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.
A new form of treatment for cancer is to activate a patient’s own immune system to recognize and destroy tumor cells. Called cancer immunotherapy, this strategy has proven to have a remarkable impact on long-term survival for patients with a wide range of cancer types, but only a subset of individuals has sustained responses that can lead to a long-term cure. In order to advance cancer immunotherapy, it is critical to understand the immune signals responsible for robust tumor immunity.
One key part of the immune response to cancer is a cellular protein named STING (Stimulator of Interferon Genes) that allows immune cells to detect DNA derived from tumors. STING naturally responds to drug-like small molecules, and an exciting new area of study is the idea of “STINGing cancer” – using compounds that specifically activate STING to boost tumor recognition and patient responses to cancer immunotherapy. In spite of the clear role of STING in immune cell responses, STING signaling is poorly understood and we do not understand how signaling leads to improved patient responses.
Our research will determine how STING transmits signals to the immune system and which STING signal is critical for combating cancer. These experiments will provide the foundation for the design of next-generation drugs that target STING and, ultimately, will help us understand how to use cellular proteins like STING to better control human immune responses and treat cancer.
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.
Funded by Team V runner Jack Daly’s fundraising efforts in loving memory of his wife, Bonnie
In 2016, pancreatic cancer overtook breast cancer to become the third leading cause of cancer related death in the United States. Therapies used to treat pancreatic cancer to date have provided limited benefit, indicating that an improved understanding of complex mechanisms of disease progression are needed to develop more effective therapeutic strategies. Pancreatic cancer is characterized in part by an exuberant fibrotic and inflammatory reaction which infiltrates and surrounds tumors, together known as the tumor microenvironment. The pancreatic tumor microenvironment both creates a harsh environment for cancer cells to grow, by limiting blood flow and nutrient availability within the tumor, but also provides factors that enable cancer cells to survive and adapt in the context of this nutrient-poor, challenging microenvironment. I hypothesize that particular cells within the pancreatic tumor microenvironment known as stellate cells, have evolved mechanisms to “feed” energy to cancer cells to simultaneously promote their survival and growth, and to regulate expression of cancer-supportive genes. To test this hypothesis, I will use a combination of patient-derived cancer and microenvironmental cells; these cell types will be cultured together to understand on a molecular level the impact of supportive cells on pancreatic cancer cell survival and behavior. These mechanistic studies will be accompanied by investigation of relevant metabolic pathways in mouse models of human pancreatic cancer, testing both genes and pharmacologic agents which may inhibit microenvironment-mediated tumor growth. Together, these studies have the potential to identify a novel metabolic liability of pancreatic cancer, which may be targetable for therapeutic benefit.
