Funded by the 2019 Wine Celebration Fund a Need for Canine Comparative Oncology
Glioblastoma (GB), one of the most common tumors of the brain, has no known cure and human patients diagnosed with this awful disease survive an average of 14 months despite aggressive therapy. Our immune system is made to naturally attack foreign materials that invade our bodies, such as viruses, bacteria, or abnormal (tumor) cells. However, many tumor cells, including GB, have the developed the means that allows them to hide from the normal immune response so they can grow and spread inside our bodies. We discovered methods to expose these tumor cells to the normal immune response that then allows killing of tumor cells. We developed a small compound (peptide) that binds to tumor cells and makes them vulnerable to immune cells that can then kill them. In this project, we will devise a method to deposit that peptide into the normal brain tissue around the site of tumor removal that usually contains invasive tumor cells. Then other injections will be given that will stimulate immune cells to attack any remaining tumor cells. This new treatment will be used in pet dogs that naturally develop GB-like brain tumors but are rarely offered effective treatment. If this treatment is successful in dogs, similar treatment will be used in human GB patients.
Funded in partnership with the Kansas City Chiefs Football Club
Modern cancer treatments cause serious side effects and often fail. Cancers often contain rare stem cells that resist treatments and cause the cancer to come back. At that point, cancer becomes even more difficult to treat. In children, leukemia is the most common type of cancer, and treatment failure occurs in about one in four patients. This situation has remained essentially unchanged for decades, which indicates an urgent need to develop new treatments focused on eliminating cancer stem cells.
Two genetic pathways, which are among the most commonly activated in human cancer, interact to drive cancer stem cell development and resistance to therapy. Surprisingly, we found that a certain common chemotherapy drug can inhibit the cancer stem cell driving interaction of these pathways at low doses. Unlike current practice of using this drug to kill rapidly dividing cells, we changed its use to specifically target treatment resistant cancer stem cells in an animal model.
Cancer is normally held at bay by the immune system. Only when the immune system is undermined can cancer take hold. Our results indicate that the immune system can once again be activated against cancer stem cells. How it does so and how we might improve these responses in patients is mostly mysterious. Now, we will use single cell DNA sequencing to obtain a large scale view of immune effects of our new treatment. This will eventually inform the design better treatments.
Gastric cancer is the fifth most frequently diagnosed malignancy in men and women, with nearly 800,000 deaths per year, making it the third leading cause of cancer related death worldwide.Therefore, it is critical to find more effective therapeutic approaches for this disease. Our group has investigated the molecular make up of gastric cancer using large patient cohorts to better understand the differences of molecular markers in gastric cancer and to identify new targets for drug development. Our research was able to find one of the main regulator of tumor growth and spread. This genetic alteration is called lysine methyltransferase 2 (KMT2) which is frequently altered in gastric cancer and a key driver of tumor growth.When normal tissues loses this gene, this tissue can became cancerous by promoting the development of tumor cells. Our group (Wang J, et al., JCO, 2020) was one of the first working on this particular gene and has recently conducted a comprehensive analysis of 1,245 patients with advanced gastric cancer, whose tumors were analyzed using with comprehensive and cutting edge molecular testing technologies. We found that patients with the KMT2 mutation have very unique tumor characteristics such as changes in the DNA repair pathways which makes them very vulnerable to specific chemotherapeutic drugs but also novel targeted therapies. Our project focuses onstudyingwhat the best treatment therapies for this uniquely subgroup of gastric cancer patient will be and explore existing and novel agents to improve outcome in patients with gastric cancer. The goal is that our project will lead to more effective and less toxic treatment options for patients with gastric cancer.
Funded by the 2019 Wine Celebration Fund a Need for Canine Comparative Oncology
Sarcomas are malignant cancers that form in bone and soft tissues (muscle, cartilage, nerves) in many species. Sarcomas are rare and often affect children and teenagers. Outcomes have not changed much in the last 10 years. New treatments are needed to better cure these tumors. Because sarcomas are not common in people, it can be hard to test new treatments. Pet dogs commonly develop sarcomas, and their tumors behave like human tumors. Pet dogs with sarcoma give usa chance to test new treatments that can help both dogs and people.Radiation therapy is commonly used to kill sarcoma cells in dogs and humans but it cannot cure tumors by itself. Radiation therapy can also causean anti-cancer immune response, where the body’s own immune cells kill tumor cells for a short time. In this study, we are exploring a new way to use the immune system to work with radiation therapy to destroy sarcoma cells. We have invented a designer drug specifically for dogs that “kick-starts” the anti-cancer immune response. We expect that this drug will help us improve outcomes for patients with sarcomaswhen radiation therapy is used. We will test this expectation in the laboratory and in pet dogs with sarcomas that need treatment.This project will help uslearn to use a drug like this in people with sarcomas that need radiation therapy.
The goal of “Campaign to Improve Access to Clinical Trials” at the University of Arizona Cancer Center (UACC) is to increase the clinical trial access to a diverse population in Arizona. Dr. Chalasani, Breast Cancer Disease Oriented Team Leader, will oversee the campaign to improves access by involving the breast multidisciplinary team, patient navigators and physician liaisons to develop educational materials and outreach programs. Patients and community physicians will be targeted through proposed outreach programs by developing targeted educational materials. Materials and training will be provided to introduce and educate about clinical trials to patients early by various members of their cancer team. The goal of this campaign is to become a model for other disease teams and cancer centers to implement to improve clinical trial enrollment.
This application focuses upon the need to develop new therapies for stomach cancer, which is the 3rd leading cause of cancer mortality in the world. In our laboratory’s prior studies, we described the patterns of disruptions in the genome (or DNA of the cell) that develop in the stomach cells which become cancerous. The overall hope for this work is that finding the genetic causes of cancer can be a source of development of new targets for guiding cancer therapy. The primary way to try to use genomic understanding of cancer to guide therapy has been to find specific genes which are aberrantly activated in cancer. However, to date, approaches to use this approach to guide therapy for stomach cancer has been largely disappointing despite individual successes. Therefore, this new research program supported by the V Foundation and the Gastric Cancer Foundation aims to develop alternative approaches to use our understanding of the gastric cancer genome to guide development of new therapies. Instead of focusing on the genomic alterations that impact individual genes, we are now pivoting to more broadly evaluating the patterns of genomic alterations and the classes of instability or genomic disruptions that occur in cells. We have developed new approaches to classify the types of genomic disruptions that are characteristic of gastric cancer and then directly connecting these patterns to possible new therapeutic targets. We believe that this work may serve as a critical foundation for novel development of therapies for these deadly cancers.
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.
Leukemia is a cancer that starts in blood-forming cells found in the bone marrow. It is the most common cancer in children and teenagers, accounting for almost 1 out of 3 cases. Despite recent advances in the treatment of childhood leukemia, a substantial proportion of patients are resistant to conventional treatments. For these children, the probability of cure is very low (<30-50%). The best treatment for leukemia patients, especially those who have not responded to other therapies, is stem cell transplant, but the application of this life-saving treatment has been traditionally limited by a lack of suitable donors. The lack of suitable donors is a particular problem in African American or mixed heritage populations because finding a matched donor is less likely in these populations. We have developed a stem cell transplant strategy that greatly increases the number of patients who can receive transplants. However, this strategy cannot provide the critical anti-leukemic and infection fighting functions required to kill all the leukemic cells and is therefore unable to give patients who receive transplants long term cancer-free outcomes. In this project we willperform three clinical trials designed to testthe safety of three innovativecell therapies, which, when givenin conjunction with our stem cell transplant strategy, have the potential to fight leukemia. Our ultimate goal is to identify the optimal anti-leukemic cell product that improve cancer-free outcomes for children with leukemia.
Supported by Bristol-Myers Squibb through the Robin Roberts Cancer Thrivership Fund
Survivors of childhood cancer are at high risk of late health problems related to cancer treatment. Our early work suggested that health problems differ among survivors based on social-economic status like level of education, household/personal income, and the neighborhood in which they live. In the proposed research, we will describe and measure differences in health problems among childhood cancer survivors based on the social-economic status. We will focus on common health problems including obesity, high blood fat levels (triglycerides or cholesterol), abnormal blood sugar control, high blood pressure, heart muscle weakness, and heart attack. We will use stored blood samples and data already available from the St. Jude Lifetime Cohort Study to study biologic changes that may predict a survivor’s risk of health problems and links to social-economic factors. We hope that the results of this work will help identify survivors at higher risk for health problems and guide new research aiming to reduce, reverse, or prevent the harmful effects of social-economic factors on health problems after treatment for childhood cancer.
Supported by Bristol-Myers Squibb through the Robin Roberts Cancer Thrivership Fund
Colorectal cancer starts in the large intestine. It is the second leading cause of cancer death in men and women in the US. Alaska Native people have among the highest rates of colorectal cancer in the world. Alaska Native people also die more often of this disease than any other racial or ethnic group in the US. The reasons for these health disparities are not fully understood.
Almost no research exists on molecular changes in Alaska Native colorectal cancer tumors. In this study, we will look at the genes expressed in these tumors. Genes code for proteins which support normal cell function. Changes to genes may result in abnormal growth of the cells resulting in cancer. Studying gene expression tells us which genes in the tumor may be causing the cancer and will help us understand more about the patterns of gene expression among Alaska Native colorectal cancer patients. We will also examine if tumor gene expression can tell us which patients will live longer with their cancer.
This research will help to identify colorectal cancer patients with aggressive disease at diagnosis. This could help to guide clinical decision making and improve disease outcomes. Also, this research may tell us if Alaska Native colorectal cancer patients might benefit from available or new treatments.
