Funded by WWE and the Dick Vitale Gala in memory of John Saunders
High-risk neuroblastoma (HR-NB) remains a challenge in childhood cancer, with five year survival of only 50%, despite improvements seen from intensive chemotherapy, radiation therapy, isotretinoin, and immunotherapy. Indeed, therapy has reached a maximum tolerable intensity and survivors often have lifelong treatment-related disabilities. Further advances require increased understanding of the fundamental molecular basis of neuroblastoma and the development of more individualized targeted therapies. The New Approaches to Neuroblastoma Therapy (NANT) consortium is an established collaboration between clinical and laboratory investigators which has developed innovative treatments based on identifying novel mechanisms of therapy resistance and targetable genetic/epigenetic abnormalities. Biology studies are part of all clinical trials, and provide samples to collaborating labs to further test and improve their strategies. NANT includes 15 highly motivated and geographically distributed pediatric cancer centers and 4 guest members (including sites in Australia, United Kingdom and France). NANT is the only consortium solely dedicated to early phase trials of novel agents and biomarkers for relapsed/refractory HR-NB. NANT provides the clinical expertise and established infrastructure to translate novel laboratory findings into early phase clinical trials that provide the necessary safety and preliminary tumor response data to inform (inter)national trials to test the impact of NANT-developed therapies on improving patient outcomes. Ongoing translational work in NANT is focused on immunotherapy, targeting specific biologic pathways in tumor cells and in the tumor’s environment that promote tumor survival, and individualizing therapy based on patient-specific variables that change over the continuum of cancer care.
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.
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.
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.
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.
Treatment for children with relapsed leukemia has been transformed by the use of chimeric antigen T-cells (CAR-T), which use a patient’s own immune cells after they’ve been engineered to kill leukemia cells by recognizing specific proteins on cells. Yet, about a third of children will again suffer relapse after CAR-T cell treatment when the leukemia cells stop expressing the target protein on the surface of the cell. This makes the leukemia cell invisible to the CAR-T cells and blunts eradiation of the leukemia. This occurs when the leukemia cells express alternative forms of the target protein. It is not well understood if these alternative forms only occur after pressure of the CAR-T treatment or if they exist already within the patient’s cells and are only revealed after CAR-T treatment. There is suggestion that healthy cells express the alternative protein forms as well. There is need to better understand what healthy cells express the variant protein forms, what their role is in normal cell biology and if leukemia cells, without pressure of CAR-T targeting express these proteins. We will use novel single-cell technologies to examine healthy bone marrow cells and diagnostic leukemia cells to determine if these cells express the variant proteins and to what extent. We will examine how these variant proteins help cells to survive. Finally, we will examine samples from patients treated with CAR-T cells to determine if these cells exist before receiving CAR-T treatment and how the treatment favors emergence of resistant cells expressing variant proteins.
OLE Health, St. Joseph Health Queen of the Valley (Queen of the Valley) and Adventist Health St. Helena (AHSH) are collaborating to nearly triple the number of OLE Health patients between the ages of 50 and 75 receiving colorectal cancer screenings and appropriate referrals to hospital partners for care navigation, additional testing and cancer treatment. Grant funding will enable the countywide consortium to develop and maintain a continuum of care for patients referred from OLE Health for further colorectal cancer diagnostics and care.
Funded in memory of Tony Smith, EdD, Member of the V Foundation Board, 2003-2017
Blood cancers, such as leukemia, often begin in the bone marrow where rare blood-forming stem cells regenerate normal blood cells throughout life. Many blood cancers can be eliminated with chemotherapy, but chemotherapy also destroys normal stem cells. Thus, many cancer patients depend on receiving stem cell transplants after therapy. Sadly, many patients are unable to receive life-saving transplants because of insufficient numbers of available stem cells. One way we can overcome this challenge is to develop ways to grow and expand blood-forming stem cells outside the body, but previous efforts to do so have been unsuccessful. Recently, we discovered that stem cells make new proteins much more slowly than other blood cells, and this slow rate of protein production is crucial for stem cell function. Proteins are the functional products of genes and perform many specialized tasks within cells. Making proteins too quickly increases assembly errors leading to the production of dysfunctional and toxic proteins. In contrast, producing proteins slowly helps ensure that new proteins are precisely assembled, are of high quality and function correctly. We found that growing stem cells outside the body increases the rate of protein assembly and decreases protein quality, which impairs stem cells. We are using new and innovative strategies to enhance protein quality within stem cells that could, for the first time, enable expansion of blood-forming stem cells in the laboratory. These discoveries could provide new therapeutic possibilities for numerous cancer patients.
Each year, around 10,000 patients with Acute Myeloid Leukemia (AML) in the US will die from the disease. About a quarter of AML patients have a particular change in the FLT3 gene. This change leads to a lower chance of surviving the disease. This genetic change causes a FLT3 protein to be defective. Drugs such as tyrosine kinase inhibitors (TKIs) are used to treat the effects of abnormal FLT3 protein (FLT3-ITD). However, they are not very effective.
A particular type of cancer cells called leukemia stem cells (LSCs) is not removed by drugs like TKIs. Researchers think LSCs are responsible for the disease coming back in people with AML. Thus, LSCs with FLT3-ITD are considered responsible for resistance to TKI treatment. Understanding why LSCs are resistant to TKIs will allow us to target these stem cells, and possibly cure people.
FLT3-ITD signals can be changed by modifying the protein in different ways such as methylation. Our studies found a link between methylation of FLT3-ITD and LSC resistance to TKI treatment. Thus, we think that FLT3-ITD methylation helps these stem cells resist drug treatment. We want to understand better how methylation helps LSCs survive. Also, we will test whether a lower amount of methylated FLT3-ITD protein leads to fewer cancer stem cells in test animals. Targeting protein methylation could lead to new ways to treat people with FLT3-ITD leukemia.
Funded by the Stuart Scott Memorial Cancer Research Fund
Tamoxifen is an estrogen-like drug that is used to treat breast cancer patients, breast cancer survivors, and patients with a family history of breast cancer. As a treatment, tamoxifen is extremely effective at decreasing the changes of getting cancer and increasing patient survival. Unfortunately, tamoxifen also causes negative side effects such as hot flashes and bone loss. Because of these concerns, up to a quarter of all patients fail to complete the treatment. The goal of our research is to understand how tamoxifen can cause hot flashes and bone loss. We will use genetically engineered mice to identify the brain regions that mediate the effects of tamoxifen on temperature control and bone density. We will also use cutting-edge molecular tools to determine precisely how these brain regions are affected by tamoxifen. To model the treatment conditions in humans, our studies use females of reproductive age and a long-term treatment using the same dosage given to humans. In the end, our studies will identify the specific areas that are responsible for the negative effects of tamoxifen. This information will help us design and begin to test strategies for alleviating hot flashes and/or bone loss in patients. Any treatments that provide relief from the side effects of tamoxifen will increase patient quality of life, increase the chances that patients will complete their treatments, and ultimately save lives.
