Acute myeloid leukemia (AML) is one of the deadliest blood cancers. Current treatments are very toxic and most patients will die from their disease. Metabolism is the process that converts food into energy and building blocks for making and maintaining our tissues. Metabolism is also essential for cancer cells and we have known for over a hundred years that cancer cells have different metabolism requirements than normal cells. The challenge has been to fully understand these differences and to target these unique requirements to kill cancer cells without killing normal cells. The DeGregori lab has generated exciting data showing that a new therapy for AML (“FLT3-inhibitor”) results in dramatic changes in metabolism within leukemia cells. FLT3 has been shown to be important for the formation and growth of AML. The new FLT3-inhibitor therapy is being tested in hospitals for patients with AML. However, while a lot of AML cells die after treatment with FLT3-inhibitor, enough leukemia cells survive to rapidly cause the AML to come back. Proposed studies will attempt to take advantage of the new weaknesses of AML cells caused by this therapy, in order to develop new combination therapies that better eliminate leukemia cells with reduced side-effects to the patients. These new therapies will be like “one-two punches”, with the first punch (FLT3-inhibitor) weakening the AML cells. The second punch takes advantage of this weakness, helping to eliminate the surviving AML cells. The development of these new combination treatments is expected to lead to better results for patients with AML, using less toxic drugs.
Each year in the United States over 30,000 patients with breast cancer are treated with a class of drugs known as the anthracyclines. The anthracyclines are one of the oldest and most effective chemotherapies for breast and other cancers. However, some patients do not benefit from this therapy for reasons that are not understood. Moreover, because the anthracyclines target TopoII isomerase (TopoII), a remarkable protein that is vital for normal cellular functions such as untangling DNA, they can have serious side effects. Recently, we have found that we can predict whether cancer cells will respond to TopoII inhibitors based on their genomic profile. Our over-arching goal is to spare patients treatment with this highly toxic class of drugs if they will not benefit from their use. By performing a simple genomic test on the patient’s tumor sample obtained at the time of diagnosis, we aim to predict which patients will benefit from anthracyclines and thereby inform treatment decision-making. In this manner, treatments can be personalized so that patients receive the best possible current therapy to treat their specific tumor, while being spared ineffective drugs and their side-effects.
Triple negative breast cancer often strikes young African-American and Hispanic women and spreads to the lungs and brain. There are no approved drug treatments for this type of breast cancer other than chemotherapy. Clearly, there is a pressing need to develop better treatments for this disease. We have developed a new approach that uses diet to prime tumor cells to respond better to cancer drugs. The diet we are using is similar to a vegetarian diet. We will test this diet in combination with a new drug that kills tumor cells in mice and in patients with triple-negative breast cancer. We predict that the combination will be better than the drug alone. Our goal is to improve survival for patients with triple negative breast cancer.
Despite improvements in treatment, breast cancers recur in some patients years after their initial treatment. Recurrent cancers arise from the small number of cancer cells that survive standard treatments, and ultimately resume growth. We have developed a way to find these cancer cells in mice and in patients, have identified how these cancer cells survive, and have found drugs that can kill them. In particular, we have found that treating mice with drugs that block a protein called “c-MET” can kill residual cancer cells and thereby prevent breast cancers from recurring. Our goal is to now to determine whether we can use this approach in patients. To accomplish this, we will first study when c-MET gets “turned on” in cancer cells that survive treatment in patients. Second, we will treat mice bearing cancer cells with the anti-c-MET drug to determine if it will kill these cells and thereby prevent breast cancers from coming back. Third, based on these findings we will plan a clinical trial for women with breast cancer that will be able to determine whether anti-c-MET drugs can kill residual cancer cells and, ultimately, whether it can reduce recurrence and increase the likelihood of cure.
Leukemia is a type of blood cancer. Leukemia is the most common cancer in children. Overall, the chance that a child with leukemia can be cured is high. However, when leukemia occurs in babies, the chance of cure is much lower. We are trying to find new and better treatments for these babies. These leukemias have abnormal ways of organizing their DNA. This may be making them harder to cure. We want to understand this better. We want to find new treatments that can fix this abnormal DNA organization. We hope this will help cure more babies.
Uterine cancer is a cancer that grows in the lining of a woman’s uterus (womb). In the United States, uterine cancer is the most common cancer of the female sex organs. Most often, women with this type of cancer have periods that are not normal or have bleeding after they have gone through menopause. By the time this bleeding starts, the cancer may have spread to other sites and organs. If it is caught at an early stage, it can be treated more easily and there is a higher chance of cancer cure. Right now there is not a screening test for this cancer. Our research project aims to design a simple screening test for uterine cancer.
Uterine cancer is caused by changes in the normal cells lining it. These changes can be found in the blood and fluid that passes into the vagina from the uterus. This fluid can be collected using a tampon. Better understanding changes in normal sex organ tissues and in different types of uterine cancer will help us identify the changes that truly represent the presence of a cancer. Our screening test will find the changes that identify cancer in fluid that can be collected using a tampon. We also expect that the cancer changes will be found even in women without bleeding that have an early cancer. The hope is that finding cancer early will lead to improved cancer outcomes.
This research will help us improve a new type of therapy for children with neuroblastoma. Neuroblastoma is a deadly tumor in the nervous system outside the brain. With this therapy doctors administer both chemotherapy and a protein (antibody) that attaches to tumor cells at the same time. This combination, a form of chemo-immunotherapy, was tested on children whose tumors had not decreased even after many rounds of chemotherapy. These children would have died, but chemo-immunotherapy literally melted the tumors off after a few rounds of treatment. The results of this study have not been published yet but are already being used by doctors to successfully treat these children.
Despite this great outcome, half of the children did not respond to the new treatment. There is still a lot to learn about chemo-immunotherapy. In this study, we will test patients’ tumors and find out how their blood cells change with chemo-immunotherapy. We hypothesize that chemo-immunotherapy is assisted by white blood cells destroying tumor cells. Our goal is to study how tumor cells stop or slow down the effect of this therapy. If we are successful, we can modify chemo-immunotherapy to work in all children with neuroblastoma.
The initial treatment of men with prostate cancer is highly successful in stopping the primary cancer. However, years later men often develop cancer again and it is commonly deadly. One explanation for cancer returning is that the cancer was sleeping and in doing so, it was not affected by the first medicine. Our team discovered a new treatment to put cancer to sleep in the body. By using laboratory tests and information from patients, we discovered a “fingerprint” that can tell us if and how the cancer is sleeping or growing. However, for reasons that remain unclear, the sleeping cancer eventually awakens in a deadly form. We discovered that using known medicines we could keep the cancer asleep. We propose to use these medicines that are available for other diseases to induce an constant sleeping state in cancer, preventing its awakening. We will also find new indicators of the sleeping or growing state of cancer using a blood test. If successful, our new treatment to keep cancer sleeping may provide a new cure for men with prostate cancer.
A set of proteins are highly active in cancer. They can add small groups to a series of target proteins. These uncommon additions are often linked with tumors found in breast, liver, and other tissues. To date, it is still unclear how those aberrant proteins cause cancer. To answer this question, it is crucial to know all the targets that they act on in live cancer cells. But no method has been made available to resolve this key issue. In this project we are aimed to create an innovative platform to achieve this goal. Our research plan will use chemistry and biotechnology to make new tools for target identification. A particular member in this group will be chosen for this work. Because it shows much higher activities in diverse types of cancer. The full range of targets for this protein in live cancer cells will be clearly assigned for each specific type of cells. Moreover, the patterns, levels, and time courses of such additions in live cells can be directly viewed and precisely measured by our creative approach. These findings will lead to unveil the interaction networks of this cancerous protein to guide our further studies. The fundamental knowledge obtained from this work will advance our understanding of cancer. Importantly, it will foster the development of new approaches for cancer detection and treatment.
Prostate cancer is the second most frequently diagnosed cancer worldwide. In the US, more than 230,000 cases are diagnosed yearly, affecting 1 in 7 men. If detected early, the cure rate for these cancers is high – nearly all patients will be disease-free after five years. However, in patients whose cancers either re-appear after treatment or spread to other organs, therapies are limited mainly to symptomatic relief. Patients diagnosed at this stage usually live no longer than 20 months. Therefore, a major challenge in treating advanced prostate cancer is that the standard therapies, including radiation and medicine, are not effective in killing these cancer cells.
A small proportion of tumor cells, known as cancer stem cells (CSCs), is particularly important in promoting cancer, because they 1) can give rise to an entire tumor from a single cell, and 2) are more resistant to treatment than other tumor cells. Efforts to identify and then kill CSCs hold the key to effective prostate cancer treatment. The goal of our work is to define the molecular mechanisms that drive growth of prostate cancer CSCs. Once identified, those factors could serve as “biomarkers” or diagnostics. In addition, drugs could be designed to target those factors as a way of blocking tumor growth.
