Facilitate the transition of projects from the laboratory to the clinic. Translational researchers seek to apply basic knowledge of cancer and bring the benefits of the new basic-level understandings to patients more quickly and efficiently. These grants are $600,000, three-year commitments
Funded by the Stuart Scott Memorial Cancer Research Fund
Stem cell transplantation is an effective way to treat patients with blood cancers. However, this treatment can cause short- and long-term side effects. These side effects may affect quality of life and increase risks for other diseases. Doctors must balance these risks with the potential for stem cell transplant to cure patients. A risk-prediction model can help with such decisions, but current models are inadequate. Risk-prediction models are often based on a patient’s age, but people of the same age in years may not be alike in terms of underlying health. Underlying health can be estimated with various “biomarkers.” Our proposal is designed to identify a new biomarker that shows whether a patient is fit for stem cell transplant. We are studying clonal hematopoiesis of indeterminate potential (CHIP), a group of genes that indicate the health of a patient’s blood cells. Our hypothesis is that patients with CHIP in the blood before stem cell transplant will have poor outcomes after transplant. To test this, we will use a large collection of blood samples taken from blood cancer patients before stem cell transplant. We also have information about each patient’s health after transplant. We will use DNA sequencing to measure CHIP genes in the blood samples. We will use statistics to compare CHIP in the samples with patient health after stem cell transplant. If these correlate, it will show that CHIP is a good biomarker for use in a risk-prediction model. This will help doctors make personalized decisions that improve the lives of blood cancer patients.
Sarcomas are cancers of bone and connective tissue. These cancers are not very common in people, but they are no less serious than other, more common cancers. One reason there are few new treatments for sarcoma is that their rarity makes it difficult to obtain material for study. To overcome this, we have studied sarcomas in animals, and especially in pet dogs. Dogs share our environment and their risk to develop cancer is about the same as it is for humans. But unlike people, dogs develop sarcomas very commonly. Over the past twenty years, we have found how sarcomas of dogs are like sarcomas of people. This creates opportunities to develop new sarcoma treatments in dog “patients”. For this project, we are studying how we can activate the immune system to kill sarcomas – and specifically bone cancer. Our strategy starts with a virus that infects and kills cancer cells. Because this allows the immune system to recognize the tumor, we can then add a protein to enhance the potency and duration of this immune response. The idea is that the treatment will eliminate the primary tumors and prevent or delay cancerous spread to other organs. We will test our strategy in the laboratory and in dogs with bone cancer in a clinically realistic setting, which will provide avenues to move our findings more quickly to human patients who will ultimately benefit from this therapy.
Over the past several decades, there has been a steady increase in cure rates in children with the so- called B-cell acute lymphoblastic leukemia (B-ALL), a type of blood cancer. Yet many B-ALL patients who failed the initial chemotherapy still die from their disease. Five years ago many of these high-risk patients began to benefit from immunotherapy, whereby patients’ own immune systems are trained to recognize and destroy the leukemic cells. One common form of immunotherapy is based on recognition of CD19, a protein residing on the surface of most leukemic cells. However, even this breakthrough treatment fails in about a third of patients, suggesting that other leukemia proteins need to be targeted in parallel. One alternative protein target is called CD22. CD22-directed immunotherapies show promise, but are not without their own record of failures. Our previous studies led us to believe that one common cause of treatment failure is improper assembly of the CD22 protein, resulting in re-shuffling of its key parts called ectodomains. This re-shuffling could result in CD22 becoming unrecognizable to the immune system. On the other hand, improperly assembled CD22 could be targeted using a new type of immunotherapeutics, which are trained to recognize improper junctions between ectodomains. The proposed work will test these ideas using leukemic cells grown in Petri dishes and in mice and samples from ongoing clinical trials. It will also extend our current studies to other cell surface proteins. In the end, the TVF-funded work would lead to a more precise matching of future patients to best possible treatments and thus much better outcomes.
First year of this Vintner Grant funded by the 2018 V Foundation Wine Celebration in honor of Suzanne Pride Bryan
Approximately 20-25% of breast cancers express the human epidermal growth factor receptor 2 (HER2). These tumors are associated with a high risk of recurrence because of possible resistance to HER2-therapies. Therefore, new therapies are needed to treat this fast growing form of breast cancer.
Poly (ADP-Ribose) polymerases (PARP) inhibitors have been used to treat breast and ovarian cancers with DNA mutations. In addition to its roles in DNA damage repair, PARP1 has other roles such as activation of genes, which control tumor cell growth. PARP inhibitors may be used as a treatment to block tumor cell growth. In this study, we will determine the safety and effectiveness of combining the PARP inhibitor niraparib with the HER2-targeted agent trastuzumab to treat HER2+ breast cancer in a clinical trial. We will also examine tumor tissue samples to help us understand how the treatment effects tumor response. Our goal is to develop better therapies to improve the survival of breast cancer patients who are at high risk of relapse.
JMML is a type of blood cancer that affects infants and young children. The cancer cells cause children with JMML to experience belly pain, have difficulty breathing, and be more likely to have bleeding problems. The only way to cure JMML is to kill off every blood cell using harsh medications, and then use someone else’s healthy blood cells as a replacement, known as a stem cell transplant. This treatment causes many side effects like vomiting, hair loss, and can lead to serious infections. Equally upsetting is that this intensive treatment only works half the time with few children surviving if the transplant does not work.
Over the past several years, we have developed lab tests that predict which patients are likely to respond or not respond to this type of intensive treatment. The first aim of this grant is to turn our research test into a clinical test that can be ordered by any doctor around the country to help them decide how to treat their patients with JMML. Our second aim to test two different, new and safer medications in mice to see what the best way is to combine them. Lastly, the overall goal of this grant is to start a trial that uses the clinical test that we described in our first aim to help pinpoint the patients that will benefit from the two medications in our second aim. We expect that by adding these medications we will improve the lives of children with JMML.
Diffuse Large B-cell lymphoma (DLBCL) is a common cancer in the US, causing tens of thousands of deaths each year and their incidence is on the rise. MicroRNA regulate the use of other genes and they are frequently mutated in human cancer One of these, miR-155 has been shown to be overproduced in several different lymphoma types, including cutaneous T-cell lymphoma (CTCL) and diffuse large B-cell lymphoma (DLBCL). This miRNA is an excellent target for therapy in DLBCL. miRagen Therapeutics, Inc. is currently testing the safety and efficacy of an inhibitor to miR-155 in patients with CTCL and DLBCL. This is an entirely novel class of drug, and as such requires some research into the parameters for successful delivery and monitoring. In this proposal we seek funding to allow studies that would support these clinical trials. We propose to identify biomarkers to help stratify patients to enroll in the clinical trial, biomarkers of response, and to determine the best route of delivery and the best source of tissue for miR-155 detection.
The studies of this proposal will address a central question in personalized cancer treatment. Many recent studies have generated three-dimensional tissue models of human tumors, known as organoids, which can be grown and analyzed in the laboratory. Thus, these organoids can be considered “avatars” of their corresponding patient tumors. However, it is unknown whether drugs that affect organoid growth in the laboratory would have similar effects in patients. If so, patient-derived tumor organoids could be used to predict effective treatment.
We will utilize patient avatars to investigate muscle invasive bladder cancer, a highly lethal disease that is treated by chemotherapy followed by surgical removal of the bladder, which drastically affects quality of life. We will use an approach known as “co-clinical trials” to simultaneously test drug response in the clinic with that of patient avatars in the laboratory. In particular, we will determine whether patient avatars are able to predict which patients who have no residual tumor after chemotherapy can safely avoid removal of the bladder.
We have assembled an outstanding research team to investigate whether the response of patient-derived organoids to chemotherapy in the laboratory correlates with the response of the corresponding patients in the clinical trial. In addition, we will examine whether there are specific genetic alterations that are associated with sensitivity to chemotherapy. Consequently, our findings have the potential to greatly improve the standard of care for patients with muscle invasive bladder cancer.
Synovial Sarcoma is a cancer that affects 800 Americans every year, generally teenagers and young adults. Although it can be cured if caught early, it often spreads though-out a patient’s body making it very difficult to eradicate. A new type of therapy, known as immune checkpoint inhibitors, can unleash anti-tumor immune responses against many types of cancer. But these treatments are not effective against Synovial Sarcomas. We think this is because immune cells rarely enter the tumor, and the few immune cells that are nearby cannot “see” the tumor. We have worked to address this barrier and our early findings suggest that combining checkpoint inhibitors with an old drug called interferon gamma can empower immune cells to eliminate Synovial Sarcoma.
In our new project, we will test the interferon + checkpoint inhibitor combination in a clinical trial. Using tumor and blood samples from patients, we will perform a thorough analysis of both tumor and immune cells in order to learn how to make this therapy work better and for even more patients. While Synovial Sarcoma is a rare cancer, there are other cancer types that seem to be resistant to checkpoint inhibitors for similar reasons, and our findings will likely be broadly applicable.
Cancer typically arises from a very small number of cancer stem cells. Cancer stem cells that survive initial therapy can hide for a long time. Even years after successful treatment, the cancer stem cells can prompt the cancer to return. If the cancer returns after treatment, it becomes much harder to treat, so doctors try to avoid this. On the other hand, killing cancer stem cells has proven to be an effective strategy to achieve long-term cure and to prevent the cancer from returning at a later time. In addition, this strategy helps to improve survival and reduce side-effects of treatment. This proposal studies cancer that arises from cells of the immune system, the so-called “B-cells”. Unlike other types of cancer, stem cells in B-cell cancer have not been identified. As a consequence, the therapies that are tailored to target stem cells in other types of cancer would not work for patients with B-cell cancer. We recently discovered that stem cells in B-cell cancers express a surface molecule, which allows to escape drug-treatment for some time. We have shown that a drug that delivers a poison into the cancer cells has strong effects in animals that bear the human cancer. In addition, we have engineered a patient’s own immune cells to recognize and fight B-cell cancer stem cells. This strategy will help the patient’s immune system to spot and kill B-cell cancer stem cells more efficiently. We will leverage these approaches to improve outcomes for patients with B-cell cancer while at the same time we aim at reducing the burden of side-effects that would come from typical chemotherapy.
RAS is a gene when mutated causes a wide variety of human cancers. However, there is no specific therapy against cancers driven by RAS mutations. Metastatic melanoma is an aggressive skin cancer, and up to a third of cases are caused by RAS mutations. In this study, we propose to develop a specific therapy against RAS mutated melanoma. This therapy involves starting with one drug that optimizes the patient’s own immune system against the cancer followed by adding on a second drug that blocks an overactive cancer-causing pathway driven by mutated RAS. We will first test this therapy in animal models in order to understand the mechanisms. We will then begin to design and initiate a clinical trial to test this regimen in patients whose melanoma harbor RAS mutations. Thus, we will test the hypothesis that distinct drugs when combined in a specific sequence may have dramatic anti-cancer effects not expected of individual drugs.
