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Shahana S. Mahajan, PhD from Hunter College of the City University of New York Repurposing drugs for metastatic osteosarcoma
Our research goal is to determine a novel therapy approach for osteosarcoma using an FDA approved drug, Riluzole. Riluzole has been in use for the treatment of Amyotrophic Lateral Sclerosis (ALS) since 1995. Riluzole acts by blocking glutamate secretion and is shown to be effective in preventing cancer growth in types of cancer which depend on glutamate for their growth. Since Osteosarcoma was shown to secrete glutamate and utilize it for growth, we were able to block osteosarcoma growth with Riluzole. We want to further evaluate the efficacy of Riluzole using patient derived samples (PDX) which will provide data to support a clinical trial in the near future. Osteosarcoma is not only the most common bone tumor occurring in adolescent and young adults, but it is also highly difficult to treat. The 5-year survival rates for primary localized tumor are 70% and an abysmal 30% for metastatic disease when the tumor spreads to the lungs. The survival rates have not changed for over three decades and there is a dire and unmet need for better treatment outcomes for metastatic osteosarcoma. Osteosarcoma is difficult to treat because the tumors show a large variation in their genetic material thereby making osteosarcoma difficult to treat using targeted therapy. The use of a therapy where high drug efficacy is obtained regardless of the genetic variation is highly desirable. Our data supports that Riluzole inhibits growth effectively in both primary tumor and metastatic tumor cells that harbor varying genetic mutations. We want to test the efficacy of Riluzole, prodrug FC-3423 in PDX in cultures and in animal models. Dr. Healey, a renowned orthopedic surgeon has developed PDX models which will be used in our study to determine the efficacy of Riluzole as a therapeutic agent. The data from the study will be used to set up a clinical trial in 2 to 3 years from now. Since Riluzole is an FDA approved drug, it will expedite the translation.
The main goal of the proposal is to develop a therapeutic strategy with Riluzole/FC-3423 as the drug either alone or in combination with other drugs for chemotherapy for OS. The successful completion of the study will provide data to support a clinical trial in the near future, therefore the proposed research will have a near-term impact on the osteosarcoma young patient (12-21 years) population. Riluzole is an FDA approved drug with a lot of pharmacokinetics data already available from patients since 1995. The translation of the research into clinical applicability is enhanced by low toxicity and good tolerance of Riluzole in patients on Riluzole therapy, therefore, the proposed research has direct clinical applicability for achieving better patient outcomes. Clinical trials in melanoma patients have demonstrated drug safety as well as potency with both Riluzole and FC-3423. However the efficacy of Riluzole in patient-derived samples needs to be evaluated. Upon successful completion of the proposed study, we anticipate that the results will have a positive impact on the patient population afflicted with osteosarcoma. The data from the study will be used to set up a clinical trial in 3-4 years from now. Since Riluzole is an FDA approved drug, it will expedite the translation from bench to bedside. The survival rates of the osteosarcoma population have not improved in over the last 3 decades, and given the low toxicity of Riluzole/FC-3423, the patient population will not experience the dreadful post-chemotherapeutic side effects. The data from the study will be used to set up a clinical trial in 2 to 3 years from the grant start date.
Jill Kolesar, PharmD from University of Kentucky Markey Cancer Center Macrophage Engineered Vesicles for Pediatric Osteosarcoma
The overall goal of this project is to prevent lung recurrences in children, adolescents and young adults with osteosarcoma (OS). The osteosarcoma cells that cause this recurrence are generally present at diagnosis but are too small to be detected. They are also slow growing which makes them insensitive to chemotherapy. In addition, they are protected by tumor associated macrophages (TAMs). TAMs make an environment for osteosarcoma cells that encourages their growth and protects them from being taken up by the immune system. To prevent lung recurrences, we have developed and tested a novel biological therapy, M1 Macrophage-derived Engineered Vesicles (MEVs). MEVs are nanoparticles derived from anti-cancer type macrophages that can go specifically to tumors and eliminate TAMs and OS cells. In addition, in an osteosarcoma model system we have shown MEVs 1) are tumor specific; 2) have no observed or laboratory adverse effects after 12 weekly doses; 3) are more effective than regular cancer drugs; and 4) prevent the development of lung recurrences. Given impressive activity, no toxicity and clear unmet medical need, the overarching goal of this proposal is to further advance MEVs as a therapeutic strategy. To do this we need to complete 3 crucial investigational new drug (IND) enabling activities. 1) Establish a measure of potency; 2) transfer manufacturing to a clinical facility and 3) conduct a dose response study. Our central hypothesis is that MEVs eliminate TAMs, which will eradicate micro-metastatic disease and ultimately prevent the development of metastasis and improve survival in OS. Successful completion of this proposal will enable initiation of a phase 1 clinical trial is pediatric osteosarcoma.
OS is a rare cancer and prior to the development of effective drug regimens, OS was nearly universally fatal. Currently, two of three children with OS are cured of their disease, however one of three still die, usually of an OS recurrence in the lung. A treatment preventing OS lung recurrences would be the single most significant improvement in outcome since the advent of anticancer drugs in the 1960s. A strategy that can eliminate TAMs and lingering osteosarcoma cells can prevent the development of lung recurrences, and ultimately improve survival for children with OS.
Arianexys Aquino-López, MD, PhD from Baylor College of Medicine Repurposing Virus Specific T cells as Immune Therapy for Osteosarcoma This grant was awarded Because of Sydney.
Osteosarcoma is a bone cancer that generally affects children and adolescents. Chemotherapy for osteosarcoma has remained the same since the 1980’s, with no improvement in survival. Furthermore, when cancer spreads to the lungs (metastatic disease), it is difficult to treat. Only between 10% to 40% of patients with lung spread survive for 5 years. Current therapies for metastatic osteosarcoma include drugs and surgery, but these often fail. To develop a better approach, I will redirect the patients’ own immune system to treat the tumor like a curable virus infection rather than a resistant cancer. When we get sick with a virus, cells from our immune system, called virus specific T cells (VSTs), eliminate unhealthy cells infected by virus. The way the immune system finds the unhealthy cells is by recognizing “viral signals” on the surface of the infected cells. I propose using a virus combination called CAdVEC to modify cancer cells and make them show these “viral signals”. This will trigger the immune cells in our body to attack and eliminate the cancer cells.
Viral infections trigger immune cells in our body called virus specific T cells (VSTs) to be able to eliminate cells infected with the virus. What if we could make these immune virus specific T cells recognize and kill cancer cells as well? Through my project I will re-purpose VSTs that normally recognize virus infected cells, to also recognize and kill osteosarcoma cancer cells. I will begin by targeting the cancer cells that have spread to the lungs which is a common place for the spread of osteosarcoma. To do that, I will use a virus combination called CAdVEC to introduce into the cancer a mixture of “virus signals” and immune system stimulants. Once cancer cells show these “virus signals” on their surface, they will alert the immune system and bring the virus specific T cells to the cancer. Once the VSTs are in the tumor, the immune stimulants present in CAdVec will amplify and maintain this antitumor response. A combination virus similar to the one I will use is now being used in a clinical trial in adults with solid tumors, where it has shown safety and responses that have included disappearance of the cancer for more than 2 years (NCT 03740256). In addition, our center has a Good Manufacturing Practices (GMP) facility that allows it to make VSTs which have been safely used in pediatric patients with viral infections. Our application of this combination immunotherapy to children, adolescents, and young adults with metastatic osteosarcoma already has promising preliminary results from nonclinical studies. Further support by the MIB Agents Outsmarting Osteosarcoma Young Investigator Grant will allow us to complete these studies and obtain permission for a Phase 1 clinical trial with the potential for substantial impact in the management of pediatric and young adult patients with metastatic osteosarcoma.
Chelsey Burke, MD from Memorial Sloan Kettering Cancer Center Evaluating tumor evolution and mechanisms of resistance in osteosarcoma This grant was awarded Because of Ava.
Outcomes for children with cancer have steadily improved over the past several decades. However, the overall survival of children with advanced osteosarcoma has not changed appreciably over the last 30 years. Unfortunately, less than 20% of osteosarcoma patients who present or develop metastasis will survive long-term. These dismal outcomes are due, in part, to our lack of understanding of tumor evolution and how this informs treatment resistance. In this proposal, we will use patient-derived xenograft models to study the evolution of osteosarcoma to better understand the mechanisms of resistance and the trajectory of metastatic progression. Additionally, we will utilize a novel systems biology approach to identify key proteins driving the cancer cells, the so-called “Master Regulators” (MRs). We will then identify and validate drugs that target these MRs in order to overcome the drug resistance that occurs in progressive osteosarcoma. By prioritizing clinically applicable drugs, we anticipate generating translational results that will support the development of future pediatric clinical trials. This innovative approach addresses current challenges in precision medicine while also meeting a critical unmet need for children and adolescents with osteosarcoma.
Although there have been great advances in childhood cancer, high-risk osteosarcoma remains challenging to treat with drug resistance being a major cause of treatment failure. In this proposal, we seek to study the effects of treatment on osteosarcoma tumor evolution with the hope of identifying mechanisms that gives rise to the development of drug resistance, knowledge that is currently lacking. We utilize a novel systems biology approach to identify new therapeutic options that can target tumor vulnerabilities to evade treatment failure. Knowledge from this study promises to yield insights into mechanisms behind drug resistance and malignant progression. With this new understanding of osteosarcoma evolutionary dynamics, we will be able to implement therapeutic changes earlier in management to overcome drug resistance, thus preventing metastatic progression and improving survival for children and adolescents with osteosarcoma. Application of these outcomes can be expanded to a broad number of high-risk sarcomas, thereby providing significant innovation and therapeutic potential to many children with cancer.
Betsy Young, MD from University of California, San Francisco Tumor-intrinsic cGAS-STING activation promotes anti-tumor inflammatory response in osteosarcoma
In cancers including osteosarcoma (OS), malfunctioning DNA replication results in a warning signal to the immune system via the cGAS-STING pathway, which we believe is modified in OS tumors to evade immune-mediated tumor killing. We have identified that about 50% of OS patient-derived cell lines respond to cGAS-STING activation with a drug treatment, whereas the other half do not. Additionally, using RNA sequencing, we defined the specific genetic changes that occur in OS upon activation of the cGAS-STING pathway. Our preliminary studies of a STING activating drug in animal models have shown that this therapy can slow tumor growth and increase anti-tumor immunity. Overall, we have discovered two subsets of OS with differing capacity to generate an anti-tumor immune signal and demonstrated the benefits of activating STING in patients and in immune assays. Our proposed ongoing work will confirm the effects of STING activation, supporting the translation of this novel approach to activating immune surveillance in osteosarcoma.
This work will identify ways to activate the immune system to fight osteosarcoma, which is critically important to improve the treatment options available for children affected by this disease. Doctors and researchers have known for some time that our immune system can recognize cancer and remove it. In fact, many new cancer treatments have used this “immunotherapy” approach, but we haven’t yet figured out how osteosarcoma hides from the immune system or how to reverse this. In this project, I have identified that the cGAS-STING pathway allows osteosarcoma to avoid the immune system, and I am now testing a new approach of activating STING to unleash the immune system to treat osteosarcoma. We believe this research will result in improved understanding of how osteosarcoma avoids immune surveillance, and in a novel treatment paradigm for this highly aggressive pediatric cancer. I am very excited to continue this work which I think in the next few years could result in a new treatment for patients with osteosarcoma. Recent attempts to introduce better treatments for osteosarcoma have not been successful, and this data can serve as the basis for the development of a broad range of new immunotherapy treatments for this disease.
