Advancing the Most Promising Research

Redefining residual disease detection in pediatric AML

Dr. Green Gladden is using a new technique (single-cell RNA sequencing) to better understand the risk for relapse due to the presence of low levels of cancer cells following standard treatment in children with acute myeloid leukemia (AML).

As part of this CURE-funded study, Dr. Green Gladden proposes to redefine the way leukemic response to chemotherapy is measured by not just asking, “How much disease remains?” but “What is the biology of the disease that remains?” which is evaluated by looking at the gene expression of residual leukemic cells.  By better understanding risk for relapse and improving how risk is determined and categorized, she hopes to improve outcomes for patients with AML.  Understanding the biology of residual disease will pave the way for future therapy development.

Defining determinants of a cGAS-STIGN-mediated anti-tumor inflammatory response in osteosarcoma

Dr. Young’s research aims to gain an improved understanding of how osteosarcoma avoids the body’s immune surveillance and to deliver a novel treatment paradigm for this highly aggressive pediatric cancer. Recent attempts to introduce better treatments for osteosarcoma have not been successful, and this research aims to be the basis for the development of a broad range of new immunotherapy treatments for osteosarcoma. Her laboratory has identified that activation of a biochemical pathway called STING has anti-tumor benefits in animal models and a protective effect in human disease. Therefore, they will study this pathway as an important therapeutic target. This proposal will serve as the foundation for ongoing work to translate STING-activating therapies for patients with osteosarcoma.

Defining replication stress and DNA damage as a therapeutic vulnerability in osteosarcoma

The goal of Dr. Sweet-Cordero’s research is to evaluate new combination therapies for osteosarcoma, a disease for which few improvements in therapy have been achieved in the last 40 years. In this research, his lab will utilize a unique collection of patient-derived cell lines that reflect the true state of patients’ cancers. Through previous extensive studies, the Sweet-Cordero lab identified a potent and promising combination of drugs (gemcitabine/ATRi). In this CURE-sponsored research, the lab will test this drug combination further on human and mouse models. These studies will serve as necessary evidence to support the development of possible clinical trials within the next 18-24 months.

Targeting and imaging serine metabolism in the tumor microenvironment in pediatric brain tumors

Diffuse midline gliomas (DMGs) are the deadliest form of brain cancer in children, and no effective treatments currently exist. Dr. Viswanath has shown previously that DMG tumor growth depends on serine (an amino acid crucial for cell function), and blocking serine in the tumor environment sensitizes the cancer cells to existing immunotherapy. Dr. Viswanath’s lab has also found that a new tumor imaging technique called deuterium metabolic imaging allows them to identify whether the tumor is responding to therapy quickly. In this CURE-funded study, they will determine whether reducing serine has a therapeutic effect and whether deuterium metabolic imaging can be used to monitor treatment response in mouse models of DMG. These studies will lay the foundation to bring this innovative therapeutic and imaging strategy to children with DMG in the near future.

c-MYC protein degradation in therapy-resistant pediatric leukemias

Dr. Andreeff’s research is focused on reducing the levels of c-MYC, a protein that is known to play a critical role in regulating cell growth and proliferation, in pediatric leukemias that do not respond well to traditional treatments. Dr. Andreeff proposes to investigate a novel drug candidate, GT715. His lab has already demonstrated highly promising therapeutic effects in cell and animal models, though the drug has not yet been tested in patients. Dr. Andreeff will also be working on testing another promising therapy, called venetoclax plus 5’-azacitidine or nelarabine to enhance the therapeutic effect of GT715. This experimental approach is aimed at finding alternative therapies to improve treatment outcomes in very challenging cases, and the hope is that this research will lead to early-phase clinic trials soon.

Metabolic reprogramming of the Ewing sarcoma tumor microenvironment using pramlintide to augment NK cell immunotherapy

The treatment options for children and adolescents with metastatic Ewing sarcoma are limited, and thus new strategies are needed. Dr. Kleinerman’s research aims to develop a strategy where pramlintide, a synthetic hormone involved in regulating blood sugar levels, is used to alter the metabolic conditions within the Ewing Sarcoma tumor environment. Decreasing available sugar in the tumor environment has the potential to starve the tumor cells and reduce their ability to spread. This alteration aims to improve the effectiveness of NK cell immunotherapy against Ewing Sarcoma (Natural Killer, or NK cells are a type of immune cell that can directly kill cancer cells), potentially making the tumor more susceptible to immune attack by NK cells. These studies can provide the necessary justification to rapidly move to a clinical trial.

Development of a GPC2 CAR T cell amplifying RNA vaccine

Dr. Bosse’s research aims to develop a novel therapy for neuroblastoma that involves using an RNA vaccine to boost the function of an immunotherapy involving CAR T cells engineered to target GPC2. GPC2 is a protein that is found on the surface of neuroblastoma cells, but not on healthy cells. Thus, the engineered CAR-T cells can specifically seek and destroy neuroblastoma while leaving healthy cells unscathed. If this research strategy is successful, Dr. Bosse’s lab will have developed a novel technology that will hopefully cure children with neuroblastoma and several other different types of pediatric tumors that also have high levels of GPC2.

Effective TGF-beta signaling blockade synergizes cryoablation-induced STING activation in treating refractory and metastatic sarcoma

Effective therapy for refractory or metastatic osteosarcoma, rhabdomyosarcoma, and other sarcomas remains a major challenge. Dr. Huang’s lab will combine two approaches that are believed to be promising in treating metastatic disease: cryoablation (an FDA-approved approach using extreme cold against the tumor) and the non-toxic drug Vactosertib (a-TGF-beta inhibitor). cryoablation, through mechanisms that are not completely understood, can increase the patient’s immune response against the spreading tumor. However, the response is inconsistent between patients and is often weaker than necessary. It is believed that Vactosertib can augment the immune response and work in concert with cryoablation to mount anti-tumor immune responses in patients. Dr. Huang hopes that, if successful, these CURE-funded studies can provide the preliminary data required to enter a clinical trial in the near future.

Dissecting and targeting PAK4-mediated signaling in Ewing sarcoma development and metastasis

Ewing sarcoma is the second most common bone tumor in the pediatric population, and overall survival rates have improved to approximately 70%. However, despite maximizing treatment regimens, long-term outcomes for patients with metastatic disease remain extremely poor, with overall survival rates dropping to 20-30%. Thus, finding different treatments, or combination of treatments, is essential in order to increase survival for Ewing sarcoma patients. With funding from CURE, Dr. Yustein’s lab will determine if inhibiting PAK4 (a protein that plays a role in regulating cell growth and movement ) in combination with other Ewing-relevant therapies will be effective in blocking metastasis. In addition, they will also further understand the role of PAK4 in the Ewing sarcoma cell, which can identify additional treatment options. Completion of these CURE-funded studies will impact Ewing sarcoma patients by identifying new treatment regimens that can be quickly transferred to clinical trials for high-risk disease.

Defining the druggable GLI Interactome in medulloblastoma

The most common malignant pediatric brain tumor is medulloblastoma. Although much is understood about the genetic makeup of this tumor, there are still forms of the disease that do not respond to therapy. Further, children who do respond to therapy suffer from intellectual and cognitive deficits. Therefore, we urgently need to identify new, more effective, and less-toxic drugs for the treatment of these tumors. In this CURE-funded study, Dr. Robbins will work to better understand a collection of over 200 proteins, called the GLI Complex, that work together in Medulloblastoma to drive mortality and morbidity. As part of this study, they will also identify and test drug candidates that are expected to inhibit the GLI Complex and, in so doing, stop the spread of MB. Importantly, as part of this work, they will also investigate the toxicity of the drug candidates, ensuring that any new treatments will be minimally or non-toxic to the developing brain.

Rapid Transition of B7-H3 Targeted Therapies to High-Risk Childhood AML

Dr. Meshinchi aims to use his CURE funds to rapidly develop two complementary therapies targeting B7-H3, a protein expressed in very high-risk pediatric acute myeloid leukemia (AML). The project combines short-term repurposing of an antibody-drug conjugate called Vobramitamab duocarmazine (Vobra duo), currently in clinical trials for prostate cancer, with the long-term goal of establishing immunotherapeutic cures for aggressive pediatric AML expressing B7-H3 using CAR T cells. Based on his preliminary data, Dr. Meshinchi believes that effectively targeting B7-H3 could transform outcomes for these very high-risk AML. In the very near future, Dr. Meshinchi hopes to have enough pre-clinical data to support compassionate use access to Vobra duo and will pursue clinical trials with both pediatric and adult AML patients.

Biological consequences of altered chromosomal organization in rhabdomyosarcoma cells

Dr. MacQuarrie’s research is investigating the role of altered chromosome organization in rhabdomyosarcoma, a type of cancer that often has poor outcomes when a fusion protein called PAX-FOXO is present. This protein disrupts gene regulation and DNA organization, which may contribute to the cancer’s aggressive behavior. Dr. MacQuarrie’s study will use a technique called chromosome painting to explore how chromosome structure differs between normal and tumor cells, aiming to understand how these changes affect gene expression and DNA damage. This research could reveal new insights into the basic mechanisms of cancer, potentially improving risk assessment and treatment strategies for rhabdomyosarcoma and other cancers with similar chromosomal abnormalities.
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PBK and let-7 in Group 3 medulloblastoma treatment resistance

Medulloblastoma is the most common type of brain cancer in children, and it comes in four different varieties. The “Group 3” type is particularly dangerous, with the worst survival rates because it grows quickly and doesn’t respond well to standard treatments like chemotherapy and radiation. The researchers have found evidence that three biological factors (LIN28B, let-7, and PBK) might be responsible for making Group 3 medulloblastoma so difficult to treat. They plan to study how these factors help the cancer cells resist treatment and then test whether blocking these factors can make the cancer more vulnerable to therapy. The lab will conduct experiments in both cancer cells and mice to test a new combination of drugs that target these factors. If successful, this research could lead to better treatments not only for children with this aggressive brain cancer but potentially for other types of cancer as well.

Tumor microenvironment modulation as an effective therapy for osteosarcoma

Dr. VanHeyst’s research focuses on developing a new treatment strategy for osteosarcoma, a type of bone cancer that can be particularly challenging when it has spread. Her approach combines cryoablation, a technique that destroys tumors with extreme cold, with a novel, non-toxic drug called Vactosertib, which blocks TGF-beta—a protein involved in cancer progression. The goal is to enhance the immune system’s ability to target not only the primary tumor but also any cancer cells that may have spread to other parts of the body. This study is exciting because it explores how manipulating the tumor environment can boost immune responses against cancer. By combining cryoablation with this new inhibitor, Dr. VanHeyst hopes to improve treatment outcomes for osteosarcoma patients and offer new options with fewer side effects.

Targeting RAS pathway mutations for pediatric acute leukemia therapy

Dr. Pikman’s research is focused on improving treatments for pediatric acute leukemia, specifically acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Her team is investigating mutations in the RAS pathway, which are common in relapsed cases. They plan to test combinations of the drugs Pimasertib and Tovorafenib with chemotherapy to find the most effective treatments. This research is crucial because single-drug treatments have been inadequate. If successful, the new treatments could significantly advance therapy options for children with leukemia, offering hope for better outcomes and fewer side effects.

Empowering pediatric immunotherapies by HSC engineering

Dr. Genovese’s research aims to advance treatment for acute myeloid leukemia (AML) in children, a challenging cancer with high relapse rates and limited treatment options. His approach involves modifying bone marrow cells from healthy donors using CRISPR gene editing to make them invisible to the immune system. This modification aims to protect healthy cells while targeting leukemia cells with CAR-T therapy, a type of treatment that uses genetically engineered immune cells to attack cancer. By making healthy cells undetectable to the immune system, this method hopes to reduce the risk of harmful side effects and improve treatment effectiveness. If successful, this research could offer new hope for children with AML, potentially transforming how this aggressive cancer is treated.

Second generation gamma delta T-cell therapy for neuroblastoma and osteosarcoma

Dr. Goldsmith’s research is exploring a promising new approach to cancer treatment using gamma-delta T-cells. Unlike traditional CAR-T therapy, which relies on a specific type of T-cell from the patient’s own body, gamma-delta T-cells can be sourced from healthy donors and are effective at recognizing and attacking cancer cells. These cells are known for their ability to fight infections and are particularly useful in cancer treatments because they can target a wide range of cancer cells without being affected by the patient’s stressed immune system. Additionally, she is investigating how genetic and ethnic differences might affect treatment responses, which is crucial for creating personalized and equitable cancer therapies. This research not only aims to enhance cancer treatment but also to ensure it is effective across diverse populations.

Nanotherapeutic targeting of PPM1D inhibitors across the blood-brain barrier for DIPG

Dr. Raju’s research focuses on diffuse intrinsic pontine glioma (DIPG), a particularly aggressive and hard-to-treat brain tumor for which there is no effective treatment. DIPG is challenging because traditional treatments struggle to penetrate the brain due to the tight blood-brain barrier. Dr. Raju is working on a groundbreaking approach using nanoparticles to deliver drugs directly to the tumor. These nanoparticles, made from a substance called fucoidan, target a specific protein on the blood vessels of tumors, helping the drugs cross the blood-brain barrier more effectively. Dr. Raju’s team is also exploring how combining these nanoparticles with low-dose radiation can enhance drug delivery. This innovative approach not only aims to improve outcomes for DIPG patients but could also be applied to other brain cancers and inflammatory diseases, making it a potentially transformative strategy in the fight against cancer.

Development of receptor tyrosine kinase-targeting chimeric antigen receptor T-cells as dual hematopoietic stem cell transplantation conditioning and immunotherapeutic agents for cure of pediatric acute myeloid leukemia

Dr. Czechowicz is developing a novel treatment for pediatric acute myeloid leukemia (AML), which currently has a low survival rate. Traditional treatments are highly toxic and have a high relapse rate, often due to the persistence of “leukemic stem cells” (LSCs). To address this, Dr. Czechowicz has engineered a new type of CAR-T cell that can eradicate these problematic cells, offering the potential for a cure with significantly less toxicity. Dr. Czechowicz’s work holds promise as a transformative approach to treating AML, potentially becoming a standard care method. Her CAR-T cells aim to provide a one-time, curative treatment with minimal side effects. This breakthrough has garnered significant recognition, and Dr. Czechowicz was one of only seven established investigators to receive a grant for this pioneering research.

Augmenting the efficacy of BET inhibitors for metastatic Ewing sarcoma

Dr. Lawlor is working on a novel approach to treat Ewing sarcoma, a rare and aggressive childhood cancer. The focus of her research is on particular proteins called BET, which play a crucial role in activating genes that promote cancer growth. BET inhibitors have shown promise in slowing tumor growth, but the cancer cells often find another pathway to escape and resume growth. Dr. Lawlor aims to tackle this problem by simultaneously targeting both pathways, hoping to prevent the cancer cells from adapting and continuing to grow. This dual-targeting strategy holds promise for significantly improving treatment outcomes for children with Ewing sarcoma, potentially leading to more effective and lasting therapies.

Small molecule targeting of epigenetic reader MBD2 for medulloblastoma therapy

Dr. Van Meir is researching a new treatment for medulloblastoma, a type of brain cancer where over 30% of patients do not survive, and those who do often suffer severe long-term effects. His project focuses on a small molecule compound called KCC07, which can cross the blood-brain barrier and target specific genes that cause the tumor to grow. The research aims to systematically modify KCC07 to develop related compounds that are even less harmful to the brain. Dr. Van Meir’s work represents a pioneering effort in using epigenetic therapy to combat medulloblastoma, offering hope for more effective and less damaging treatments for children affected by this devastating disease.

Genetically engineered gamma delta T-cells for treatment of metastatic osteosarcoma

Dr. Webber is developing a novel immunotherapy for metastatic osteosarcoma, a type of bone cancer where survival rates have stagnated for the past four decades and remain below 29% for metastatic cases. His research focuses on genetically engineered gamma delta T cells, which can recognize cancer cells without requiring a patient-specific match. This makes them suitable for off-the-shelf therapy. Unlike traditional CAR-T cells, GD T cells may be more effective against solid tumors due to their unique properties and potential to persist without becoming exhausted. This research has the potential to revolutionize treatment not only for osteosarcoma but for various other solid tumors as well.