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.
Cancer researchers have found that the immune system plays an important role in cancer. Our immune system I programmed to kill cancer cells. But, cancer cells eventually develop ways to escape the immune system and grow and spread. While it is unclear how this happens, many scientists are now developing therapies to reactivate the immune system to attack cancer cells. This field is called immunotherapy. While promising, we are still in early days, and there is much about the cancer immunology we don’t understand. Through our studies, we have identified a protein called APOBEC3A that might prevent the immune system from destroying cancer cells. APOBEC3A is an interesting protein since it is found in high amounts in many types of cancers, including lung, breast, colon and pancreatic cancer. Here, we will try to understand how APOBEC3A exactly affects the immune system in cancer. Secondly, we have found that human and mouse tumors that have high levels of APOBEC3A also tend to have high levels of molecules that specifically stop immune cells from attacking cancer cells called checkpoints. In a novel preclinical trial, we will see if a combination of drugs that target these molecules can effectively treat cancers that express high levels of APOBEC3A. If this trial works in mice, then this approach may be lead to a new treatment strategy in a subgroup of patients with many types of cancer, including pancreatic cancer.
Funded by the Dick Vitale Gala and Northwestern Mutual in memory of John Saunders
Over one-quarter of children with acute myeloid leukemia (AML) have a form called core binding factor (CBF) AML. Despite intense therapy, ~30% of these patients will relapse. Thus, identifying new therapeutic targets is necessary to develop more effective, less toxic treatment regimens. The CBF complex coordinates the expression of genes required for normal development of blood cells. CBF AMLs harbor one of two genetic changes (t(8;21) or inv(16)) that interferes with the function of the CBF complex. While often grouped together, t(8;21) and inv(16) affect different members of the CBF complex and have unique disease features, suggesting important, yet unknown, biological differences exist. Interestingly, t(8;21) AML and inv(16) AML have different combinations of other cancer-causing mutations, providing potential clues to the genesis of t(8;21) and inv(16) AML. In particular, mutations affecting another complex that regulates gene expression, called the cohesin complex, are common in t(8;21) AML, yet never occur in inv(16) AML. The frequency of cohesin mutations with t(8;21) suggests that cohesin dysfunction cooperates with t(8;21) to cause leukemia by collaboratively activating cancer-causing genes, which could represent targets for therapy. Conversely, the absence of cohesin mutations with inv(16) indicate a dependence upon intact cohesin function, and perhaps the cohesin complex itself could be targeted in inv(16) AML. We will explore the interactions between the cohesin and the CBF complexes in AML using murine and human systems. Our study will provide novel insight into the mechanisms driving CBF AML, likely uncovering herapeutic targets for the treatment of children with this disease.
Tumors that spread to the brain, called brain metastases, are the cause of death of half of patients with metastatic melanoma. The metabolic environment of the brain is uniquely low in two amino acids, serine and glycine, which carry messages between nerve cells. This ensures accurate nerve cell communication, but should prevent or slow the growth of tumors, as tumor cells need large amounts of serine and glycine to make DNA and proteins to divide and grow. Yet, tumors can spread to the brain, and are incurable once they have done so. We hypothesize that tumors metabolically adapt to the brain’s metabolic environment by increasing their ability to make serine and its product glycine, and that blocking the production of serine should either attenuate the development of brain metastases or help treat existing brain metastases. We will determine if serine synthesis is increased in brain metastases, and if tumor cells adapt to, or are selected for, the environment of the brain by increasing their production of serine and glycine. In addition, we have developed small molecules that inhibit serine synthesis, and will test these compounds in mouse models of melanoma brain metastases with the goal of reducing their initiation or growth. These studies will demonstrate that targeting the serine synthesis pathway might be useful in treating melanoma brain metastases and offer proof of concept that small molecule inhibitors of serine synthesis might be effective in treating patients with melanoma brain metastases and brain metastases from other tumors
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