Almost all of our knowledge about cancer and medicine is about the proteins that are encoded by only 2% of human genome (the DNA that is contained in our chromosomes and carries the program for making our cells and controlling them). However, in the recent years the scientific world has been transformed by the revelation that significant parts of our genome are expressed as molecules called long noncoding RNAs (lncRNAs), which do not code any proteins, but nevertheless play critical roles in normal and diseased conditions. LncRNAs are critical for gliomas, reveal novel molecular mechanisms of cancer progression and are new targets for therapy. LncRNAs are expressed in different subtypes of gliomas at higher or lower levels compared to the surrounding normal brain, and this makes them useful as novel markers that may help in diagnosis and in predicting outcome for the patient. So far only a few lncRNAs associated with gliomas have been functionally characterized, and even less is known about their mechanisms of action and their usefulness as markers. In this collaboration between Drs. Dutta and Abounader we will focus on novel lncRNAs- H19, LINC00152 and several TUCRs, that are differentially expressed in gliomas and that influence the way a glioma behaves. Our objective is to determine the mechanisms by which these RNAs affect glioma biology, get a comprehensive catalog of all TUCRs that are differently expressed in gliomas and to determine whether targeting these lncRNAs will be therapeutic for gliomas.
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.
Participation in breast clinical trials ranges from about a low of 0.5% to a high of 2-3% in patients with breast cancer. The majority of these trials have involved surgery, chemotherapy, and radiation all with substantial side effects but even when the safety profile is minimal these trials have not appealed to patients. More recently it has become clear that the immune response plays a large part in determining how well someone does when diagnosed with breast cancer. It is even possible now to utilize that immune response in the blood to predict response to therapy and predict recurrence. This means that the immune response can be used to predict cancer development, predict response to therapy and possibly improve outcomes by manipulating the immune response using immune stimulants, vaccines, cell therapies, and adoptive cell strategies to bolster the immune response to prevent recurrence. The purpose of this project is to develop an educational program in the burgeoning field of breast immunoncology for breast cancer oncologists and other physicians, patient advocates, patients and care givers to improve awareness about the immune response in breast cancer and how we can use the immune response to optimize our current therapies and where additional immune manipulations will improve outcomes. Our goal is to increase awareness about clinical trials in breast immunotherapy that ultimately increase patient accrual on studies and more rapidly move these promising modalities to clinically useful treatments for all patients with breast cancer.
The purpose of our project is to create educational materials that can be used to increase the awareness of a minority populations of the benefits of cancer clinical trials. Our expectation is that an increased awareness will help make cancer clinical trials more understandable and will increase the likelihood that they will be considered as an excellent option for minority cancer patients needing therapy.
In order to create the educational materials, we plan to bring together a multidisciplinary group of cancer providers which will include physicians, nurses, social workers, and cancer research coordinators. This group will help develop the educational information. In addition, we will also bring together minority cancer patients to advise us as to potential concerns or barriers that minority patients may have in regards to clinical trials. In this way we will be able to address those concerns in our educational materials.
Utilizing the information that we will obtain from these activities, we plan to create an educational video that can be distributed and shown to minority cancer patients that will help them have a deeper understanding of the benefits of cancer clinical trials. This approach will be applicable across all cancers.
Neuroblastoma is the second most common tumor in childhood accounting for 7% of all children with cancer. There are about 800 new cases of neuroblastoma each year in the US. Treatments for neuroblastoma include surgery when tumors are localized or chemotherapy and radiation therapy when tumor spreads to other parts of the body. Cure rates are high for low-risk children, but only about 50% for high-risk children such as those whose tumor has spread. For these reasons, neuroblastoma is still the deadliest cancer in the childhood. With our research we aim at increasing the cure rates of neuroblastoma, particularly in high-risk children. To achieve this goal, we will harness the immune system of the children by instructing their lymphocytes to specifically identify a molecule called ALK in tumor cells. To obtain the highest potency and accuracy, we will exploit not only one immunotherapy, but rather a novel dual immunotherapy that will combine a cancer vaccine with engineered lymphocytes, both primed to recognize the same ALK target on tumor cells. This novel concept of dual immunotherapy will be tested in mouse models of neuroblastoma and will provide essential information on how the immune system can be exploited to target this tumor. These findings will lay the foundation for future clinical trials that will exploit this dual immunotherapy approach in children.
The University of Arizona Cancer Center (UACC) Arizona TrialRunners aims to increase the number and diversity of breast cancer clinical trial participants through a culturally relevant outreach and education campaign. Directing the campaign is Dr. Elizabeth Calhoun, Associate Director for Population Sciences at the University of Arizona Cancer Center, along with the support of nurse and outreach navigators to target breast cancer patients, as well as physician liaisons from Banner Health and Dignity Health to reach community physicians and members beyond the UACC’s established patient catchment area. The collaboration leaders of Arizona TrialRunners are developing a strategic plan to improve the participation from persons that are not typically enrolled in clinical trials, such as racial and ethnic minority populations, the elderly, and the underinsured. Innovative engagement techniques include creating an environment of awareness for all faculty, staff and patients to improve effective clinical trial recruitment strategies for UACC and its statewide partners. Arizona TrialRunners hopes that this campaign will become a model for cancer centers to execute in an effort to improve expansion of clinical trial enrollment and to improve health outcomes.
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.
V Scholar Plus Award – extended funding for exceptional V Scholars
It is now clear that our immune system has the capacity to both recognize and destroy cancer cells. Unfortunately, tumor cells escape this immune-mediated destruction by activating inhibitory switches to turn off T-cells. These switches, called immune checkpoint receptors (ICR), are now being targeted in early-phase clinical cancer trials in hopes of restoring and boosting immune-targeted killing of cancer.
However, despite showing promise in animal models of cancer, it remains unclear whether drugs targeting more recently identified ICRs will work in humans. Most importantly and a major focus of this proposal, while ICR therapies were previously assumed to bind and target only immune cells as noted above, our data newly identifies ICR expression directly on cancer cells along with therapeutically promising anti-cancer as well as pro-tumorigenic activities. What’s more, levels of cancer cell-ICRs could be dynamically regulated by cytokine stimulation. Overall, these findings raise unanswered questions on ICR-specific drug safety, specificity, potency and optimization that challenge existing, even false, assumptions within the immunotherapy field and invite further inquiry of these entirely unexplored tumor-intrinsic pathways.
This interdisciplinary proposal functionally dissects one particular tumor cell-expressed ICR and its undiscovered roles in cancer progression. As our seminal data reveals that it powerfully regulates cancer growth and metastasis, this research lays the groundwork for developing innovative drugs to block cancer advancement. Results will not only raise awareness of unanticipated impact of ICR drugs on a new tumor-intrinsic pathway but also invite further scientific and therapeutic inquiry and exploitation of this undefined pathway in cancer.
Brain cancer is now the No. 1 cause of cancer-related deaths in children. A tumor known as pediatric high-grade glioma (PHGG) is the most deadly type. Even though children with PHGG get intense treatment, including surgery, radiation, and chemotherapy, most patients still die within two years of their initial brain cancer diagnosis. Part of the problem is that PHGG tumors are not all the same. However, our research has recently identified a clear group of PHGG tumors in which there is damage to the system of proteins that promote healthy cell growth. The system is supposed to work like the accelerator and brake pedals of a car, allowing the body to keep cell growth in control; but when gene mutations produce bad proteins, the system behaves as though the accelerator is stuck and the brakes have failed. The system becomes overactive and promotes unstoppable tumor growth. This system, called PI3K/AKT, is also a factor in many other aggressive cancers. We think that restoring the proper function of PI3K/AKT is possible and could halt or even shrink PHGG tumors. Our proposed research will test and validate new therapies to do this.
