to making the TME more inhospitable and dampens the ability of the patient's own immune system to eradicate this tumor. TGF-beta expression is increased in the serum of patients with OS compared to healthy individuals, and high TGF-beta correlates with high grade OS and pOS. Effective targeting of TGF-beta would therefore be a desirable therapeutic approach for treating pOS and rOS. The aims of this project are to 1) Examine immune-mediated anti-tumor effects of TGF-beta-inhibitor, TEW-7197 (“Vactosertib”; MedPacto, Inc.) and its potential efficacy with immune checkpoint blockade in human OS TME and 2) translate this preclinical data into a Phase I/II clinical trial in an effort to provide more therapeutic options for patients with this disease. This novel possibility may highly impact the survival of pediatric and adolescent and young adult patients with pOS or rOS by offering real clinical opportunities for treatment.


Immunotherapy is an innovative field that provides novel possibilities offering hope for finding curative options for pediatric and adolescent and young adult patients. Immunotherapy has shown promise in the treatment of multiple cancers, but effective treatment responses have yet to be realized in osteosarcoma (OS). Current standard of care therapy for the treatment of OS, whether a patient has metastatic disease at the time of diagnosis or not, is the same. It consists of neo-adjuvant chemotherapy in combination with surgical resection. This standard of care has not changed in decades, and neither has the overall outcome for patients with metastatic OS or recurrent/refractory disease. The prognosis for these patients is grim. Additionally, the chemotherapeutic agents the patients receive impart caustic and sometimes devastating side effects and toxicities. For these reasons, it is imperative to advance our understanding of the OS tumor microenvironment (TME) as components of this could be targets for therapy. We have already garnered support from MedPacto, Inc, a South Korean based pharmaceutical company who is collaborating with us in utilizing their first-in-class, orally-available non-toxic small molecule inhibitor, TEW-7197 (“Vactosertib”). We have also generated some initial promising preclinical data that supports further exploration of this drug in preclinical models of OS with a high likelihood that this will translate to the clinical setting in the very near future. Even more exciting is that our ongoing data enabled FDA issuance of Orphan Drug Designation for Vactosertib for treating OS in 2021. We are now working on developing an investigator initiated trial. Through better understanding of the TME and how to modulate it in such a way that it is no longer hospitable to tumor cells, these scientific concepts can potentially be applied to other sarcomas and malignancies alike. Improving overall survival outcomes for these patients is critical.

Outsmarting 2022 Award Programs

MIB Agents is now accepting applications for our 2022 Outsmarting Osteosarcoma grant cycle. We are thrilled to offer multiple awards this year in addition to introducing a new Young Investigator award.

The Outsmarting Osteosarcoma Research Award
$100,000 grant over one year to any investigator with a proven track record in osteosarcoma and a compelling study that will Make It Better for osteosarcoma patients.

The Outsmarting Osteosarcoma Young Investigator (YI) Research Award
$50,000 grant over one year to any young investigator with a promising and compelling study that will Make It Better for osteosarcoma patients.

Awards may be sponsored by one MIB Agents Family Fund or individual donor, which is co-branded in
honor of the Family Fund. Multiple grants will be awarded in 2022, and the number of grants by award type will be determined based on budget and program goals during programmatic review.


$950,000 awarded to date
The OutSmarting Osteosarcoma Research Grant is an annual award begun in 2017. For the past five
years, $100,000 has been awarded each year to a project that will focus on moving research forward for
osteosarcoma patients.

Family Funds Supporting Science
Collaboration among the scientific and patient community is a key hallmark of MIB Agents. MIB Agents
Outsmarting Osteosarcoma grants are supported by MIB Agents Family Funds, osteosarcoma patients
and families who raise funds in honor of an OsteoWarrior or OsteoAngel. Their dedication to Making It
Better and fostering collaboration and education in the scientific community makes every MIB Agents
award incredibly meaningful.

Our collaborative and robust review process
The two tier review process results in a robust and collaborative review process that uniquely
incorporates patient and family perspective.

Please email christina@mibagents.org with any questions.

Outsmarting Osteosarcoma
Grant Applications Due March 11, 2022

2021 OutSmarting Osteosarcoma Meeting
2021 OutSmarting Osteosarcoma Meeting
2020 OutSmarting Osteosarcoma Meeting
2019 OutSmarting Osteosarcoma Meeting in Chicago, IL
2018 OutSmarting Osteosarcoma Meeting in Washington DC
2017 OutSmarting Osteosarcoma Meeting in Sofitel DC

Proposal Form

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