Joelle Straehla, MD

Funded by the Dick Vitale Pediatric Cancer Research Fund with support from the Scott Hamilton CARES Foundation

One major challenge in treating any type of cancer is resistance, or when a cancer stops responding to a certain type of drug or therapy. Some cancer cells may become resistant my changing the way they read and write their DNA, or the genetic blueprint in the cell nucleus. Other cells may change the way proteins are expressed on the surface, which can change their shape or ‘stickiness’ and ability to move in the body.  When doctors can understand exactly how cancer cells become resistant to a certain drug, they can sometimes combine two or more drugs together to overcome this.

For some new classes of drugs, we have not even begun to explore how cancer cells might become resistant. One of these classes is nanoparticle drugs, which usually involves bringing together molecules like fats or polymers to help delivery drugs into certain cells. The goal of this research project is to identify the ways that pediatric cancer cells can become resistant to nanoparticle drugs, and find new drug combinations that are more effective and less toxic to children with cancer. Many lab-based studies of nanoparticles are performed in common cancers of adulthood such as breast cancer, and this has led to new treatments in the clinic, but there have been very few studies of nanoparticle drugs in childhood cancer. Currently, there is only one nanoparticle drug approved for use in children. By studying resistance to nanoparticle drugs in a deadly childhood brain tumor, we can take the first step towards a new clinical treatment for these children.

David Langenau, PhD

Funded by the Dick Vitale Pediatric Cancer Research Fund

Children with muscle cancer commonly develop resistance to therapy.  This is a major problem and most kids will die from resistant disease.   Our group has developed a new combination of drugs to kill muscle cancers and is now being tested in kids and young adults.   Yet, drug resistance to this same combination has been reported in other cancers and may develop in our patients. Our work will uncover how resistance develops and identify a new drug that can restore sensitivity to chemotherapy.  This work is important because the new drugs we identify could be used to treat kids in the future.

Scott Armstrong, MD, PhD

Funded by the Dick Vitale Pediatric Cancer Research Fund with support from the Marc and Peg Hafer Family

Acute myeloid leukemia (AML) remains one of the most difficult leukemias to treat. Pediatric patients with AML have relied on standard toxic chemotherapy and bone marrow transplantation for the past few decades for treatment without any advancement in the development of targeted therapeutics for this disease. The development and clinical investigation of a new class of orally available drugs, called Menin inhibitors, has shown great promise in patients with specific, hard-to-treat subtypes of AML. However, we have recently described acquired resistance to Menin inhibitors through genetic mutation in the Menin gene during treatment. After characterizing and understanding the mutations in Menin, we now aim to try to overcome and possibly prevent resistance with the next generation of Menin inhibitors or with combinations with other drugs that show promise in treating AML. The experiments proposed here will guide the clinical implementation of Menin inhibitors into the standard of care in children with either newly diagnosed or refractory AML. We hope/expect that these approaches will, over time, supplant the need for chemotherapy much as has been the case for targeted therapy in APML, which previously required bone marrow transplantation, but is now cured with two oral therapies that have minimal toxicities.

Robert Manguso, PhD

Funded by the McAdam Family

CAR T cell therapy is an exciting new cancer therapy where immune cells from a patient, called T cells, are reprogrammed outside the body to seek out and kill tumor cells. While this approach has been highly effective for some types of cancer such as lymphoma and leukemia, it has not yet been effective for solid tumors such as ovarian cancer and pancreatic cancer. One reason for this failure is that many tumor cells have found ways to hide from the engineered immune cells and avoid being killed. We call the genes that enable tumors to hide “immune evasion genes.” Our lab has identified one of the key immune evasion genes, called NKG2A-HLA-E. We believe that blocking this gene could make tumor cells more visible to CAR T cells and greatly increase their cancer killing abilities. This would result in more effective therapies for patients that could lead to longer survival. Additionally, our lab has also developed new ways to identify all the evasion genes used by tumors to hide from CAR T cells. This exciting new approach could reveal several additional genes that tumors use to escape CAR T cells, and we identify these genes and attempt to block them to determine if this also improves the ability of CAR T cells to kill tumors. This work could help to identify the ways tumors escape from the immune system and could provide researchers and clinicians with the information required to build more effective cancer therapies using the immune system.

Alejandro Gutierrez, MD

Funded by the Dick Vitale Pediatric Cancer Research Fund

Asparaginase is an important drug for the treatment of childhood leukemias.  However, some leukemias become resistant to asparaginase, and this makes them very difficult to treat successfully.  We discovered that by blocking a protein called GSK3α, we can make drug-resistant leukemia cells sensitive to asparaginase again. Although this finding is promising in the lab, there are currently no drugs known to block GSK3α that can be used to treat patients.

This proposal is focused on overcoming this problem by testing two different but related ideas.  First, we will test the hypothesis that some existing drugs, which have already been developed for other purposes, also possess the ability to block GSK3α.  Because these drugs are already approved for use in patients, we would be able to quickly start testing these in patients with leukemia.  Second, we have engineered several new compounds that are specifically designed to target GSK3α.  Fortunately, these have shown early promise in the lab, and we are ready to evaluate whether these newly engineered compounds fit the criteria as candidates for new drug development.  If this line of research is successful, we expect it will lead to two different treatment strategies combining asparaginase with a drug that blocks GSK3α.

With support from the V Foundation for Cancer Research, we are optimistic that our work has the potential to lead to the development of potent new treatment strategies for some of the most difficult-to-treat forms of childhood leukemia.

Sarah Johnstone, MD, PhD

Cancer arises from alterations, termed mutations, of a cell’s genetic material (DNA). Understanding how different types of mutations promote cancer cell growth requires precise modeling of these mutations in tumor cells in order to discern how they specifically impact cell function. We propose to do this for two proteins that are frequently mutated in ovarian cancer. These proteins, CTCF and BORIS, bind to the DNA and can change the DNA’s structure to turn genes on or off. However, how their mutations affect the DNA binding for these two proteins and impact ovarian cancer cells is unclear. We propose to generate cellular models of BORIS and CTCF mutations and measure their impact on DNA structure and gene expression. From these data, we will discern the molecular alterations and functional consequences of their mutation. The goal is to define the mechanism by which these frequent mutations impact ovarian cancer cells, with the ultimate hope that such mechanistic insights can lead to novel therapeutic approaches to ovarian cancer.

Kimberly Stegmaier, MD

Funded by the Dick Vitale Pediatric Cancer Research Fund in partnership with Mat Ishbia and Justin Ishbia

Childhood cancer remains the leading cause of death from disease in children in high-income countries. Our lab has used cutting-edge technologies to hunt for new drug targets in high-risk pediatric cancers.  In neuroblastoma, a common pediatric solid tumor, we discovered a new potential therapeutic target. Drugs have been developed against this target, but they have not been tested in neuroblastoma. In this proposal, we will perform the critical testing of these drugs in high-risk neuroblastoma models in the lab. We will also determine why neuroblastoma cells depend on this target for survival.  It is our long-term goal to develop clinical trials testing these drugs in children with high-risk neuroblastoma.

Mark Awad, MD, PhD

Funded by Lloyd Family Clinical Scholar Fund

Some cancers grow because of an abnormality (or “mutation”) in a gene called ALK. Currently, there are FDA-approved pills that shut down this abnormal ALK protein and cause cancers to shrink down. However, over time, cancer can develop resistance to these treatments and start to regrow and spread, and once that happens, there are few effective treatment options for these cancers. We are working to develop a cancer “vaccine” to treat patients with ALK-mutated cancer. Similar to how vaccines against COVID-19 or influenza help the body fight off these viral infections, our new cancer vaccine is designed to cause a patient’s immune system to attack cancer cells and shrink down tumors. Hopefully these treatments will help our patients to feel better and live longer with their cancer. 

Debattama Sen, PhD

Abeloff V Scholar*

Funded by Friends and Family of Loie Conrad and Stacey Sanders

CAR-T cells are a new therapy where a patient’s own white blood cells are isolated, modified in a dish to better recognize their tumor, and infused back in. These engineered T cells have transformed the treatment of blood cancers and are being actively considered for solid tumors such as triple-negative breast cancer (TNBC) and ovarian cancer. Unfortunately, CAR-T cell treatment success has been limited partly because these cells eventually lose their ability to control tumors in a process called T cell exhaustion. Understanding why CAR-T cells become exhausted in solid tumors is absolutely required to improve patient outcomes and get better immune-targeted treatment responses. These dysfunctional T cells show many defects, including overproduction of a receptor known as PD-1 that inhibits T cells. It is not currently known why high levels of PD-1 are found on exhausted CAR-T cells and what the consequences of high PD-1 expression are. We hypothesize that by focusing on exhaustion-specific regulation, we can rewire CAR-T cells to prevent PD-1 mediated dysfunction in tumors while minimizing side-effects. These will be attractive targets for translation to early-phase CAR-T clinical trials in breast cancer, ovarian cancer, and other solid tumors, where there is intense interest in reducing T cell exhaustion.

Francisco Sánchez-Rivera, PhD

Funded by Constellation Gold Network Distributors in honor of the Stuart Scott Memorial Cancer Research Fund

Humans are genetically diverse and exhibit variable susceptibility to developing diseases with a strong genetic component, leading to significant health disparities. The mechanisms by which certain genetic alterations differentially impact disease development and progression depending on the genetic background and the type of genetic lesion remain poorly understood. To tackle these problems, my group has developed sophisticated methods to rapidly engineer and probe endogenous gene function in primary cells and tissues of living animals in a manner that is agnostic to an individual’s genetic background. My lab is using these methods to elucidate the specific ways that different genetic alterations influence cancer development, progression, and therapy responses, with the goal of using this knowledge to better diagnose and devise novel strategies to target cancers in a more precise, personalized manner.

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