State: California

Funded in partnership with Quad W

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.

Funded by 2015 Wine Celebration Fund-A-Need

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.

Funded by the Gastric Research Foundation

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.

Funded by 2017 BRCA Fund-A-Need

Nearly 1 million individuals in the United States have inherited mutations in the BRCA1 or BRCA2 cancer 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. Many types 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 RNA and DNA may get tangled, creating RNA-DNA hybrid molecules, or R-loops, that cause the DNA to be broken. BRCA1 and BRCA2 proteins help 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.

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.  

Funded by Hooters of America, LLC

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 by the Gastric Research Foundation

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. 

Funded by Bristol-Myers Squibb

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.