Funded in partnership with the SAGERSTRONG Foundation in memory of Craig Sager
There are trillions of bacteria, viruses and fungi inside each and every human. We call this the microbiome. Scientists have found that the microbiome can change how cancer grows and how people respond to cancer therapies. Our lab wants to make the lives of cancer patients better by improving their microbiomes. The usual ways to change the microbiome are through diet, antibiotics, and by eating live bacteria in food. An example of a food with live bacteria is active culture yogurt. We are doing an experiment to see if a special type of fiber can improve the human microbiome. This fiber is digested by specific bacteria in the gut. When it is digested, it is turned into molecules that control the human immune system. We are giving cancer patients this fiber to see if we can increase these immune system-controlling molecules. If this works, we will prevent the immune system from doing harm in cancer patients. We hope to help patients like those who get blood and marrow transplants for treatment of leukemia or lymphoma. Once we understand how these fibers and our microbes change the immune system, we can figure out precise ways to use this knowledge to make the immune system work better. For example, we may be able to make exciting new cancer therapies, like immunotherapy, work better.
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.
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.
Co-funded with Carousel of Possible Dreams/Friends of Cathryn and the Dick Vitale Gala
Only 45% of children with high-risk neuroblastoma are cured. The New Approaches to Neuroblastoma Therapy (NANT) consortium links laboratory and clinical investigators to develop therapies with high potential for improving survival and performs the first testing of them at 13 neuroblastoma centers. We propose new clinical trials for patients with resistant or recurrent disease that aim to 1) improve immunotherapy; 2) improve chemotherapy by targeting key drivers of the disease; and 3) improve measurement of response and prediction of outcome with a “biomarker” test for blood and bone marrow. We anticipate that these innovative studies will improve survival for children with high risk neuroblastoma.
Children with diffuse intrinsic pontine glioma– a specific brain tumor type- continue to have a dismal prognosis and most children die from this disease within months from diagnosis. Despite multiple national clinical trials, no change in outcome has been achieved over the last several decades. Two potential reasons why we have not made any progress in this disease are a) treatment is not matched to each child’s individual tumor characteristics and b) due to the presence of a tight blood-brain barrier medications given either by mouth or vein are not getting in sufficient enough concentrations to the tumor. To address these issues we are currently conducting a clinical trial through the Pacific Neuro-Oncology Consortium (www.pnoc.us, PNOC003). In this trial we will profile each child’s tumor with state of the art next generation sequencing and determine a treatment plan based on the specific characteristics of the tumor. A specialized tumor board that consists of several neuro-oncologist, pharmacologists and researches with an expertise in next generation sequencing meet and discuss the results and determine a specialized treatment plan, which consists of up to four FDA approved drugs. Specific attention is being paid to the drug brain penetration of recommended drugs. Correlative aims of this feasibility study is to develop patient derived mouse models as well as to test if tumor specific DNA can be detected in blood and be used as a marker for clinical response.
One of the most promising approaches for patients with advanced Ewing sarcoma is the use of therapies directed against the insulin-like growth factor-1 receptor (IGF-1R). Preclinical studies provide strong biologic rationale for targeting the IGF-1R pathway in Ewing sarcoma. Early clinical studies of monoclonal antibodies directed against IGF-1R have demonstrated that patients with relapsed Ewing sarcoma have one of the highest response rates to this class of agents. However, only a minority of patients with relapsed Ewing sarcoma responds to IGF-1R inhibition, though often with dramatic clinical responses.
Based on these promising results, the clinical development of IGF-1R inhibitors for patients with Ewing sarcoma is a high priority. The Children’s Oncology Group (COG) is soon to activate a randomized phase II trial for patients with newly diagnosed metastatic Ewing sarcoma to compare standard multiagent chemotherapy to this same chemotherapy with the addition of an anti-IGF-1R monoclonal antibody. I will chair this important clinical trial that has the potential to transform the care of patients with metastatic Ewing sarcoma.
A major component of this trial will be an evaluation of potential predictors of patients with metastatic Ewing sarcoma who are most likely to benefit from IGF-1R inhibition. Identification of these predictors is absolutely critical since data from patients with relapsed Ewing sarcoma suggest that that only a subset of patients will respond to this therapy. This trial provides an ideal and unique opportunity to investigate potential predictive markers of response to IGF-1R inhibition in this disease, both because it is a randomized trial and because it will be the first large-scale evaluation of IGF-1R inhibition in patients with newly diagnosed Ewing sarcoma.
All 126 patients enrolled to the trial will participate in the correlative studies. By evaluating these potential markers in patients treated with and without the IGF-1R inhibitor, we will be able to distinguish prognostic markers from markers that are predictive of response to this targeted therapy.
We will assess several promising markers in this trial, including:
Tissue markers of IGF-1R expression and IGF-1R pathway activation;
Expression of IGF-1R on bone marrow tumor cells at diagnosis and over time in response to IGF-1R inhibition;
Serum markers of the IGF-1R pathway at diagnosis and over time in response to IGF-1R inhibition, including IGF-1, IGF-2, IGFBP3, and growth hormone; and
The COG has funds to conduct this trial, but does not have funds to support the critical embedded correlative biology studies embedded within this trial. Therefore, we are seeking funds to support processing and analysis of samples obtained. Some of these funds will be used directly at UCSF as the evaluation of bone marrow tumor cells is performed at UCSF using only fresh samples. Additional funds would be used by the COG Biopathology Center at Nationwide Children’s Hospital in Columbus, Ohio to support the processing of samples into serum and DNA for testing.
Children with diffuse midline gliomas continue to have a dismal prognosis and most children die within one year of their diagnosis. Decades of clinical research and hundreds of clinical trials have not been able to change the outcome for these patients. Studies have shown that the majority of these tumors carry a specific mutation referred to as H3.3K27M which is present in almost all tumors cells making this a very attractive target for immunotherapy approaches.
Within this proposal we are aiming to assess the benefit of a specific immunotherapy approach referred to as T cell receptor approach. We have been able to show in the laboratory that this approach is able to kill H3.3K27M tumor cells very effectively. Based on our exciting animal data, we propose to test this new therapy approach in clinic. Subjects whose tumors carry the H3.3K27M will undergo collection of their own T-cells prior to start of radiation therapy, which is considered the standard of care for these tumors. These T cells will subsequently be modified in the laboratory to specifically recognize the specific H3.3K27M mutation. These modified T cells will then be given back to subjects once they completed radiation therapy.
Within this project we will assess if such a therapy approach is feasible and safe. This project has the potential to significantly impact the treatment approach for a disease for which we have not achieved any improvement for the last several decades and is the first of its kind for this devastating disease.
My research interest is cancer genetics with an emphasis on clinically relevant questions that will improve our understanding of the cancer genetics of clinical phenotype and simultaneously improve patient care in oncology. I have extensive bench research experience in the fields of genome sequencing technology development, human genetic analysis through human genome sequencing and molecular assay development. My research benefits from the various innovations in genomic and genetic technologies that my group has developed.
Nearly 1 million individuals in the United States have inherited mutations in the BRCA1 or BRCA2cancer susceptibility genes and have a very high risk for several cancers, including breast and ovarian cancer in women. Although clinical screening in individuals with known genetic risk can help identify cancers early when they are potentially more curable, this approach is imperfect. Therefore, there is an urgent need to identify ways to better detect and treat cancers in this high risk population. Like most cancers, those that arise in BRCA1/2 mutation carriers have an unstable genome.Manytypes of genomic instability are initiated by DNA breaks, particularly in BRCA1/2 carriers, as these genes are normally involved in DNA repair. Understanding how DNA breaks arise and are repaired is thus critical for understanding how cancer arises, and for developing therapies that specifically kill cancer cells or prevent their development.Our work indicates that when genomic DNA is transcribed into RNA, the RNAand DNA may get tangled, creating RNA-DNA hybrid molecules, or R-loops, that cause the DNA to be broken. BRCA1 and BRCA2 proteinshelp prevent R-loop formation. This raises the possibility that BRCA1 and BRCA2 prevent breast cancer development by regulating the formation of R-loops. In this proposal, we will explore what BRCA1 and BRCA2 do at R-loops, determine where R-loops form in cells without these genes and explore the possibility of using RNA-DNA hybrids as early, sensitive markers of cancer to improve detection and treatment.
