The goal of this project is to make new drugs against ovarian cancer genes using a new drug discovery method. Ovarian cancer (OC) remains a deadly disease. OC will be diagnosed in over 21,000 women in the United States this year and 13,770 patients are expected to pass away during this time. While initial responses to the best anti-cancer drugs are frequent, most patients with OC will experience disease again after 24 months of treatment, and most women will unfortunately pass away from this disease within five years. Thus, there is an urgent need to make new drugs to treat ovarian cancer. The classic approach to drug discovery is both time intense and costly, and most cancer drug discovery is focused on making drugs against cancer proteins whose shape is considered readily ‘druggable’. Our central premise is that many ovarian cancer proteins can be drugged. To test our idea, we will use a new tool that finds druggable proteins by detecting drug binding to cancer causing proteins in OC cell lines and patient tumors. If successful, this program should develop a new class of anti-cancer drugs to help women suffering from OC.
Fighting cancer is like a game a chess: each treatment can be followed by the adaptation of the tumor. Our next move requires the development of a novel treatment strategy. This is however a difficult task.
My research goal is to develop novel strategies to treat breast and ovarian cancers that are resistant to common drugs. Many breast and ovarian cancers are no longer capable to correctly repair DNA when it is broken. This Achille’s heel can be used to eliminate cancer cells without damaging healthy tissues. My research team has identified a novel protein that help repair DNA and that is essential in these cancers. Our goal is to develop a drug against this protein and to test if we can use it to kill certain cancers that became resistant to current treatments.
Though survival for patients with advanced melanoma has improved over the last decade with the introduction of anti-PD-1 antibodies, half of patients treated with this therapy have disease that recurs. Both combination immunotherapies and single-agent anti-PD-1 antibodies are currently used to treat melanoma. However, combination therapies have higher responses but also higher toxicity rates. Currently, there are no definitive biomarkers that can predict which therapy choice is correct for metastatic melanoma patients.
This project is focused on understanding why patients are resistant to PD1-based therapies. We recently discovered that patients with more CD26 (a type of protein) foundin the tumor’s immune cells are more responsive to treatment. These collective findings beg the question: What is the role of CD26 in the immune response to melanoma?
To answer this question we will study CD26 melanoma immunity using melanoma patients’ blood and tumor samples. This data will allow CD26 to be used as a biomarker in prognosis for patients treated with PD-1-based therapies, and allow for future studies for clinicians to use CD26 as a predictive biomarker to help select the appropriate treatment for a patient, i.e., combination or single-agent immunotherapy.
The role of CD26 activity in melanoma immune response will be defined by this project. Findings from this research will be the basis for future clinical trials to target CD26 in order to enhance immunity against tumors that are unresponsive to PD-1-based therapy in order to create new hope for patients with PD-1-refractory melanoma.
Funded by the Stuart Scott Memorial Cancer Research Fund
Using immunotherapy to treat advanced cancer has improved the outlook of cancer treatment in many cancer types. However, most of the gastrointestinal cancers, including pancreatic adenocarcinoma, do not benefit from such advances in immunotherapy. Upon further research, we have learned that dense non-cancer cells that surround these cancers not only prevent the chemotherapy drugs from reaching the cancer cells, but also prevent the tumor-targeting immune cells that allow immunotherapy to be effective. Research from Washington University show that a molecule called IRAK4 can control such a process and make pancreatic cancer respond better to chemotherapy while allowing immunotherapy to be effective. Based on the promising data from the laboratory, we propose a clinic trial of CA-4948, a drug that inhibits IRAK4 and has shown to be safe by itself, to be added to standard chemotherapy drugs to ensure safety. Then an immunotherapy drug will be added to the combination. We plan to collect blood and tumor samples from the patients receiving the combination of CA-4948, chemotherapy, and immunotherapy, to understand how these drugs change the tumor and components of the immune system in patients. In addition, we plan to further test this combination in animal models to test additional mechanisms that can improve immunotherapy in pancreatic cancer.
Funded by the Dick Vitale Pediatric Cancer Research Fund
Acute myeloid leukemia (AML) in children is difficult to treat, and thus it is important to identify new and less toxic therapies. We have identified a protein called CD97 that is present on AML cells and is required for their maintenance. Because CD97 is present in multiple forms, we will determine which are required in AML cells. We also will make and test the ability of antibodies we have made against CD97 to eliminate AML cells. We expect our studies willnot only reveal the role of CD97 in the development of childhood AML, butidentify a potential newdrug that may be used to treat kids with AML.
Lung cancer is a deadly disease. One common cancer treatment called immunotherapy boosts the body’s natural defenses to fight the tumor. However, while some lung cancer patients respond well to immunotherapy treatments, other patients do not respond to the therapy. This suggests that we need to find new ways to improve these treatments. Our research supported by the V Foundation aims to improve the body’s ability to fight lung cancer. We will study mechanisms to boost the effects of immunotherapy and we will test these new approaches using cancer models. This work has the potential to improve immunotherapy and expand the use of these treatments for larger numbers of lung cancer patients.
Funded by the Dick Vitale Pediatric Cancer Research Fund
Ewing sarcoma is the second most common bone tumor in children, adolescents, and young adults. Patients who are diagnosed with a tumor that has not spread are usually cured. Those who are diagnosed with metastases (the tumor has spread from its initial location) are rarely cured despite decades of clinical trials and intensifying treatment regimens aimed at improving their survival. In preliminary animal experiments, we found that a drug called DFMO, already approved by the FDA for the treatment of African Sleeping Sickness, can inhibit Ewing sarcoma metastasis. We will test the hypothesis that DFMO acts by interfering with critical metabolic pathways in tumor cells, that it is safe to combine DFMO with chemotherapy, and that the combination of DFMO and chemotherapy will work better than chemotherapy alone in prolonging the lives of mice with Ewing sarcoma. Assuming we can show that the combination of DFMO and chemotherapy is better than chemotherapy alone in our mouse model, this will provide the rationale for future clinical trials testing the effectiveness of adding DFMO to standard chemotherapy regimens for Ewing sarcoma patients.
Breast cancer is the most common type of cancer in women, causing many deaths each year. When the cancer has spread in the person’s body, the available treatments have many side effects and often cannot cure the disease. Research has shown promising results using immunotherapies, which make the patient’s own immune system attack the cancer. T cells are important cells of the immune system and can be very effective at attacking and killing cancer cells. Some breast cancers have a protein called HER2 that can be used as a target for T cells to attach. We plan to take the patient’s own T-cells and train them in the laboratory to attack breast cancer cells that have HER2. This treatment has proven safe in other cancer types and should have minimal side effects. However, breast cancer tumors are made up of different kinds of cells, not just cancer cells. Thus, we also plan to arm the T-cells with extra measures to get rid of the other bad cells in the tumor, making it easier for the T cells to eliminate all of the cancer. Based on previous research, we know that when successful, results using this kind of T cell-based therapy are long lasting for patients and can even cure their disease. With the recent FDA approval of T-cell therapies for several cancers, we are confident that the proposed project has the potential to improve the lives of patients with breast cancer.
Funded by the Dick Vitale Pediatric Cancer Research Fund
Outcomes for children with brain cancer are poor and current therapies are harmful to normal cells in thebody. New therapies that only target cancer cells are greatly needed to improve outcomes for this terribledisease. We tested the ability of a modified cold-sore virus to target and kill brain cancer while not injuringnormal cells in children. Results from the clinical trial were very exciting. We found that the virus directlykills cancer cells and also stimulates a child’s own immune system to attack the tumor. From the trial, welearned that in order to achieve even greater responses from the therapy, we need to continue theimmune system attack on the tumor. To achieve this goal, we will combine two therapies that work welltogether: the altered cold-sore virus with a unique cancer vaccine. When the cancer vaccine is givenbefore the virus, it prepares the immune system to fight the cancer and improves the virus’ ability to killthe cancer and stimulate the immune system attack on the cancer. We plan to create the ideal cancervaccine with the cold-sore virus in the lab and then conduct a clinical trial of the combination therapy tobenefit children in great need of more effective and less-toxic treatments. Weexpect these excitingtherapies will result in even better outcomes in children with brain cancer.Importantly, this combinationtherapy can be used to treat other pediatric cancers, increasing the overall potential to help children withcancer and their families.
Funded by the Constellation Gold Network Distributors
Although cancer immunotherapies are beneficial for many patients, about half of patients fail to respond to treatment or may only respond for a short time. Identifying which patients are benefitting from treatment is an important goal, as non-responders are subjected to needless treatment and deprived of potentially beneficial alternative therapies. To address this challenge, we have developed a new PET scan to identify which patients are experiencing a tumor remission rapidly after the start of treatment. We will first evaluate patients with non-Hodgkin’s lymphoma that are receiving CAR T cell therapy. If our imaging technology successfully identifies patients that are responding to treatment, we expect it could also help patients with other types of cancer that are receiving immunotherapies. Another long term goal will be to test if our imaging technology can help physicians understand if new immunotherapies in clinical trials can eliminate tumors.
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