V Scholar Plus Award – extended funding for exceptional V Scholars
Ewing sarcoma is the second most common bone cancer in children and is a very aggressive cancer with a rate of survival of only 60-70%. One important path to finding new treatments for this disease comes from the fact that all Ewing sarcoma cases have an abnormal fusion protein known as EWS-FLI1 which activates genes that drive the formation of tumors. In a prior study we characterized the genes that are activated by EWS-FLI1 in Ewing sarcoma and identified the kinase VRK1 as a promising new therapeutic target. We have also demonstrated that inactivation of VRK1 results in a strong reduction of Ewing sarcoma growth. In this proposal our goal is to characterize the role of VRK1 in Ewing sarcoma and to better understand the mechanisms that regulate its expression in these tumors. These experiments will validate the potential of VRK1 as a therapeutic target and will point to molecular pathways that account for its importance in this disease.
Queen of the Valley Medical Center (QVMC) in collaboration with OLE Health and St. Helena Hospital (SHH) will develop and launch a countywide colon cancer screening initiative. This integrated effort will ensure timely diagnosis and access to treatment and care for patients regardless of health insurance status. OLE Health will provide the outreach to patients, administer the FIT test and refer patients to Queen or the Valley Medical Center or SHH as indicated for further testing and treatment. Queen of the Valley will collaborate with OLE Health to identify patients that may also be candidates for clinical trials or research. The three organizations will work together on shared messaging to the community to raise awareness about the collaboration and opportunity for cancer screening.
This V Foundation grant will stimulate an innovative countywide “new” system of care between OLE Health, Queen of the Valley and SHH utilizing cancer nurse navigators to ensure a warm hand off and a solid continuum of care. Queen of the Valley Medical Center Patient Navigator role will support and link the continuum of care for patients referred from OLE Health for further cancer diagnostics and care as appropriate. This grant will be used to hire staff and support other components of patient navigation. Queen of the Valley Medical Center believes that our cancer patients deserve the very best in treatment – more cures, and better quality of life.
V Scholar Plus Award – extended funding for exceptional V Scholars
Cervical cancer is responsible for 15% of cancer-related deaths in women worldwide, with highest frequency occurring in resource-limited settings. In addition, incidence and mortality rates are disproportionately higher in African-American and Hispanic populations within the United States, compared with other ethnic/racial groups. Many patients die of cancer either because it spreads to other body organs (metastasis), or because the cancer grows again in the same organ (recurrence). In cervical cancer, 90% of recurrence cases occur within 3 years of diagnosis, and less than 5% of these patients survive beyond 5 years. It is therefore essential to find ways to predict the likelihood of tumor recurrence in order to improve the management and prognosis of cancer patients. We hypothesize that the biological events that lead to tumor recurrence are already at play, even at the time of treatment. In particular, we believe that several biological molecules (human, viral and bacterial) play role in this complex process. We therefore seek to identify and compare these factors in surgically removed cervical tumors and their adjacent normal tissues between 2 groups of women: those with tumor recurrence within 3 years of surgery, and those without recurrence despite longer follow-up. We hope to identify differences in the relative abundance of these biological molecules that will serve as sentinels (we call them biomarkers) to warn us of the likelihood of tumor recurrence. This work has the potential to lead to the development of diagnostic tools for predicting and preventing recurrence in and beyond cervical cancer.
OLE Health will focus on increasing the number of patients successfully completing fecal immunochemical test (FIT) tests for colorectal cancer screening, and providing referrals for the patients determined to need follow-up tests and treatment. Cancer screening is the crucial life-saving step needed to ensure early detection and treatment. It is particularly important to OLE Health patients because screening rates are generally lower in Hispanic/Latino populations, and Latinos represent 62% of OLE’s patients. In addition, 88% of OLE patients are uninsured, on Medi-Cal, or Medicare. According to the American Cancer Society’s Cancer Facts & Figures 2015, “Uninsured patients and those from ethnic minorities are substantially more likely to be diagnosed with cancer at a later stage, when treatment can be more extensive, more costly, and less successful.
Cancer therapy has undergone a revolution in recent years as a result of the success of several immunotherapies, providing hope to patients with once-thought incurable cancers. One of the most powerful technologies is engineered T cell therapy. By reprogramming a T cell, a type of immune cell, to recognize and kill a cancerous cell, we have seen remissions in over 90% of children and young adults with very resistant acute lymphoblastic leukemia (ALL). Because T cells are living cells, they have the potential to last in the body for months or years and may provide long-term disease control. While most of these remissions are long-lasting, with 60% of responding patients still in remission at 1 year, relapse remains the key mode of treatment failure. One of the reasons for relapse is short lifespan of the engineered T cells in some patients. In this study, we will ask why T cells live many months to years in some patients while they live only weeks to a few months in others. We will use this information to open a clinical trial to test the combination of engineered T cells with a medication to augment T cell function. As we improve on the percentage of long-term remissions, we hope to not only increase the chance of cure but also reduce the number of patients who require intensive therapies, including bone marrow transplant.
Funded in partnership with the Kansas City Chiefs Football Club
Recent successes demonstrate the power of using the immune system clinically to destroy cancer. One such therapy involves the infusion of cells called natural killer (NK) cells. This therapy works well for blood cancers. However, there has been limited success with this therapy against solid cancers. The ultimate goal of our research is to increase this efficacy. NK cell killing occurs when receptors expressed on the NK cells are bound. One of these receptors, Natural killer group 2 member D (NKG2D), plays a critical role in the killing of cancers in both mice and humans. My lab has recently generated data that indicate there is a role for NKG2D-binding partners expressed on NK cells in cancer destruction. We demonstrate that upon activation, human and mouse NK cells express these binding partners on the cell surface. We further show that this alters the secretion of factors that play critical roles in cancer destruction. We propose to test the hypothesis that expression of these NKG2D binding partners alters the ability of NK cells to kill cancer cells and that manipulation of this expression can be used to increase the efficacy of NK cell therapy. We will use mouse models to test this hypothesis with both mouse and human NK cells and cancers. At the completion of these studies we will know 1) whether expression of NKG2D binding partners by NK cells affects NK cancer therapy and 2) whether manipulation of this expression is likely to increase the efficacy of clinical NK therapy.
Funded in partnership with St. Baldrick’s Foundation
Alveolar rhabdomyosarcoma is one of the most common children tumors. Traditional dogma is that a particular molecular event is unique to the tumor, like a “signature”. We recently found the same event in normal cells, with a physiological function. This discovery raises the possibility that the tumors initiated from the same cells that harbor this “signature” fusion during normal development. Like fingerprints at a crime scene, this molecular event is giving us clues about the process of tumorigenesis. We will figure out the meaning of this signature molecular in normal development and how its’ going awry will drive rhabdomyosarcoma. In addition, cells at the same development stages harbor several other fusions that are also present in alveolar rhabdomyosarcoma. One of the newly identified fusions led us to uncover a potential new oncogene, which drives the tumor. Our finding will not only lead to better understanding of the tumor, but also have the potential for uncovering new treatment for the disease.
Although childhood cancer survival rates have improved over the past 40 years, pediatric acute myeloid leukemia (AML) is still very difficult to treat successfully. This is partially because the immune system has a hard time recognizing and killing AML cells. Though white blood cells usually fight infections or cancer, certain types of “tumor-permissive” white blood cells (APCs) make it easier for cancer to escape being recognized by the immune system. These tumor-permissive APCs send out signals to other immune cells telling them to relax and not kill leukemia cells. Our research goal is to find ways to make these APCs stop sending tumor-permissive signals, so that the immune system can recognize AML cells better and get rid of the leukemia. Specifically, we found that APCs use a protein called MerTK to send tumor-permissive signals to other immune cells. When we block MerTK using a new orally-active drug, APCs stop sending tumor-permissive signals and instead, start sending new signals that tell other immune cells to fight leukemia. MerTK drugs are headed to clinical trials for their anti-cancer effects; our research demonstrates that these drugs could also be used to boost the immune system against cancer. With this grant, we will investigate the cellular steps involved in blocking MerTK, so that we can determine how to use MerTK inhibitors most effectively to treat pediatric patients with AML. We hope to show that this novel therapy will help improve pediatric AML survival rates and patient’s quality of life.
There is much controversy about the best age to begin mammograms (age 40 or 50?), and how often to do them to improve women’s health. National mammogram guidelines from various organizations give differing recommendations, causing much confusion for women and their health care providers. The University of California and the Sanford Health System (in South Dakota) launched the Wisdom Study to try to come up with a better way to help women determine what mammogram schedule is best for them.
The Wisdom Study compares annual screening to a personalized screening approach. Women in the personalized screening arm of the study receive a screening recommendation based on their individual risk factors (age, personal and family history, genetic risk factors, and breast density). We are comparing the two strategies to determine if personalized screening is as safe as annual screening, as assessed by no increase in diagnosis of Stage 2B breast tumors, and if it will reduce false-positive results and over diagnosis. We will also determine if personalized screening is readily accepted by women and if knowledge of their own risk and the reason for less screening will reduce or at least not increase anxiety about breast cancer. If the trial is successful, we anticipate benefits to women of screening age will include: 1) fewer women suffering from anxiety and stress of false positive mammograms and unnecessary biopsies; and 2) women gaining a realistic understanding of their personal risk of breast cancer, which may reduce general worry about breast cancer.
Funded in partnership with the Lung Cancer Initiative of North Carolina, utilizing Stuart Scott Memorial Cancer Fund matching funds, and the Richard Jones Fund for lung cancer
Lung cancer treatment has dramatically changed, particularly with the introduction of immunotherapies aimed at jump starting a patient’s immune system to fight cancer. Along with the development of new treatments, biomarkers have become increasingly important to disease sub-typing and evaluation. EGFR, ALK, and ROS1 are genes that can be mutated in patients with non-small cell lung cancer and serve as biomarkers. An individual’s tumor may have one or many mutations. The mutational landscape of the tumor has been shown to be an important determinant of response to immunotherapy. PD-L1 also serves as a biomarker, but there have been mixed results as to whether PD-L1 is appropriate for selecting immunotherapy treatment. Microsatellite instability (MSI) and mismatch repair (MMR) are new markers and may also predict response to therapy. Combinations of new and existing biomarkers may be better indicators of response to immunotherapies.
Many factors may contribute to the complex makeup of a patient’s immune response and each patient’s response may differ. Factors that may influence response include the patient’s own baseline immune landscape, age, gender, race, or environment.
Assessing biomarkers from patient’s blood and tumor samples may guide immunotherapy selection and treatment duration to optimize overall patient benefit. This study will assess the predictive utility of our blood immune response test to select patients appropriate for immunotherapy, as well as manage treatment over time. Of importance, this study will assess samples across patient populations, including African Americans, longitudinally and will evaluate differences in immune landscapes and how biomarkers may determine treatment.
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