Of the cancers that affect both men and women, colon cancer is the second leading cause of cancer deaths and the third most commonly diagnosed cancer in the United States. Interestingly, evidence from the clinic links disruption of normal 24-hour rhythms with many diseases including a higher risk of cancer. Our internal clock controls sleep/wake cycles, feeding and metabolism and disruption of the clock has been reported in several cancer types, including colon cancer. Yet, the precise process of clock disruption in colon cancer remains undefined. We are interested in cells that have the ability to initiate tumors because these cells have been found to be treatment resistant. We propose to determine how loss of the clock can promote colon cancer by changing the cues that direct these cells that initiate cancer. To accomplish this, we have generated a mouse model to understand the effects of clock disruption on cell growth in the intestine. We propose that disruption of both the clock and loss of cues that control normal cells in the intestine can result in colon cancer. The goal of these studies is to provide new directions towards clock-dependent treatments that can target colon cancer.
Vintner Grant funded by the 2018 V Foundation Wine Celebration in honor of Karen Aldoroty
Immunotherapy is a very promising new treatment that uses the body’s own immune system to recognize and fight cancer. This research project focuses on immune cells called macrophages, which are a group of white blood cells in the body. Previous studies have showed that when cancer cells grow in the body, they use signals to protect themselves and escape from macrophages. When treatment was given to block these signals, macrophages were able to recognize and attack cancer cells. In the tumors, in addition to cancer cells, there are many other groups of cells including macrophages. Cancer cells can travel from the primary tumors and grow in organs such as the lung, liver and brain. This caused over 90% of cancer patient deaths. Importantly, these organs also have many macrophages. It is very important to examine if and how macrophages can be used to defend against tumor cells and thus to treat cancer. However, there is much that we do not understand about what exactly occurs during these processes. In this study, we would like to understand how macrophages and cancer cells interact with each other and how macrophages decide if or not they should attack tumor cells. This knowledge will be used to develop new immunotherapies that block cancer cells’ protective traits and allow macrophages to attack and clear them.
Lung cancers are often driven by genetic changes. The focus of my research is on a type of lung cancer that is driven by changes in the EGFR gene. This type of lung cancer often occurs in younger patients who are non-smokers. New medications can target these changes. This has allowed patients to live longer. However, patients are almost never cured of their disease. My goal is to understand why responses to these EGFR targeted treatments are almost never curative. Then I will work to identify new medications that can be used together with EGFR inhibitors. This may allow patients to live longer. I will accomplish this goal by identifying all of the genetic changes present in patients’ tumors. This will allow us to understand which ones may be allowing cancer cells to survive. I will also assess tumors for other changes that occur within cancer cells. In addition, I will look at the immune cells that are in the tumor. To summarize, the goal of this research is to identify new combination therapy strategies that can improve the depth and duration of response to EGFR targeted therapies, allowing patients with this deadly disease to live longer.
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.
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