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 KAAB Memorial Foundation and the Stuart Scott Memorial Cancer Research Fund
Cancer kills millions of people every year. The deadliest cancers are those that have high rates of metastasis.Metastasis is the movement of cancer cells from one organ site to another. Many of the current therapies aredesigned to kill cancer cells from the original tumor but not the secondary tumors that follow. We find genes responsible for normal embryonic development are improperly present in tumors but not in normal adulttissue. Many of these abnormally expressed genes control activities required for successful invasion andmigration to distant organ sites. The purpose of the proposed research project is to comprehend how tumorsuse these embryonic genes to become metastatic and resistant to chemotherapy. This research will ultimatelyenable researchers to better target these aggressive gene programs, leading to increased patient survival andhopefully eradication of the metastases. My training as a cancer and developmental biologist puts me in aunique position to tackle these difficult questions. The medical community has finally realized that there willnot be one treatment for cancer and each tumor is as unique as the individual is. Therefore, we must thinkoutside the box to design therapies that target genes that responsible for growth, resistance to chemotherapyand metastasis. This current project seeks to understand why developmental pathways are re-expressed as wellfind ways to specifically target these pathways to inhibit metastasis.
Funded by the Constellation Gold Network Distributors
Cancer cells divide rapidly. To be able to do this, cancer cells often rewire their metabolism to produce more building blocks of life- proteins, nucleotides, and lipids. Our lab studies a molecule known as NADPH, which is necessary for the production of these building blocks. We recently discovered that NADPH produced in the mitochondria is essential for the synthesis of an amino acid called proline. Cancer cells that are deficient in an enzyme called NADK2, which maintains mitochondrial NADPH levels, cannot synthesize proline and fail to grow under low proline conditions.
Our analysis of proline production in mice showed that the pancreas makes the most proline. We propose that pancreatic tumors strongly depend on proline and that blocking proline uptake and production should kill pancreatic cancer cells. In the proposed work, we will test whether inhibiting proline production through targeting NADK2 together with the removal of proline from the diet is an effective strategy in reducing pancreatic tumor growth. To test this, we will use a mouse model that mirrors pancreatic cancer. This research will pave the way for new ways to treat patients that have pancreatic cancer and this treatment strategy has the potential to be applied for other cancer types that rely on proline for growth.
The term DNA damage response (DDR) inhibitors is used in cancer treatment to refer to a group of drugs, which block important processes that cancers rely on to repair their DNA. While PARP inhibitors (a type of DDR inhibitor) are approved, they do not benefit all patients, and their effects are not long-lasting. Combining PARP (or other DDR inhibitors) with drugs that may boost their effects is a promising approach, which has been shown in laboratory studies (cancer cells or animal testing) to be more effective than each drug given alone. My program of DDR inhibitor combination trials aims to benefit patients with cancers with defects in DDR and other important processes by matching them with suitable DDR inhibitors in combination with carefully selected drugs, therefore personalizing cancer treatment for each patient. Multiple new and promising DDR inhibitor combinations will be tested. Trials not well-tolerated or effective will be stopped early, while trials with promising combinations will be increased in size. We will personalize these treatments for each patient by studying their cancer/blood samples to ensure that the genetic defects of the tumor match the combination treatment, so as to increase the chance of success. If patients stop responding to treatment, they will be allowed to switch to a different DDR inhibitor combination guided by fresh analyses of new cancer/blood samples. This program of trials aims to advance our DDR scientific knowledge, improve outcomes for each patient and guide future trials in order to get better treatments approved.
Funded by the Constellation Gold Network Distributors in honor of the Dick Vitale Fund
Scientists have given immune cells a detector forB-cell acute lymphoblastic leukemia (ALL).Theycalled these cells CAR T cells. In some patients, these CAR T cells disappear before they can clear the tumor. In others, these cells become too exhausted to work. We have recently identified the molecular code that prevents T cells from dying off or becoming exhausted. With the funding support, we will use this molecular code to make CAR T cells stay in cancer patients longer and clear B-cell ALL more effectively.We hope to use this strategyto cure a much larger population of pediatric cancer patients with B-cell ALL.
Funded by the Constellation Gold Network Distributors
Patients with pancreatic cancer are usually diagnosed with advanced disease and suffer from a very poor prognosis with limited treatment options. This is due to the lack of early detection tests and the largely asymptomatic onset of the disease. In the past decade, drugs that pit the body’s immune response against cancerous cells—also known as immunotherapeutics—have been used to treat a variety of cancers but seem to only benefit a limited number of patients. In particular, immunotherapeutics seem generally ineffectiveagainst pancreatic cancer, although it is unknown if there is a subset of pancreatic cancer patients who may benefit from this therapeutic approach. To understand why, we will use a new platform developed in our laboratory to study how different populations of cancerous and immune cells within the tumor interact with each otheras well as with the other cells in the tumor’s surroundings (i.e. tumor microenvironment). Additionally, the platform will track how these interactions change when the tumor is exposed to disturbances such as immunotherapeutics. Our study will allow usto understand how individual cell populations contribute to the pancreatic tumor’s response—or lack thereof—to immunotherapeutics as well as its ability to evade the immune response.Ultimately, our findings can be used to develop tests that can predict whether a patient with pancreatic cancer will benefit from a certain immunotherapeutic approach.
Funded by the Hirsch Family in memory of Ann Hirsch
There is a strong need for new treatments for brain tumor patients. To address this need, we asked how a common mutation in brain tumors may create weaknesses that we could use to develop new treatments. We identified a process that brain tumor cells with this common mutation rely on to live. Next, we used a drug to block this process and found that it kills brain tumor cells with this common mutation. We would like to know why these cells rely on this process and whether brain tumors grown in mice respond to this drug. If our work is successful, our efforts could lead to new studies that will test this drug in human brain tumor patients. We are hopeful that our discovery could lead to improvements in the lives of brain tumor patients.
Colon cancer is the second leading cause of cancer-related deaths in the United States. An increasing number of human studies have highlighted the association among the consumption of sugary drinks, obesity, and the risk of colon cancer. It is currently thought that sugar is harmful to our health mainly because consuming too much can lead to obesity. It is well known that obesity increases the risk of many types of cancer, including colon cancer. However, whether a direct, causal link exists between sugar consumption and colon cancer has remained unknown.
Our group recently showed that consuming a modest amount of refined sugar every day—the equivalent of a human drinking about 12 ounces of a sugar-sweetened beverage daily—accelerates colon tumor development in mice, and it does so independently of causing obesity. The proposed project will identify the molecular mechanisms by which sugar enhance colon tumor development. In particular, we will focus on how sugary drinks alter the bacteria living in the gut and how these altered gut bacteria contribute to tumor development. To this end, we hope to identify bacteria that increase specifically in response to sugar consumption that could serve as new targets for prevention and treatment for colon cancer patients. Given that more than half of American young adults consume at least one sugar-sweetened beverage daily, and that young-onset colon cancer is on the rise for unknown reasons, any positive findings from this project will be of immense significance.
Funded by the Stuart Scott Memorial Cancer Research Fund
Cancer cachexia is a wasting disease with significant fat and muscle loss occurring in 1/3 of all patients with cancer and causing 1/3 of all cancer patient deaths. It is also makes patients not want to eat. Cancer patients with cachexia live half as long as patients with the same cancers without cachexia. These patients have a poor quality of life which prevents them from taking medications to treat their cancer as well. Currently there are no treatments for this wasting disease. Therefore, clinicians often use medications that are not approved by the government to treat cancer cachexia with little benefit.
We aimed to better understand how cancers can cause cachexia wasting in order to create new medications for this disease. Our research has identified a molecule made by cancers that causes fat breakdown and causes decreased food intake. These cancer-secreted factors do this by acting directly on the fat and the part of the brain that controls food intake. These factors also reprogram the fat to secrete other factors that also affect the brain’s appetite center. We believe the combination of these events is responsible for the wasting seen in these cancer patients. Our research proposal will try to identify how these molecules affect the fat tissue and the brain to cause cancer cachexia to help us develop new medications for this under-treated disease. Creating a treatment for cancer cachexia will improve cancer patients’ quality of life and overall life span.
Pancreatic cancer is the 3rd leading cause of cancer-related death in the United States, with a five-year survival rate of less than 9 percent. Activation of the immune response in the microenvironment is associated with better outcomes in pancreatic cancer patients. The tumor and gut microbiota has recently been shown to influence tumor progression by modulating the tumor microenvironment.
We have recently demonstrated that the composition of the gut microbiome may determine tumor behavior and outcomes in pancreatic ductal adenocarcinoma (PDAC) patients. We have identified specific bacteria signatures in the tumors of long-term survivors (LTS) compared to the stage-matched- short-term survivors (STS). We have also shown that transplantation of fecal microbiome from LTS or healthy controls of pancreatic cancer patients into a mouse model of PDAC significantly reduces pancreatic cancer growth. These important findings prompted us to target tumor microbiome as a therapeutic approach in pancreatic cancer patients. Here, we propose to transplant stools from PDAC long term survivals or healthy controls into PDAC patient to change their immune suppressive behavior to immunoactivated one. To this end, we will first analyze the changes in microbiome of PDAC patients after the transplantation of gut microbiome from long term survivals or health controls. Next, we will evaluate the tissue obtained from biopsy and surgical specimen for the changes in tumor microbiome of PDAC patients. Finally, we will characterize the tumor immune infiltrates from tissues obtained from PDAC patients to see if we can switch PDAC immunosuppressive TME into immunoactivated by fecal microbial transplantation. This proposal would be the stepping stone to move forward efficacy trials in PDAC patients combining FMT with standard treatment or immunotherapy.
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