Our Research

Engineering TCR-T cells to overcome trafficking barriers in Ewing sarcoma

Ewing sarcoma is an aggressive cancer of bone and soft tissue that primarily affects children and young adults. While many patients can be cured with surgery, radiation, and chemotherapy, those whose disease has spread or returned face survival rates below 20%, and new approaches are urgently needed. Dr. Alvarez Calderon is developing an immunotherapy that uses a patient’s own immune cells—specifically T cells engineered to recognize a protein found only in Ewing sarcoma tumors—to seek out and destroy cancer cells. The target protein arises from a unique genetic fusion that is present in virtually all Ewing sarcoma cells and absent from normal tissues, making it an ideal and specific target.

A major challenge for any solid-tumor immunotherapy is getting the engineered immune cells to penetrate the tumor. Ewing sarcoma creates physical and chemical barriers that repel immune cells before they can do their work. This project addresses that problem directly by modifying the engineered T cells to disable a repellent signaling pathway—involving proteins called SEMA3A and PLXNA4—that normally keeps immune cells from entering the tumor. Early experiments already show that knocking out this signal allows T cells to infiltrate Ewing sarcoma tumors far more effectively in laboratory models. The project will validate these trafficking-optimized T cells in patient-derived tumor models and establish a framework for clinical translation, with a first-in-human trial targeted within four to six years. The approach is also broadly applicable to other fusion-driven pediatric cancers.

Rewiring neuroblastoma immune circuits with tumor arrays

High-risk neuroblastoma is one of the most difficult childhood cancers to cure. An immunotherapy drug called anti-GD2 has improved survival, but its effects are often temporary because it does not reliably generate lasting immune protection against the cancer. Dr. Carbone studies why this happens and how it can be changed. Her early findings suggest that the three main types of immune cells needed to mount a sustained anti-tumor response—natural killer (NK) cells, dendritic cells, and CD8+ T cells—are present in some neuroblastoma tumors but are failing to communicate and coordinate with each other effectively. Two suppressive signals produced by the tumor, called PGE2 and galectin-9, appear to be responsible for disrupting that coordination.

This project will use a novel tumor platform that allows multiple tumors to grow in a single mouse simultaneously, enabling the team to compare regressing and progressing tumors under identical conditions and understand in real time why some immune responses succeed and others fail. The first aim will test whether blocking PGE2 and galectin-9 restores immune communication during anti-GD2 therapy. The second will examine how the functional state of NK cells—whether they are primed to kill or to support other immune cells—shapes the broader immune response to treatment. Because the pathways being studied are already targeted by approved or emerging drugs, including widely available anti-inflammatory agents and checkpoint inhibitors currently in clinical development, positive results could move rapidly into clinical combination studies and improve the durability of responses for children with high-risk neuroblastoma.

Development of targeted cell therapy approaches for ATRX mutant neuroblastoma

ATRX in-frame fusion (ATRX-IFF) neuroblastoma is one of the most lethal subtypes of an already-dangerous childhood cancer, with survival rates below 10% and no approved targeted therapies. Dr. Jonus and her team identified a protein called PTK7 that is present at high levels on ATRX-IFF neuroblastoma cells and have used it as a target to engineer a new type of immune cell therapy. Rather than using a patient’s own T cells—which can be difficult to manufacture and require weeks of preparation—the project uses a specialized class of immune cells called gamma delta (γδ) T cells derived from healthy donors, which can be prepared in advance and given off-the-shelf to patients without the delays associated with personalized cell manufacturing.

The project will optimize how the PTK7-targeting receptor is engineered onto these donor T cells, testing different configurations to maximize cancer-killing power and persistence. It will also address one of the central challenges of solid-tumor immunotherapy: the suppressive environment inside the tumor that can neutralize immune cells before they destroy the cancer. The team will test strategies including a drug called zoledronate and a membrane-anchored form of the immune activating molecule IL-12 to reprogram tumor-associated immune cells from a tumor-protecting to a tumor-fighting state. Studies will be conducted in advanced patient-derived organoid systems and humanized mouse models. The project is specifically designed to generate the preclinical data package required by the FDA to initiate a clinical trial, and the team already operates an active clinical γδ T-cell therapy program, accelerating the path to patients.

Enhancing GD2.CAR-NKT anti-tumor efficacy against neuroblastoma and tumor microenvironment through targeting PRDM1 and ZBTB7B

High-risk neuroblastoma remains one of the hardest pediatric cancers to cure, with approximately 45% of patients classified as high-risk and poor survival despite intensive multimodal treatment. Dr. Tian’s team is working to improve a specialized immunotherapy that uses natural killer T (NKT) cells—a type of immune cell with unique properties—engineered with a chimeric antigen receptor (CAR) targeting GD2, a marker found on the surface of neuroblastoma cells. Early clinical trials demonstrated that these CAR-NKT cells are safe and produced some tumor responses, but responses were frequently short-lived because the immune cells did not persist long enough in the body to sustain an attack on the cancer.

This project tests whether knocking out two specific genes—PRDM1 and ZBTB7B—in the engineered NKT cells can simultaneously extend their survival, enhance their killing power, and improve their behavior within the suppressive tumor environment that neuroblastoma creates. Prior work in the lab showed that removing PRDM1 extended persistence but reduced cytotoxicity, while removing ZBTB7B had the opposite effect, improving killing and reprogramming tumor-associated immune cells into a cancer-fighting rather than cancer-supporting state. This project will test whether combining both knockouts achieves the best of both outcomes. Experiments will be conducted in laboratory models and in humanized mouse models of neuroblastoma, with the results intended to support a Phase I clinical trial in relapsed or refractory neuroblastoma. The work may also inform next-generation cellular therapies for other GD2-positive pediatric cancers beyond neuroblastoma.

Targeting antigenic escape to strengthen immunotherapies in pediatric leukemia and lymphoma

Many children with B-cell acute lymphoblastic leukemia (B-ALL)—the most common pediatric cancer—relapse after receiving CAR-T cell or antibody-based immunotherapies. A key reason is that leukemia cells can reduce the amount of a surface protein called CD22 on their exterior, allowing them to hide from treatments designed to recognize that target. This process, known as antigen escape, represents one of the most pressing barriers to durable remission. Dr. Aifantis and his team identified a molecular switch called METTL3 that controls how much CD22 appears on the surface of B-ALL cells, opening a new avenue for intervention.

Using genome-wide CRISPR screening, the team discovered that blocking METTL3—either genetically or with an experimental drug—increases CD22 levels on leukemia cells and makes them significantly more sensitive to existing CD22-targeted therapies, including the FDA-approved drug inotuzumab ozogamicin. This project will define precisely how METTL3 regulates CD22, test METTL3 inhibitors in patient-derived leukemia models, and identify the genetic pathways that allow cancer cells to resist multiple immunotherapies at once. Critically, METTL3 inhibitors are already being tested safely in human clinical trials, making rapid translation into pediatric leukemia treatment a realistic near-term goal. If successful, this work could restore responsiveness in children whose leukemias have stopped responding to immunotherapy and reduce relapse rates across this important disease.

Targeting neutral lipogenesis in MYCN-driven neuroblastoma

Neuroblastoma accounts for approximately 15% of all pediatric cancer deaths, and children whose tumors carry an amplification of the gene MYCN face particularly poor outcomes—most relapse early and develop resistance to current treatments. There are no effective targeted therapies for this group. Dr. Barbieri’s laboratory has discovered that MYCN-driven neuroblastoma cells rewire their fat metabolism in a distinctive way, accumulating large stores of lipids in structures called lipid droplets. Rather than serving as passive reservoirs, these droplets appear to function as active hubs that support tumor growth, help cancer cells resist treatment, and influence interactions with the immune system.

This project will investigate how lipid droplet formation drives MYCN-dependent tumor growth and explore whether disrupting this process creates a new vulnerability that can be exploited therapeutically. Specifically, the team will study whether blocking lipid droplet production makes neuroblastoma cells susceptible to a form of cell death called ferroptosis, and test combinations of lipid synthesis inhibitors—including two drugs already in Phase II clinical trials—with standard relapse chemotherapy regimens. Studies will be conducted across multiple complementary preclinical models, including paired tumor samples collected at diagnosis and relapse from individual patients. If the results are positive, the team will pursue an early-phase clinical trial at Texas Children’s Cancer Center, with potential implications extending to other cancers driven by MYC-family oncogenes.

Advancing local drug therapy for pediatric diffuse midline glioma through precision infusion and drug efflux modulation

Diffuse midline glioma (DMG) is one of the most lethal brain tumors in children, and despite more than 200 clinical trials, no chemotherapy regimen has meaningfully extended survival. The fundamental problem is not that drugs are ineffective in laboratory settings—it is that they cannot reach the tumor in sufficient concentrations or stay there long enough to work. The brain’s natural protective barriers limit how much a drug can enter, and even when a drug is delivered directly into the brainstem using a technique called convection-enhanced delivery (CED), it is cleared so quickly that therapeutic levels are never sustained. Dr. Daniels and his team are pursuing a new strategy focused on keeping drugs in the tumor longer, rather than simply finding new drugs.

The project will test whether combining direct drug infusion with a second medication that blocks the brain’s drug-removal machinery can significantly prolong the time a chemotherapy agent remains active in tumor tissue. Preliminary data show that the drug everolimus, taken orally, slows the removal of a CED-delivered chemotherapy called topotecan from brain tissue and improves survival in animal models of DMG. This project will carefully define how long the drug stays in the brain, how it spreads through tissue, and whether the combination is safe—using a large-animal model whose brainstem closely resembles a child’s. Alongside these pharmacokinetic studies, the team will use neural monitoring probes to track real-time brain activity during and after drug infusion, potentially establishing a new safety tool for future clinical trials. The results are intended to directly support an application to the FDA and the design of a Phase I pediatric trial.

Molecular targeting of MiT fusion proteins in translocation renal cell carcinoma

Translocation renal cell carcinoma (tRCC) is a rare and aggressive kidney cancer that primarily strikes children and adolescents. Fewer than 10% of patients with metastatic disease survive five years, and no targeted therapies exist—standard kidney cancer treatments have little effect. The cancer is driven by chromosomal rearrangements that fuse a gene called TFE3 with various partner genes, creating abnormal fusion proteins that force cells to grow uncontrollably. Because TFE3 is a transcription factor with no conventional drug-binding pocket, it has long been considered essentially undruggable using standard small-molecule approaches.

Dr. Huang’s team is pursuing two innovative strategies to get around this problem. The first uses tiny protein fragments called nanobodies—the team has already identified candidates that attach specifically to the TFE3 fusion protein—engineered to recruit the cell’s own disposal machinery and destroy the cancer-driving protein from within. The nanobodies will be delivered into tumor cells using engineered vesicles designed to home in on a surface marker that is elevated in tRCC. The second strategy uses computational design tools, including artificial intelligence–based protein modeling, to engineer miniature proteins that physically block TFE3 from binding DNA and activating cancer-promoting genes. Over 1,600 candidate mini-proteins have already been computationally identified. Together, these parallel approaches represent a substantial and well-de-risked effort to develop the first targeted therapy for this orphan pediatric cancer, with a clear path toward IND-enabling studies and clinical trials.

Dual targeting lymphoid and myeloid antigens by a novel switch adaptor protein for LS acute leukemia

Children with KMT2A-rearranged acute leukemia face one of the most devastating possible complications of modern immunotherapy: their cancer can transform from one type of leukemia into another under the selective pressure of treatment. This phenomenon—called lineage switch—occurs when a B-cell leukemia that has been successfully targeted by CD19-directed CAR-T cell therapy transforms into a myeloid leukemia that no longer carries the CD19 marker the therapy relies on. The resulting disease is extremely aggressive, essentially invisible to the treatment that worked before, and carries survival rates below 10%. No approved therapy currently exists to prevent or treat lineage-switch leukemia.

Dr. John’s team discovered that both the original leukemia and the switched form share a surface marker called LILRB4, creating a rare opportunity for a single therapeutic strategy to target the cancer across the transformation. The project will develop and test a novel adaptor protein called MAASC that acts as a molecular bridge, redirecting existing FDA-approved CD19 CAR-T cells to recognize and destroy LILRB4-expressing leukemia cells even after they lose CD19 expression. Because MAASC works with CAR-T therapies already approved for clinical use, the regulatory and manufacturing path to a clinical trial is substantially shorter than developing an entirely new cellular therapy. The project will validate MAASC in laboratory models and in mouse models of both pre-switch and post-switch leukemia, with an IND submission targeted within three to four years of award completion.

Overcoming macrophage-mediated resistance to boost chemotherapy in neuroblastoma

Neuroblastoma is the most common extracranial solid tumor in young children, and high-risk cases—including those with MYCN gene amplification or metastatic disease in children over 18 months—carry a poor prognosis despite intensive multimodal therapy. Even with the addition of anti-GD2 immunotherapy to standard chemotherapy, surgery, and radiation, many children relapse and do not survive. A key reason is that tumors recruit large numbers of immunosuppressive immune cells, particularly tumor-associated macrophages, that actively block the immune system from mounting an effective response. Dr. Joshi’s laboratory identified spleen tyrosine kinase (Syk) as a critical regulator of this macrophage-driven immunosuppression, and showed that the FDA-approved Syk inhibitor fostamatinib (R788) can reprogram these pro-tumor macrophages into anti-tumor macrophages—restoring immune activity and significantly reducing neuroblastoma growth in preclinical models.

This project will test whether combining fostamatinib with standard neuroblastoma chemotherapy (temozolomide and irinotecan) and anti-GD2 antibody immunotherapy produces durable anti-tumor immune responses and tumor-free survival in preclinical models. Preliminary data show that fostamatinib increases immunostimulatory macrophages and CD8+ T-cell infiltration, and that adding it to either chemotherapy or anti-GD2 antibody further reduces tumor growth. The project pursues three specific aims: defining the immune impact of Syk inhibition combined with chemotherapy across MYCN-amplified and non-amplified tumor models; assessing how Syk inhibition enhances anti-GD2 immunotherapy efficacy; and testing the full triple combination for maximum tumor control and durable immunity. Fostamatinib is already FDA-approved and in an ongoing investigator-initiated Phase I/II clinical trial for pancreatic cancer at UCSD, providing a direct path to clinical translation. Working with pediatric oncology collaborators at UCSD, Rady Children’s Hospital, and Memorial Sloan Kettering Cancer Center, Dr. Joshi aims to initiate a Phase I pediatric trial of fostamatinib combined with chemotherapy and dinutuximab for high-risk neuroblastoma by the end of the two-year award period.

Metastasis and cell state plasticity in rhabdomyosarcoma

Rhabdomyosarcoma (RMS) is a common childhood muscle cancer with a grim prognosis once it has spread beyond its original site—fewer than 20% of patients with metastatic disease survive. The cancer is not made up of a single uniform cell type; instead, tumors contain a mixture of cells resembling different stages of normal muscle development. Dr. Langenau’s team is investigating how the ability of these cancer cells to change their identity—a property called plasticity—contributes to the spread of the disease. Specifically, the team challenges a widely held assumption in the field: that cancer stem cells are the primary drivers of metastatic spread. Their early data suggest the opposite is true, with more mature, differentiated cells acting as the primary seeds of metastasis.

Using optically transparent zebrafish models that allow real-time imaging of individual cancer cells as they travel through the body, alongside complementary mouse models, the team will track exactly which cell types initiate metastasis, how they adapt to new environments, and what molecular machinery enables them to regenerate a full tumor once they arrive. A key focus is a muscle-regulatory protein called Myogenin, which the team hypothesizes drives metastatic colonization by activating proteins that help cancer cells attach and grow in distant organs. This work will identify new biomarkers to predict which patients are at highest risk for metastatic relapse and reveal specific molecular targets—particularly the Myogenin/integrin axis—that could be blocked to prevent the spread of disease. Findings are expected to have broad applicability across mesenchymal-derived sarcomas and to inform the development of clinical trials within two to four years.

Moving affinity-tuned T cell engagers for dual targeting of leukemia closer to clinical trials

Mixed-phenotype acute leukemia (MPAL) is a rare and high-risk leukemia in which cancer cells display surface markers from two different lineages simultaneously—characteristics of both lymphoid and myeloid cells—making it resistant to the chemotherapy regimens designed for either lineage alone. Cure rates in children range from 75–80%, and outcomes in adults are markedly worse. There is no standardized treatment approach. Dr. Loh and her collaborator Dr. Jason Price are developing a precision immunotherapy molecule—called a multispecific T-cell engager, or MTE—engineered to recognize and attack only cells that carry both CD19 and CD33 markers at the same time. Because no normal cell in the body co-expresses both proteins, this dual-requirement design is intended to destroy leukemia while sparing healthy blood cells.

A first prototype has already demonstrated highly selective cancer killing in cell culture and in mouse models, with near-negligible toxicity toward normal cells at therapeutic doses. This project will refine up to 24 variants of the molecule using state-of-the-art biophysical testing, select the most stable and effective candidate, and complete the preclinical studies required by the FDA before a first-in-human trial can begin—including pharmacokinetics, toxicity, and efficacy testing in humanized mouse models. A pre-IND meeting with the FDA is planned at the midpoint of the project. If successful, the therapy would serve not as a standalone cure but as a precision tool to reduce disease burden before stem cell transplant, with minimal toxicity. The platform also has potential applicability to the approximately 30% of B-cell ALL patients who co-express CD33 without meeting MPAL criteria, substantially broadening its impact.

Development and translational evaluation of CLEC2A-directed ADCs for KMT2A-r AML

Acute myeloid leukemia (AML) is among the most dangerous blood cancers in children, and the KMT2A-rearranged subtype is particularly resistant to treatment, with high rates of relapse and limited options. A central challenge with immunotherapy for AML is that most targets found on leukemia cells are also present on normal blood-forming cells, causing serious bone marrow damage. Dr. Meshinchi’s laboratory identified a target called CLEC2A that overcomes this problem: it is highly expressed on leukemia cells in KMT2A-rearranged AML but absent from normal blood-forming cells, making it uniquely safe to target. The team has already developed CLEC2A-directed CAR-T cells that show powerful anti-leukemic activity without detectable toxicity to healthy blood cells, and those are advancing toward a first-in-human trial.

This project builds on that foundation by developing a different class of therapy called antibody–drug conjugates (ADCs)—precision delivery systems that attach a cancer-killing drug payload to an antibody that seeks out CLEC2A on leukemia cells. Unlike CAR-T cells, ADCs are ready-made, off-the-shelf treatments that can be given immediately without requiring a patient’s own cells to be engineered. The project will generate a library of CLEC2A-targeting ADCs using multiple antibody designs and drug payloads, identify the most potent and safest combination, and test leading candidates in patient-derived leukemia models. In a final step, the best ADC candidates will be compared head-to-head with CLEC2A CAR-T cells to define whether they are best used as standalone therapies, for rapid debulking before cellular therapy, or in combination. Successful completion is expected to support an IND submission within two to three years of award completion and generate the first off-the-shelf targeted therapy for this high-risk leukemia.

Phase I Study of Azacitidine and Venetoclax for children, adolescents, and young adults with high-risk myeloid disease

Pediatric myelodysplastic syndrome (MDS) is a rare and often fatal blood disorder in children, and stem cell transplant remains the only curative treatment. Before transplant, some patients need therapy to reduce disease burden—but conventional chemotherapy is toxic, prone to causing infections and organ damage, and has shown limited efficacy in MDS. Venetoclax, a drug that blocks a protein called BCL-2 that helps cancer cells survive, combined with a hypomethylating agent called azacitidine, has shown meaningful efficacy and tolerability in adult myeloid disease. However, pediatric

MDS is biologically distinct from the adult disease, and adult trial results cannot simply be assumed to apply to children.
This project funds a multi-institutional Phase I clinical trial enrolling approximately 20 pediatric and young adult patients across seven institutions in the Dana-Farber Consortium to evaluate the safety, tolerability, and clinical activity of venetoclax plus azacitidine. The trial will establish the optimal dose for children, assess how many patients achieve disease response, and measure how many successfully reach stem cell transplant after treatment—the ultimate goal of therapy. Importantly, the trial will also include correlative biology studies to identify which molecular features predict who benefits most, including gene sequencing and analysis of how the drugs affect clonal evolution of the cancer. Pediatric MDS, including cases linked to germline predisposition syndromes, represents a group historically excluded from clinical trials; this study directly addresses that gap and will generate evidence that could inform a standard treatment approach for a vulnerable population with no good options today.

Targeting resistance to Menin inhibitors in KMTA2A-r acute myeloid leukemia

KMT2A-rearranged leukemias are among the most dangerous blood cancers in children and infants, with poor outcomes even under the most intensive treatment regimens. A class of drugs called menin inhibitors has recently shown significant promise in this disease, and some have received FDA approval—but resistance to these drugs develops frequently, leading to relapse. Dr. Resar’s team discovered that a protein called HMGA1 rises dramatically in leukemia cells that become resistant to menin inhibitors, activating gene programs associated with stem-cell-like behavior, cancer cell proliferation, and immune evasion. HMGA1 appears to act as a master regulator that allows leukemia cells to maintain their survival networks even when menin is blocked.

This project will use a combination of mouse models, patient-derived leukemia samples, CRISPR gene-editing, and single-cell genomic analysis to define precisely how HMGA1 drives resistance to menin inhibitor therapy and what genetic programs it controls. Alongside this mechanistic work, the team will apply a machine-learning platform called OptiCon to predict which existing clinical drugs, alone or in combination, can disrupt the HMGA1 resistance network and restore sensitivity to therapy. Early experiments have already demonstrated that reducing HMGA1 levels delays leukemia progression and extends survival in mouse models. If successful, this project will identify a new therapeutic target for children with relapsed or resistant leukemia and generate actionable combination treatment strategies that could move quickly toward clinical trials, given that the relevant drugs are already approved or in human testing.

Targeting CREB: CBP interaction for treatment of pediatric AML

Acute myeloid leukemia (AML) in children carries a five-year survival rate of 60–70%, falling to below 40% in relapsed disease. The only treatments currently available are intensive chemotherapy and stem cell transplantation, both of which cause significant long-term harm, and children with relapsed or refractory AML have very few options. Dr. Sakamoto’s laboratory identified a protein called CREB that is overproduced in AML cells from the majority of patients at diagnosis and is associated with worse outcomes. Reducing CREB levels in AML cells diminishes their ability to grow and survive, while normal developing blood cells are unaffected—making CREB an attractive target. The challenge is that CREB is a transcription factor, a class of proteins historically considered impossible to block with conventional drugs.

To overcome this, Dr. Sakamoto’s team, working with structural biologists and computational scientists at Stanford, is developing a new class of drugs based on miniature proteins called peptides. These peptides are engineered to physically disrupt the interaction between CREB and a critical partner protein called CBP—a connection that AML cells depend on to stay active and proliferating. The project will use physics-based computational design and artificial intelligence–based protein modeling to generate new peptide candidates with improved drug-like properties, then test the most promising molecules in AML cell lines, primary patient samples, and mouse models. The approach is analogous to Ozempic and other peptide drugs that have proven clinically successful in recent years. If successful, this would represent the first peptide drug developed specifically for any pediatric cancer and open a new class of therapeutic targets—disordered transcriptional regulators—that drive many aggressive childhood malignancies.

Preclinical efficacy of novel pH-sensitive peptide-drug conjugate in pediatric sarcoma and biomarkers of response

Rhabdomyosarcoma (RMS) and Ewing sarcoma (EWS) are two aggressive childhood cancers with survival rates below 30% after relapse—a figure that has barely changed in decades. Current treatments like irinotecan are toxic and of limited effectiveness in relapsed disease, while a more potent drug called exatecan has historically been too toxic for widespread use. CBX-12 is a novel drug designed to solve this problem by exploiting a feature of aggressive tumors: their acidic external environment. The drug uses a specially engineered peptide that inserts itself into tumor cell membranes in acidic conditions, selectively delivering exatecan directly into cancer cells while largely sparing normal tissues. Early adult studies suggest that CBX-12 is safer than conventional chemotherapy and may be effective against treatment-resistant cancers.

This project will evaluate CBX-12 in patient-derived tumor models of both RMS and EWS, including models derived from tumors that have already relapsed after treatment—conditions that closely resemble the clinical scenario the drug is intended to address. The team will also identify biological markers in tumors that predict which patients are most likely to respond, conduct high-throughput drug screening to find the most effective combination partners, and use CRISPR-based screening to identify DNA repair genes whose loss makes tumors even more vulnerable to CBX-12. Together, this work will provide the scientific foundation and biomarker framework for a pediatric Phase I clinical trial through the Children’s Oncology Group, which is already in active development. The project brings together expertise from Yale, St. Jude Children’s Research Hospital, and Wayne State University.

Developing novel miR-142-armored anti-CD19 CAR T cells to target B-ALL

B-cell acute lymphoblastic leukemia is the most common cancer in children. Modern treatments, including CAR-T cell therapies, have dramatically improved survival—but relapse remains a serious problem, and a major contributor to treatment failure is the suppressive environment that leukemia creates around itself. Dr. Zhang’s team discovered that B-ALL cells release chemical signals that lower levels of a small regulatory molecule called miR-142 inside a patient’s T cells. When miR-142 levels drop, T cells become exhausted, lose their ability to fuel themselves metabolically, and struggle to attack the leukemia effectively—which in turn reduces the effectiveness of CAR-T cell therapy built on those same T cells.

This project will develop and test a new type of CAR-T cell that has been engineered to maintain high levels of miR-142, effectively armoring the immune cells against the suppressive signals produced by leukemia. The team has already designed nine different versions of this miR-142-armored CAR-T construct, varying the design in ways that may affect how well the molecule is expressed and how it functions. The best-performing constructs, selected through a systematic laboratory screening process, will be tested in mouse models of B-ALL—including models derived from actual patient tumors—with the goal of identifying a clinical candidate that shows superior persistence, leukemia clearance, and survival compared to conventional CAR-T cells. Positive results will feed directly into a Phase I clinical trial planned for relapsed or refractory pediatric B-ALL, with an IND submission targeted within three to four years. The miR-142 armoring approach is also potentially applicable to CAR-T therapies for other blood cancers and solid tumors.

Targeting chromatin regulators of oncogenic transcription in NUP98-rearranged leukemia

This research focuses on a specific and especially aggressive type of childhood blood cancer called NUP98-rearranged acute myeloid leukemia. Children with this form of leukemia have very poor outcomes with current treatments, making it a devastating diagnosis for families and one of the most challenging childhood cancers to fight.

This cancer starts when something goes wrong with a child’s genes, creating abnormal proteins that shouldn’t exist. These rogue proteins essentially hijack the standard controls, telling cells when to grow and when to stop. In healthy cells, there’s a natural process where young blood cells gradually mature and specialize into the different types of blood cells the body needs. But these abnormal proteins keep the cancer cells stuck in an immature state, constantly multiplying instead of maturing properly. It’s like having a factory that only produces defective products and never stops running.

The research team has already had some success blocking certain protein interactions that feed this cancer. Now, they’ve identified two additional proteins, KAT6A and KAT7, that act like essential fuel sources for keeping this type of leukemia alive. Think of these proteins as power sources that the cancer cells need to survive and multiply.

What’s promising about this discovery is that drugs designed to target these specific proteins are already being tested in early clinical trials for other conditions. This means the researchers don’t have to start from scratch. They can build on existing work to figure out how to use these treatments most effectively for children with this devastating disease.

By targeting multiple protein “fuel sources” that the cancer depends on, this approach could potentially offer new hope for children with a type of leukemia that has historically been very difficult to treat.

Selective targeting of epigenetic pathways underlying drug tolerant persistence in neuroblastoma

This research tackles one of the most heartbreaking aspects of neuroblastoma. Even when doctors use the most aggressive treatments available, about 40% of children with high-risk cases will see their cancer return. And when neuroblastoma comes back, it’s almost always fatal.

The problem isn’t that the chemotherapy doesn’t work. It actually kills most of the cancer cells. But here’s what happens: a small group of especially stubborn cancer cells manages to survive even the strongest chemotherapy treatments. These survivor cells essentially go into hiding, lying dormant in the child’s body like seeds waiting for the right conditions. Eventually, these hidden cells wake up and start multiplying again, causing the cancer to return.

The research team has made an important discovery about how these survivor cells stay alive during treatment. They found that these resilient cancer cells depend on two specific proteins, called menin and MLL1, that act like protective shields, helping them survive the chemotherapy that kills other cancer cells.

The researchers’ solution is to combine the standard chemotherapy with a new type of drug called menin inhibitors. These drugs work by blocking those protective proteins, essentially removing the shields that keep the survivor cells safe. Without their protection, these previously untouchable cancer cells should become vulnerable and die along with the rest of the cancer.

What makes this approach promising is that menin inhibitors aren’t experimental. They’ve already been proven safe and effective in children with certain types of leukemia, and the FDA has recently approved them. This means the treatment could potentially be available to children with neuroblastoma relatively quickly, offering new hope for preventing the devastating relapses that currently claim so many young lives.

Targeting Proline tRNA Biogenesis as a Therapeutic Strategy in NOTCH1-Driven T-ALL

This research focuses on T-cell acute lymphoblastic leukemia (T-ALL), a type of blood cancer that affects 10-15% of children who get ALL (acute lymphoblastic leukemia). Historically, children with T-ALL have had worse outcomes than those with other forms of this cancer. For children whose T-ALL doesn’t respond to current treatments, the survival rates are very poor, and doctors currently have no other treatment options to offer these families.

The research team has discovered something important about how T-ALL cancer cells stay alive. All cells in our body need to constantly build proteins to function, like how a factory needs to manufacture products to stay in business. To build proteins, cells use special helper molecules called tRNAs that work like delivery trucks, bringing specific building blocks (amino acids) to the protein-making machinery.

The researchers found that T-ALL cancer cells have an unusual dependency: they desperately need large amounts of a specific type of delivery truck, which carries a building block called proline. Think of proline like a special type of brick needed to build certain structures. Many of the proteins that drive T-ALL cancer growth are built using lots of these proline “bricks,” so the cancer cells need an enormous supply of the delivery trucks that carry proline.

When the researchers block the production of these proline delivery trucks, something remarkable happens: the T-ALL cancer cells can’t build the proteins they need to survive, so they die. But normal, healthy cells don’t depend as heavily on these specific delivery trucks, so they remain largely unaffected.

The team plans to test a drug that blocks this proline delivery system. What’s encouraging is that this drug is already being tested safely in clinical trials for other diseases, which means it could potentially be used to treat children with T-ALL much sooner than if they were starting from scratch. This could offer new hope for families facing this challenging diagnosis, especially those whose children haven’t responded to current treatments.

Interrogation of mast cells as a high-risk biomarker in core binding factor mutated pediatric acute myeloid leukemia

This research looks at a type of blood cancer called acute myeloid leukemia that affects about 700 children each year in the US. Unfortunately, more than 30% of these children don’t survive beyond 5 years. One of the biggest problems doctors face is figuring out which kids are most likely to have their cancer come back, even among children whose cancer initially seems easier to treat; about 30% still see their cancer return within 5 years.

The researchers studied bone marrow samples (the spongy tissue inside bones where blood cells are made) from 99 children with this cancer. They found something interesting: kids with a specific type of this blood cancer had unusually high numbers of immune cells called “mast cells” in their bone marrow. Normally, mast cells make up less than 1% of the cells in bone marrow, but these children had much higher levels.

What’s concerning is that children with more of these mast cells in their bone marrow had worse outcomes, meaning they were more likely not to survive or have their cancer return. The researchers think these mast cells might actually be helping the cancer by creating a “safe space” for cancer cells to hide and grow, while also preventing the body’s natural immune system from effectively fighting the leukemia.

This discovery could help doctors better identify which children are at highest risk for poor outcomes. It might also lead to new treatments that target these challenging mast cells.

Companion Molecular Imaging for PTK7 Targeted Immunotherapies in Pediatric Solid Tumors

Scientists have created a new type of treatment called immunotherapy that works by targeting a specific protein called PTK7. This protein is found in large amounts on dangerous childhood tumors (solid masses of cancer cells), but it’s hardly found at all in healthy parts of the body, which makes it a good target for treatment.

The problem is that doctors currently have no way to tell if a child’s tumor has high levels of this PTK7 protein without doing surgery to remove a piece of the tumor for testing. This is risky and difficult for children who are already sick.

To fix this problem, the researchers are developing a new type of medical scan that works like a special camera. They’re using PET scans, a type of imaging test that’s already commonly and safely used in children with cancer, but they’re adding a “molecular probe” (think of it like a special dye) that sticks only to the PTK7 protein.

When doctors do this scan, they’ll be able to see a map of where PTK7 is located throughout the child’s entire body without any surgery. This will help them figure out which children are most likely to benefit from this PTK7-targeted treatment, and they can also use these scans to see how well the treatment works over time, all without putting the child through an invasive surgery. We are additionally excited about this research as this new way of creating molecular probes could prove to be useful in developing probes for many types of cancer, beyond PTK7 expressing tumors, so many patients in the future will likely benefit from this work.

Intranasal Delivery of Targeted Nanotherapeutics and Oncolytic Virus in Pediatric Glioma

This research focuses on a very aggressive type of brain tumor called diffuse midline glioma that mainly affects children. These tumors are devastating. Most children survive less than a year after diagnosis.

The biggest challenge with treating these brain tumors is their location. They grow in the most critical parts of the brain where surgeons can’t safely operate without causing severe damage. Making things even harder, the brain has a natural protective barrier (called the blood-brain barrier) that blocks most medicines from getting from the bloodstream into the brain. So, even when doctors give children cancer drugs through an IV, very little actually reaches the tumor.

The researchers have come up with an innovative solution: delivering treatment through the nose using simple nose drops. This might sound unusual, but there’s actually a direct pathway from the nose to the brain that can bypass that protective barrier entirely.
They’re planning to test two types of treatments delivered this way. First, they’ll use tiny particles (called nanoparticles) that carry chemotherapy drugs directly to the tumor. Second, they’ll use a specially modified virus that has been engineered to seek out and destroy only cancer cells while leaving healthy brain cells alone.

The beauty of this approach is that it’s completely non-invasive. There is no surgery, no needles, just nose drops that children can receive repeatedly as needed. This could potentially offer hope for children with these untreatable brain tumors.

Advancing Innovative and Effective Therapies for Children with Malignant Rhabdoid Tumors

Malignant rhabdoid tumors (MRT) are one of the most dangerous types of childhood cancer, and they mainly affect babies and very young children. The survival statistics are heartbreaking. Fewer than 1 out of 5 children live more than five years after diagnosis. For babies diagnosed before they’re six months old, fewer than 1 out of 10 survive to age four.

These tumors happen when children are missing a protective gene called SMARCB1. This gene normally helps keep cells healthy and functioning properly, but without it, cells can easily turn cancerous.

Scientists have discovered a promising treatment approach that combines two types of medicine: PARP inhibitors (drugs that prevent cancer cells from repairing their own damaged DNA) and temozolomide (a chemotherapy drug). When used together, these medicines can slow down tumor growth. The problem is that current PARP inhibitors cause serious and dangerous side effects in children.

The researchers are now testing two newer versions of PARP inhibitors, called AZD-5305 and AZD-9574, that have been specifically designed to be much more precise. Think of it like using a scalpel instead of a hammer: these new drugs are engineered to target and destroy only the cancer cells while leaving healthy cells alone, which should dramatically reduce the harmful side effects children experience.

This research represents new hope for families facing this devastating diagnosis. The goal is to find treatments that are both more effective at fighting these aggressive tumors and much safer for the young children who need them

METTL3-targeting ASOs and synthetic lethality approaches in pediatric neuroblastoma

Neuroblastoma is a serious type of childhood cancer that current treatments often can’t cure, especially in the most aggressive cases. What makes this cancer different from others is that it’s usually not caused by damaged genes, but rather by problems with how genes are controlled. Think of it like having healthy light switches but faulty wiring that makes them work incorrectly.

The researchers have identified a key troublemaker: a protein called METTL3 that acts like a master switch, telling genes to help tumors grow and spread. When they block this protein, the cancer slows down, and the cells start behaving more like normal, healthy cells. However, current drugs that block METTL3 have two big problems: they can harm healthy cells throughout the body, and cancer cells eventually learn to resist them.

To solve this, the research team is creating a much more precise approach. They’re developing special RNA molecules (think of them as tiny messengers) that can silence METTL3, but only inside neuroblastoma cancer cells. To deliver these messengers exactly where they need to go, they’re packaging them in microscopic particles and coating those particles with antibodies, proteins that work like GPS systems to find and attach only to cancer cells.

They’re also using CRISPR, a powerful gene-editing tool, to find other proteins that work alongside METTL3. The idea is that blocking METTL3 and these partner proteins together will be much more effective at killing cancer cells than targeting just one protein alone.

This approach could lead to treatments that are both safer for children (because they target only cancer cells) and more effective at stopping this hard-to-treat cancer, giving children and families new hope.

Novel GD2/B7-H3 Bispecific Antibody with Agonist CD40 Antibody, Epigenetic Modifier Inhibitors and Checkpoint Blockade to Improve Treatment Efficacy for High-Risk Neuroblastoma

Researchers are working on a new approach to treat neuroblastoma, a tough childhood cancer. The current primary treatment is an antibody drug that fights cancer, but it has a serious problem: it causes excruciating pain because it attacks both cancer cells and healthy nerve cells. This pain is so severe that doctors often have to give children lower doses of the medicine, which makes it less effective at fighting the cancer. Even with treatment, about 90% of children whose neuroblastoma comes back don’t survive.

The research team is developing a new “smart” antibody drug called INV724 that can tell the difference between cancer cells and nerve cells. Think of it like a guided missile that can distinguish between enemy targets and civilians. It should be able to attack the cancer while leaving healthy nerve cells alone. This could eliminate the severe pain that children currently suffer through while still effectively fighting their cancer.
But the researchers aren’t stopping there. They’re also combining this smart antibody with several other treatments that work in different ways:

• A drug that activates the immune system to better recognize and attack cancer
• Medicines that change how cancer genes work (called epigenetic modifiers)
• Drugs that remove the “brakes” from the immune system so it can fight cancer more aggressively (checkpoint blockers)

The idea is that using multiple treatments together that attack cancer from different angles will be much more effective than any single treatment alone. If this combination approach works, it could be the first truly effective treatment for children whose neuroblastoma doesn’t respond to current therapies, potentially saving many young lives while sparing them from treatment-related suffering.

Translational Strategies To Enhance B7-H3-CXCR2 CAR T Homing and Function in Sarcoma

This research focuses on pediatric sarcomas, which are aggressive cancers that develop in bones, muscles, and other soft tissues in children. These cancers have heartbreakingly low survival rates. Only 20-30% of children survive when the cancer spreads to other parts of the body or comes back after treatment. What makes this even more frustrating is that treatments for these cancers haven’t gotten much better in over 20 years, and the current treatments often cause lifelong health problems for the children who do survive.

The researchers are working on a cutting-edge treatment called CAR T cell therapy. Here’s how it works: doctors take immune cells (specifically T cells, the body’s natural cancer fighters) from the child’s own body, then genetically modify them in a laboratory to make them much better at recognizing and attacking cancer cells. Think of it like giving the immune cells a special training course and new weapons before sending them back into the body to fight cancer.

The big problem with this approach for solid tumors like sarcomas is that these specially trained immune cells have trouble actually reaching the cancer. It’s like having excellent soldiers who can’t find the battlefield.

To solve this, the research team has created enhanced CAR T cells with two special features:

1. They target a protein called B7-H3 that’s found on sarcoma cancer cells (like giving them a “wanted poster” of their target)
2. They express something called CXCR2, which acts like a GPS system that helps the immune cells follow chemical trails that tumors naturally product

This should help the modified immune cells find their way to the cancer and be more effective at destroying it once they reach it. For families who have watched their children endure years of ineffective treatments, this breakthrough could finally offer them a chance to beat this disease.

PR Domain Inhibition to Target Leukemia Stem Cells in Pediatric Acute Myeloid Leukemia

This research focuses on acute myeloid leukemia (AML), a type of blood cancer that affects 15-20% of children who develop leukemia. One of the most heartbreaking aspects of this cancer is that even when treatment initially works and the cancer seems to be gone, it often comes back later, devastating children and families with more rounds of treatments.

This happens because of special cancer cells called “leukemia stem cells.” Think of these like the roots of a weed. Even if you cut down the visible parts of the weed (destroying most of the cancer), if the roots remain underground (these stem cells hide and survive treatment), the weed will eventually grow back. These leukemia stem cells are incredibly tough and can survive chemotherapy that kills other cancer cells, which is why the cancer returns in many children.

The researchers have discovered something important: there’s a protein called PRDM16 that acts like a “master switch” or “life support system” for these stubborn stem cells. This protein essentially keeps the leukemia stem cells alive and protected during treatment.

The research team is developing a new drug that specifically targets and blocks this PRDM16 protein. The goal is to cut off the life support to these treatment-resistant stem cells, causing them to die along with the rest of the cancer. What’s promising is that this drug appears to harm only the leukemia stem cells while leaving the body’s healthy blood stem cells (which children need to make normal blood cells) completely unharmed.

This approach gets to the root cause of why cancer comes back after treatment, and because the drug specifically targets the problem cells, it could provide a much safer and more effective treatment option for children with high-risk AML. The research is advanced enough that it could potentially move to clinical trials relatively quickly, which could mean more effective treatments for children sooner rather than later.

Dual inhibition of MDM2 and tubulin for precision treatment of acute myeloid leukemia

This research focuses on acute myeloid leukemia (AML), a type of blood cancer that’s especially challenging to treat in children. Currently, fewer than 70% of children with this cancer survive five years after diagnosis, and about half of all patients don’t respond well to the chemotherapy treatments we have now. To make matters worse, these current treatments cause severe side effects that can affect children for the rest of their lives.

The researchers have made an important discovery about how this cancer works. They found that two proteins, called MDM2 and tubulin, team up inside cancer cells to help them grow and survive. Think of these proteins like partners in crime: when they work together, they make the cancer stronger and harder to defeat. This partnership is significant in about 50% of AML patients who have high levels of the MDM2 protein and tend to have worse outcomes.

The research team has identified a promising new drug called L-243 that works like a wrench thrown into the gears of this partnership. Instead of using chemotherapy that attacks all rapidly dividing cells (both healthy and cancerous), L-243 specifically targets and disrupts the connection between these two proteins. When their partnership is broken, the cancer cells can’t survive, and they die, while normal healthy cells are largely left alone.

This selectivity is what makes L-243 potentially much safer than traditional chemotherapy. It’s like using a precision tool instead of a sledgehammer. Children could potentially get effective cancer treatment without experiencing the devastating side effects that current treatments cause.

What’s encouraging is that L-243 is based on a compound already being tested in clinical trials for other types of cancer. This means the development process could move more quickly than starting completely from scratch, which could bring hope to families sooner rather than later.