“Spirit of Jimmy V” Award funded by the Dick Vitale Gala in honor of Chris Berman
Neuroblastoma is a fast-growing cancer that affects hundreds of infants and children in the U.S. each year. The age of the patient is one of the most important factors for survival. While infants diagnosed before the age of 18 months have a 95% cure rate, older children have only around 50% chance of survival. We aim to improve the treatment options against the more aggressive neuroblastomas in older children.
Recent studies show that a gene called SMARCA4 has a major role in these cancers. We are working to identify all the other genes that depend on SMARCA4 in diseased cells, and then attack the key weak spots. By targeting the whole network instead of a single gene, we will identify new ways to treat neuroblastoma in older children. Our research is a viable first step to improve survival and quality of life for children affected by neuroblastoma.
Funded by the Constellation Gold Network Distributors in honor of the Dick Vitale Gala
Children with liver cancers are hard to cure, if the tumor cannot be removed by surgery or has spread to distant organs. Current therapies cause significant toxicity and don’t work well against large tumors. These children need new approaches and immunotherapy may be a good solution. Immunotherapy relies on the body’s own infection and cancer fighting system.
A type of immunotherapy uses special white blood cells called T cells. T cells can be collected from patients and engineered with a molecule called chimeric antigen receptor or CAR. These CAR T cells can be infused back to patients to destroy the cancer cells.
We developed several versions of CARs which recognize glypican-3. This molecule is expressed in pediatric liver cancers. We systematically tested T cells expressing these CARs in preclinical models of liver cancer. We selected the CAR with the strongest antitumor activity. Now T cells expressing this CAR will be tested in a Phase 1 clinical trial in children.
With the help of the V Foundation, we will examine changes in the genetic programming of CAR T cells. We will evaluate the CAR T cell product, peripheral blood and biopsy samples. Our goal is to define the interaction between the CAR T cells and the tumor.
Immunotherapy has revolutionized cancer treatment. Immunotherapy drugs work with the immune system, which normally fights intruders such as viruses, to kill cancer cells. One approach involves taking down defenses set up by cancer cells to escape immune cells. Some tumors, such as kidney cancer, melanoma, and lung cancer, display on their surface a protein (PD-L1) that shuts off approaching killer immune cells. Drugs have been developed that mask PD-L1 allowing killer cells to dispose of cancer cells. Discoveries underlying these developments were recognized with a Nobel Prize in 2018.
However, not all tumors use the same defense mechanism. Here, we propose a novel strategy to identify patients most likely to benefit from drugs masking PD-L1. Up until now, most approaches have focused on evaluating PD-L1 on tumor biopsy samples. However, only one cancer site is sampled, few cells are evaluated, and the results are often unreliable.
We have developed a strategy adapting a radiology test, positron emission tomography (PET), and a PD-L1 masking drug, that allows us to evaluate PD-L1 across all tumor sites. In preliminary experiments, we show that we can label a PD-L1 masking drug so that it can be detected by PET. We then show, using patient tumors transplanted into mice, that we can identify tumors with high PD-L1.
Our goal is to evaluate immuno-PET (iPET) in patients in a clinical trial. If successful, iPET will better match patients to their immunotherapy drug, and identify patients unlikely to benefit and for whom other strategies should be developed.
Bladder cancer patients experience widely variable clinical outcomes. Some are cured of their disease with surgery alone, whereas others require chemotherapy, and only about half of individuals who receive chemotherapy benefit from it. These differences in clinical behavior are almost certainly based in differences in cancer biology, and the overall goal of our bladder cancer research program is to deeply define them so that optimal therapeutic approaches can be offered to each patient. We recently discovered that bladder cancers can be grouped into “intrinsic subtypes” that are remarkably similar to the ones that exist in breast cancers. One of the bladder cancer subtypes (“p53-like”) is similar to “luminal A” breast cancers, and like them, tend to be resistant to chemotherapy and metastasize to the bone. Their most distinguishing feature is that they contain large numbers of normal cells (termed “fibroblasts”) that are being implicated in drug resistance and bone metastasis in laboratory models of other types of cancer (including breast cancer). In this project we will examine further whether the p53-like tumors are chemo-resistant and metastatic to bone by analyzing several additional cohorts of patients treated with chemotherapy in clinical trials. Then we will directly examine the contributions of the fibroblasts to chemoresistance and bone metastasis in laboratory models. Our goal is to use the information to distinguish patients who will benefit from chemotherapy from those who will not. And by studying the biological mechanisms influenced by the fibroblasts, we should be able to identify new, more effective therapies for patients with chemoresistant bladder cancers.
The human immune response can not only eliminate infections caused by viruses, bacteria and fungi, but can also kill cancer cells. Immunity is mediated by white blood cells. Among the different types of white blood cells, killer T cells can eliminate cancer cells, whereas regulatory T cells and some types of macrophages can block anti-cancer immunity and actually support cancer growth. The ability of killer T cells to eradicate cancer cells can be blocked by “immune checkpoint” proteins within the tumor microenvironment. Drugs have been developed to inhibit immune checkpoints (CTLA-4, PD-1 and PD-L1); thereby releasing the “brakes” on killer T cells to fight cancer. Using a combination of immune checkpoint inhibitors more than half of patients with widespread melanoma can experience long-term remission and possible cure.
Unfortunately, immune checkpoint inhibitors have been largely unsuccessful in patients with advanced prostate cancer. To better understand why they are not more effective, Dr. Subudhi’s team has evaluated the immune profile of primary and metastatic prostate cancers. They have found that the bone metastatic site is a highly immunosuppressive environment. This likely accounts for the poor clinical responses seen in patients with metastatic prostate cancer treated with a single agent immune checkpoint inhibitor. The overall goal of Dr. Subudhi’s clinical trials program is to improve survival in patients with advanced prostate cancer by enhancing T cell functions while eradicating the immunosuppressive cells within the cancer. Ultimately, his aim is to make immunotherapies in prostate cancer as effective as they are in melanoma.
Unlike childhood leukemia that has a 90% cure rate, outcomes for adult patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) remain poor. With modern chemotherapy regimens, complete remission rates are 60-70%, yet long term cure rates remain dismal at 15-25%. Prognosis is even worse in older patients and/or those with high risk features, with remission rates of only ~35-50% and cure rates less than 10%. Efforts to improve both the remission rate and the durability of remission are paramount.
Dr. DiNardo’s team focuses on mutations in the genes IDH1 and IDH2, which occur in ~20% of patients with AML and occur more frequently in older patients. In her clinical trials, she has tested targeted drugs that inhibit these two mutated proteins (IDH1 and IDH2) and can lead to dramatic clinical responses. These novel drugs can be taken by mouth, are well-tolerated and promise to improve the survival of patients whose leukemic cells bear these mutations. The use of these drugs that can be taken by mouth, alone and in combination with other leukemia-directed therapies, will permit patients to be treated at home with less frequent trips to MD Anderson. She will carry out not just a single trial, but a program of multiple trials to have a major impact on the lives of patients whose cancers have IDH1 and ID2 mutations. Dr. DiNardo is also striving to make screening for multiple mutated genes the standard of care for patients with MDS and AML, which is not often performed in the community, in order to optimize treatment and accelerate best practices for older adult patients with AML.
One of the greatest challenges in cancer treatment is that response to standard chemotherapy is frequently incomplete and fraught with adverse events. Current treatments are often ineffective because they function as a “one-size-fits-all” approach to a very diverse disease. This lack of success is magnified in triple negative breast cancer (TNBC), whose large and diverse group of subtypes greatly increases difficulty in treating a disease that makes up 15% of all breast cancers and disproportionately affects African American and Hispanic women. The goal of our project is to address these challenges by identifying and characterizing specific tumor vulnerabilities in TNBC to pave the way for novel combined chemotherapeutic treatments. By screening through each gene in the genome, we have found that TNBC cancers rely on a protein called SIK2 for their survival. We are working to understand why SIK2 is essential and to use inhibitors of SIK2 function to reduce TNBC tumor survival.
Cancer researchers have found that the immune system plays an important role in cancer. Our immune system I programmed to kill cancer cells. But, cancer cells eventually develop ways to escape the immune system and grow and spread. While it is unclear how this happens, many scientists are now developing therapies to reactivate the immune system to attack cancer cells. This field is called immunotherapy. While promising, we are still in early days, and there is much about the cancer immunology we don’t understand. Through our studies, we have identified a protein called APOBEC3A that might prevent the immune system from destroying cancer cells. APOBEC3A is an interesting protein since it is found in high amounts in many types of cancers, including lung, breast, colon and pancreatic cancer. Here, we will try to understand how APOBEC3A exactly affects the immune system in cancer. Secondly, we have found that human and mouse tumors that have high levels of APOBEC3A also tend to have high levels of molecules that specifically stop immune cells from attacking cancer cells called checkpoints. In a novel preclinical trial, we will see if a combination of drugs that target these molecules can effectively treat cancers that express high levels of APOBEC3A. If this trial works in mice, then this approach may be lead to a new treatment strategy in a subgroup of patients with many types of cancer, including pancreatic cancer.
Funded by the Dick Vitale Gala and Northwestern Mutual in memory of John Saunders
Over one-quarter of children with acute myeloid leukemia (AML) have a form called core binding factor (CBF) AML. Despite intense therapy, ~30% of these patients will relapse. Thus, identifying new therapeutic targets is necessary to develop more effective, less toxic treatment regimens. The CBF complex coordinates the expression of genes required for normal development of blood cells. CBF AMLs harbor one of two genetic changes (t(8;21) or inv(16)) that interferes with the function of the CBF complex. While often grouped together, t(8;21) and inv(16) affect different members of the CBF complex and have unique disease features, suggesting important, yet unknown, biological differences exist. Interestingly, t(8;21) AML and inv(16) AML have different combinations of other cancer-causing mutations, providing potential clues to the genesis of t(8;21) and inv(16) AML. In particular, mutations affecting another complex that regulates gene expression, called the cohesin complex, are common in t(8;21) AML, yet never occur in inv(16) AML. The frequency of cohesin mutations with t(8;21) suggests that cohesin dysfunction cooperates with t(8;21) to cause leukemia by collaboratively activating cancer-causing genes, which could represent targets for therapy. Conversely, the absence of cohesin mutations with inv(16) indicate a dependence upon intact cohesin function, and perhaps the cohesin complex itself could be targeted in inv(16) AML. We will explore the interactions between the cohesin and the CBF complexes in AML using murine and human systems. Our study will provide novel insight into the mechanisms driving CBF AML, likely uncovering herapeutic targets for the treatment of children with this disease.
Tumors that spread to the brain, called brain metastases, are the cause of death of half of patients with metastatic melanoma. The metabolic environment of the brain is uniquely low in two amino acids, serine and glycine, which carry messages between nerve cells. This ensures accurate nerve cell communication, but should prevent or slow the growth of tumors, as tumor cells need large amounts of serine and glycine to make DNA and proteins to divide and grow. Yet, tumors can spread to the brain, and are incurable once they have done so. We hypothesize that tumors metabolically adapt to the brain’s metabolic environment by increasing their ability to make serine and its product glycine, and that blocking the production of serine should either attenuate the development of brain metastases or help treat existing brain metastases. We will determine if serine synthesis is increased in brain metastases, and if tumor cells adapt to, or are selected for, the environment of the brain by increasing their production of serine and glycine. In addition, we have developed small molecules that inhibit serine synthesis, and will test these compounds in mouse models of melanoma brain metastases with the goal of reducing their initiation or growth. These studies will demonstrate that targeting the serine synthesis pathway might be useful in treating melanoma brain metastases and offer proof of concept that small molecule inhibitors of serine synthesis might be effective in treating patients with melanoma brain metastases and brain metastases from other tumors
