One of the greatest challenges in cancer treatment is that response to standard chemotherapy is frequently incomplete and fraught with adverse events. Current treatments are often ineffective because they function as a “one-size-fits-all” approach to a very diverse disease. This lack of success is magnified in triple negative breast cancer (TNBC), whose large and diverse group of subtypes greatly increases difficulty in treating a disease that makes up 15% of all breast cancers and disproportionately affects African American and Hispanic women. The goal of our project is to address these challenges by identifying and characterizing specific tumor vulnerabilities in TNBC to pave the way for novel combined chemotherapeutic treatments. By screening through each gene in the genome, we have found that TNBC cancers rely on a protein called SIK2 for their survival. We are working to understand why SIK2 is essential and to use inhibitors of SIK2 function to reduce TNBC tumor survival.
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 remains a major cause of cancer mortality worldwide, and in 2017, 155,870 people are expected to die from lung cancer in US. African Americans have the highest lung cancer incidence and lung cancer-related death rate and develop the disease at an earlier age compared to other racial groups. African Americans also have poorer survival, because of limited access to lung cancer screening, adequate healthcare, and appropriate therapeutic interventions. Etiology studies suggest that such a disparity in lung cancer may be due to genetic susceptibility, in addition to environmental exposures to cigarette smoking, radon, asbestos, and arsenic. Recently, we identified a novel gene, DCAF4, through a large-scale meta-analysis in Caucasian populations, which is likely to be involved in cell-cycle control and DNA damage response that is relevant to African Americans as well. Our hypotheses are that dysfunctional DCAF4 impacts cancer initiation and progression by altering multiple cellular processes and that DCAF4 functional variants alter gene expression and tumor cell phenotypes, which may explain racial disparity in lung cancer. Therefore, we proposed to study the functions of this gene and its risk-associated genetic variants on cellular phenotypes in lung cancer cells, animals and human clinical samples of lung cancer. We will test the hypotheses that dysfunctional DCAF4 impacts cancer initiation and progression by altering multiple cellular processes and that DCAF4 functional variants alter gene expression and tumor cell phenotypes. By including clinical samples from both Caucasians and African Americans, we hope to identify genetic markers for disparity in lung cancer.
V Scholar Plus Award – extended funding for exceptional V Scholars
Estrogen receptor positive (ER+) metastatic breast cancer (MBC) remains the most common cause of breast cancer death. Though we have made many advances in the treatment of ER+ MBC, patients invariably develop resistance to therapies. The mechanisms of resistance are not well known. In order to improve survival for patients with ER+ MBC, it is critical to develop an understanding of this resistance.
We recently found that in 7% of metastatic tumors from patients with resistant ER+ MBC, a gene called the retinoblastoma tumor suppressor (Rb) had been deleted. Loss of the Rb gene resulted in resistance to multiple agents used for ER+ MBC. ER+ MBC that lacks Rb likely represents a growing subset of patients in whom standard therapies do not work and in whom we do not know the optimal therapies. Therefore, it is critical to develop novel approaches to treating this subtype of ER+ MBC.
The goal of this research is to better understand Rb loss in ER+ MBC and identify new therapeutic strategies. To do this, we will utilize cell line models we have generated that approximate ER+ MBC that has lost the Rb gene. We will characterize these cell lines to identify how they become resistant to therapies, and identify novel therapeutic targets to prevent or overcome this resistance. At the completion of the project, our results should enable the development of clinical biomarkers of response and resistance for patients with ER+ MBC, and, ultimately, the design of clinical trials of therapeutic approaches and rational drug combinations.
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.
Funded by the 2016 V Foundation Wine Celebration Fund-A-Need for Prostate Cancer
Nearly all patients with metastatic castration resistant prostate cancer (mCRPC) develop resistance to androgen targeting agents and ultimately succumb to their disease. Recent discoveries by our group and others have demonstrated that a significant proportion of these patients harbor somatic or germline genomic defects in DNA repair defects, and targeting this genomically defined subset with therapies affecting this pathway may impact patient care. The goal of this project is to definitively characterize the genomic and functional landscape of DNA repair defects in mCRPC, clinically test the hypothesis that tumors harboring DNA repair defects preferentially benefit from immune checkpoint blockade, and explore innovative strategies to augment the efficacy of these agents through genomic and preclinical approaches. The project described herein is the first to comprehensively bridge the DNA repair and immuno-oncology fields to directly impact patients with advanced prostate cancer. We propose an integrated strategy that leverages advances in clinical genomics, trial design, and preclinical modeling methodology pioneered by our team. Furthermore, our proposal will be the first to specifically enable immune checkpoint blockade treatment strategies for mCRPC. In summary, this project will catalyze our understanding of how DNA repair defects impact advanced prostate cancer, and how deep knowledge about these events may enable clinical development of a transformative new class of immunotherapies that are greatly needed for advanced prostate cancer patients.
Significant progress in the field of breast oncology has been made with information gathered from clinical trials. Minority patients account for less than 10% of clinical trial participants. African American and Hispanic American patients only comprised 10% and 5%, respectively, of all participants in the ACOSOG Z0011 trial for early breast cancer. Barriers to participation of minority patients include; the lack of awareness of clinical trials, an unwillingness to participate, and the need for a more labor intensive approach to enrollment. Recruitment strategies to increase minority patient enrollment include involving families and patient navigators for outreach and education, utilizing internet resources, and making physicians more aware about the up to date clinical trials available at their institution. The AVON Comprehensive Breast Center at Grady Memorial Hospital is a safety net hospital that primarily serves an urban, inner city population, where 85% of patients are African American. The goal of this study is to (1) identify the potential motivators and barriers of African American patients towards clinical trial participation at an urban hospital and to (2) identify the optimal communication strategy specific to this population, that can be employed to help increase minority clinical trial enrollment.
Funded by the Coopers Catch fundraiser, Tampa Bay Lightning Foundation and Dick Vitale
Melanoma arising in young patients (under age 21) has becoming an increasingly major problem in the US. Very little is known about the specific causes of melanoma in younger individuals, and the prognosis is very difficult to determine. In many cases, even whether a mole is benign or malignant is in question, adding to the stress of a difficult situation for patients and families. Newer molecular tests, developed for analyzing other forms of cancer, could potentially help establish the diagnosis, prognosis and treatment for patients, but these tests have not been validated in young patients and are usually not covered by insurance – forcing families to pay out-of-pocket when and if they can. Moffitt Cancer Center is one of the world’s leading centers for diagnosis, treatment and research in melanoma in children, adolescents and young adults. This project will involve molecular testing of the tumor specimens from patients under 21 who have known or suspected melanoma, avoiding out-of-pocket expenses for unproven technology, and the results of these tests will be correlated with standard pathology analysis and the results of medically necessary surgery (such as wide excision and sentinel node biopsy) and/or medical treatments (such as immunotherapy). The results will set the stage for larger efforts to discover why melanoma occurs in such young individuals, and for the validation of clinical tests to determine how patients should be treated – which could then be used to support insurance coverage for those tests that are most helpful.
Funded by the Coopers Catch fundraiser, Tampa Bay Lightning Foundation and Dick Vitale
In the 1970’s, cancer in children and young adults was almost always fatal. To address this, pediatric cancer doctors across the United States joined forces to do research as a group so they could figure out the best way to treat the cancers in this population. Through over 40 years, these research studies (also called clinical trials) have enabled pediatric cancer doctors to raise the cure rates to nearly 90%. That still means 1 of 10 children with cancer will unfortunately die. Over the years research has shown that children that enroll on clinical trials may have better survival than those that do not, and only around 40% of children enroll on treatment studies. A major reason some families do not enroll their children is that they are not properly educated by the medical team. In addition, African-Americans and Hispanic patients enroll at lower rates than Caucasian patients for several reasons, an important one being education about what clinical trials are all about. This project will create bilingual educational materials to teach families and patients about research protocols and their purpose. They will be less intimidated and more willing to allow their children to have access to the most cutting edge therapies and other studies available. We hope that these materials will lead to increased clinical trial participation and consequently greater cure rates.
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.
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