Immune checkpoint blockade (ICB) is one type of immunotherapy that has been FDA-approved for thetreatment of melanoma, bladder cancer, lung cancer, and other cancers. For some patients, ICB canlead to dramatic shrinkage of their tumors and extend their life. However, many patients do not see thisbenefit and some patients develop serious side effects. For most cancer patients, there is no way topredict if they will benefit from or be hurt by ICB.A test that could give doctors and patients a better understanding of the risks and benefits for ICBtreatment for each individual is urgently needed.Examining the blood of patients, we discovered certain immune cells in patients who are less likely tobenefit from ICB. We have found this is true for both melanoma and bladder cancer patients. We plan to examine whether these cells also matter for patients with other cancers and if there are differences in these immune cells depending upon a patient’s race. We also would like to better understand thisspecial population of immune cells and how they may be linked to immune cells in the tumor. We hopethat this will lead to the development of a safe and easy test that will provide patients betterinformation about how ICB treatment will work for them. With this information, we hope to allowpatients to feel and function better and live longer by finding a therapy that will be more likely tohelp and less likely to hurt them.
Acute myeloid leukemiais the deadliest blood cancer. The mainstay chemotherapeutic treatments have met with limited success, and most patients will die from their disease. Thus, New treatments are desperately needed. To address this need, we have identified a cellular pathway leukemia cells rely on to live. In this project, we have developed an inhibitor that blocks this pathway and found that it kills leukemia grown in mice. We would like to understand why some leukemia cells rely on this pathway to survive and what determines the response to the inhibitor. If successful, our work will provide preclinical evidence for a new pathway as a target for acute myeloid leukemia and offer needed knowledge and chemical tools to guide future clinical studies. We are hopeful that our findings could lead to improvements in the lives of AML patients.
Immunotherapy is a type of cancer treatment that uses the body’s own immune system to fight and destroy cancer cells. Despite its success in treating a number ofcancers, immunotherapy has had a limited impact on the treatment of blood cancers, known as leukemia. While there are many reasons for this, a primary reason is the current lack of understanding of how the cells of the immune system interact with leukemia cells. Present knowledge of the types ofimmune cells that live in the bonemarrow and their behavior at various stages of leukemia are almost entirely lacking. To address this, wewill perform awidespread analysis of immune cell composition and function during leukemia disease progression. We will use cutting-edge technologyto understand thebiological mechanisms that become altered during leukemia, which may cause immune cellsto promotethe cancer’sinitiation and relapse. These studies would enable the identification of “immune signatures” associated with different stages of cancer development. The findings will lay the groundwork for our understanding of the bone marrow immune landscape in the context of the human disease. We envision that these studies will fundamentally lead to new treatment strategies for this devastating cancer and thereby improve patient outcomes.
Vintner Grant funded by the V Foundation Wine Celebration in honor of Rich and Leslie Frank and in memory of Edythe Frank
When a patient is diagnosed with Follicular Lymphoma (FL) the effect the disease will have is unpredictable. Many patients will do well and live many years. But, some patients will have what are called transformation events.
Transformation is when a new, more aggressive type of lymphoma develops. When this happens patients do not do well. With no way to know which patients will transform, doctors cannot determine the best strategy for treatment. But even if they could predict transformation, it is not clear what the best course of action is since we do not understand the biology of transformation.
Recent research has shown that the non-cancerous cells in a tumor can have a major impact on how the tumor behaves.
These cells can create an environment that either encourages or limits tumor growth. The way cancerous and non- cancerous cells are organized can be thought of as the architecture of the tumor. By comparing the architecture of patients that do and do not transform, we believe that we can find better ways of predicting and preventing transformation. To do this we will employ cutting edge technologies that allow us to precisely measure features of thousands of single cells and look at how they are organized. We will use artificial intelligence to build a new approach to predict transformation using this information. This will also let us learn about the causes of transformation and how to prevent it.
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.
The treatments for head and neck cancers have been revolutionized by the development of immunotherapies. However, many treated cancer patients often experience relapse. Without a clear understanding of why and how cancer cells resists and relapses after current immunotherapy treatment, it is impossible to design a better immunotherapy, and the current treatments for cancer patients eventually fail due to relapse. For advancing clinical outcomes of future treatments, the goal of this proposal is to identify key mechanisms driving cancer relapse from immunotherapy. Recently, we discovered a special group of tumor cells that resemble the stem cells responsible for regenerating normal tissues. Importantly, these tumor cells appear to be the major survivor of immunotherapy treatment and the cause of tumor relapse. This key finding raised the possibility of targeting the critical molecular programs driving the unique immune resistance of these special cancer cells to prevent cancer relapse. In this study we will develop a new immune-oncology platform for head and neck cancer, so we can achieve rapid genetic manipulation of cancer cells directly in live mice. With this powerful approach we aim to identify the stem cells-specific factors that govern both intrinsic and extrinsic immune resistance mechanisms in head and neck cancer. The information derived from this study will pave the way to the development of the next generation of immunotherapy for head and neck cancers with the capacity to overcome relapse.
Volunteer Grant funded by the V Foundation Wine Celebration in honor of Fiorella O’Neill
Every tumor evolves from a single cell. This single cell divides to become two cells, those cells divide to become four cells, and so on, eventually creating the billions of cells that we see in a patient’s tumor. Along the way, individual cells evolve and mutate. As a result, when we look at the whole tumor, many cells look very different from each other. We often don’t know what causes these differences or which differences are important, but we know this diversity is responsible for the drug resistance seen in many patients.
Our goal is to figure out how these differences come to be. The first step is to track the pattern of cell divisions that generate the tumor. The technology we’ve developed records the family relationship between all cells in a tumor. We combine this system with single cell sequencing in mice, mapping tumor development to understand how resistant populations evolve. These maps will allow researchers to design better treatments that target these pre-resistant populations, enhancing our current treatment options.
Funded by the Dick Vitale Pediatric Cancer Research Fund in memory of Austin Schroeder
Over the past decades, the cure rate of pediatric leukemiahas significantly increased because ofimproved understanding of diagnosis, chemotherapy combinations, and supportive patient care. However, patients with MLL-rearranged subtype leukemia still face an unfavorable outcome and few therapeutic options. To date, the five-year survival of patients in this subtype is less than 70%, much lower than most other patients. To better improve the treatment outcome and increase the survival, many novel therapeutic drugs have been identified. Among these drugs,the inhibitors against BET proteins hold a great promise. So far, the mechanisms controlling drug response and resistance are not well understood.To our knowledge, our proposed research fits the goal of the V-foundation. We have conducted a successful genome-wide screen. We are going to study thefunction of novel candidate genes in drug resistance models in vitro and in vivo, as well as the working mechanism.Completing our proposed work is expected to significantly prevent and treat drug resistance and relapse, saving more patients with this deadly disease.
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.
Brain tumors are now the most common cause of cancer-related death in children. Most affected children undergo surgery and receive extensive therapy with toxic substances, yet many will succumb to their disease. It has been a major interest of the research community and pharmaceutical companies to develop more effective drugs that target specific cancer-causing proteins. However, identifying suitable protein targets is often challenging. We question if we can target a different class of molecules called microRNAs. Our work will answer which microRNAs are the most promising targets across different types of childhood brain tumors and how to target them most effectively.
We are developing a novel experimental system that allows us to collectively study the effects of all microRNAs in the human genome. Our system is based on modern genomic and computational techniques that are only recently feasible. This will enable us to identify and test the most promising targets.
We are hopeful that our findings will result in a better understanding of how microRNAs cause brain tumors and will lead to better treatments that help young patients. Better treatments will result in higher survival rates and lower side effects. In the short-term, our basic research study provides molecular rationale and pre-clinical results to further pursue developments. Over the long-term, we hope that our results will lead to novel drugs that will help affected children.
