The poor survival of pancreatic adenocarcinoma (PDAC) patients is due partly to diagnosis at late-stages, concomitant with relatively ineffective cytotoxic therapies. This poor chemotherapeutic response may relate to unique properties of the PDAC tumor microenvironment (e.g. poor perfusion, increased fibrous stroma), which may be a barrier to drug delivery. We hypothesize a link between tumor stroma and microvasculature and have developed a steady-state MRI method that quantifies microvascular imaging biomarkers to study PDAC, using long-lived FDA-approved intravascular magnetic nanoparticles (MNP). By applying these techniques to angiotensin receptor-blockade, which directly effects fibrous stroma, we have demonstrated sensitivity to vascular normalization, a direct correlation with histologic assays, and improved drug delivery as measured by 18F-5 fluorouracil (5FU) positron emission tomography (PET). Based on exciting results from the Coussens, Varner, Bar-Sagi and Simon laboratories indicating that B cell-regulated pathways foster PDAC progression, and two reports from the Levy and Soucek laboratories, indicating that therapeutic targeting of Bruton’s tyrosine kinase (BTK) reprograms the immune microenvironment in PDAC to normalize vasculature and mobilize CD8+ T cells resulting in improve efficacy of gemcitabine (Gem) chemotherapy, we propose to quantitatively evaluate microvascular changes following BTK inhibition. These provocative preclinical data are now being translated to the clinic in a funded (Stand-Up-2-Cancer (SU2C) Phase 2 trial). The goal of this proposal, therefore, is to test the hypothesis that MRI measures of tumor microvasculature using MNP are surrogate biomarkers of therapeutic response to BTK inhibition by validating in mouse models and translating in humans participating in this SU2C trial.
Cancer clinical trials provide much of the evidence for clinical guidelines and standards of care. All patients should have access to the latest treatments and the high quality care that typifies clinical trials. Unfortunately, a small percentage of patients enroll in cancer clinical trials, especially minorities. The purpose of this project is to develop and test an easy to understand culturally informed video with a racially diverse group of breast cancer patients and assess the effect of the video on clinical trial enrollment. This video, which will be easily accessed via smart phones, tablets, and computers, will provide standardized communication between the patient and healthcare provider and will address benefits and barriers through patient and physician stories. The setting for this project is Winship Cancer Institute, Georgia’s only cancer center designated by the National Cancer Institute. Our multidisciplinary research team will complete this study through the following four step process: 1) form a Community Advisory Board composed of individuals diagnosed with breast cancer to provide input 2) establish a tracking method to identify potential breast cancer clinical trials participants; 3) develop the video; and 4) pilot test the video. Simple, effective interventions are needed to support the cancer clinical trials enrollment process. This multi-disciplinary effort is a first step to provide educational programs to a diverse group of patients with the end goal of increasing enrollment rates. Results of this study will inform future educational programs and can be adapted to other minority groups.
Funded by the Dick Vitale Gala in memory of Lauren Hill
We have recently demonstrated that neuronal activity in the cerebral cortex can drive the growth of deadly brain tumors called high-grade gliomas. High-grade gliomas include tumors that affect children, teens and adults, such as glioblastoma, anaplastic oligodendroglioma and the childhood tumor diffuse intrinsic pontine glioma (DIPG). High-grade gliomas are the most lethal of all brain tumors. An important way that brain activity promotes the growth of these brain tumors is through release of a molecule called “neuroligin-3”. The purpose of this project is to develop a new therapy for these deadly brain cancers designed to sequester neuroligin-3 like a molecular sponge. We have shown that such a strategy is effective in principle, and now seek to test and optimize this strategy in preclinical models of high-grade glioma.
Dr. Hatem Soliman, a researcher and breast cancer medical oncologist at Moffitt Cancer Center, will be conducting a project to help increase accrual to clinical trials for breast cancer patients. The aim of the project is to first assess patient awareness of cancer clinical trials, perceived barriers that may prevent participation and what information would help patients to more readily participate in trials. Information will be collected from a target of 100 Moffitt breast cancer patients. Once this initial assessment is completed, the second aim of the project is to use this information to create a web hosted video to address questions and issues identified through the survey as perceived barriers to breast cancer clinical trial participation and provide vital information that may help increase participation. A short post video survey will be administered to ascertain the impact of the information presented on increasing clinical trial participation. If successful, our ultimate goal would be to expand this methodology to other cancer types to help increase clinical trial participation.
Research has advanced new anticancer drug therapies, saving many lives, but it is estimated that cancers will still kill more than half a million Americans specifically African and Hispanic Americans. New, safe and effective treatment approaches are urgently needed. Especially promising are treatments including cancer cells, through a large family of proteins called “T cell receptors” (AKA TCRs) which bind particular molecules associated with tumors Dr. Chapuis is an expert in identifying tumor antigens, genetically engineering matching TCRs, putting them in T cells and then infusing these enhanced methods to develop new engineered T cell therapies for patients for whom best available therapies are simply inadequate. For patients with non-leukemia patients, further optimizing methods that can also be used to target other antigens in tumors where WT1 is not expressed. She also proposes therapy after the safety of each is established for a broader future impact, including for other patients with urgent needs.
Ovarian cancer is a devastating disease heightened by its tendency to present when metastatic disease is already present. Many women diagnosed with the disease complain that despite their best surveillance efforts, the disease occurred completely “under the radar.” While most women are symptomatic at diagnosis, the symptoms are veiled as common inconveniences of daily life, such as bloating, fullness and pelvic discomfort. Primary treatment involves a combination of surgery and chemotherapy. Tumor control is achieved in >75%. However, despite these early treatment gains, a typical patient will suffer recurrence within 2 years, where limited curative options exist. These clinical observations have fueled the search for better treatment agents and strategies. The unprecedented explosion of information arising from analyses of the cancer cell environment has directed new investigative opportunities. One such observation in line with this clinical story is the efficacy of agents that target new blood vessel formation. Several clinical trials with these agents in both initial and recurrent disease settings have demonstrated benefit to women. However, improvement in survival has not been realized. Our investigation into why this might occur has uncovered that the immune system may be adversely contributing. Of great concern, though, is that this process appears to be induced by the very drug being used for therapy. The current proposal tackles this issue by specifically investigating and targeting these immune cells. Our clinical trial design uniquely identifies patients where this “escape” effect may be at work. The translationally-rich proposal holds promise to substantially improve treatment outcomes.
Tumors consist not only of cancer cells, but also stromal and immune cells that constitute the tumor microenvironment (TME). Cancer cells can take on dramatically different properties based on the microenvironment. The clinical impact of the TME is only becoming appreciated in recent years. In many different cancer types, including breast cancer (BC), tumors with higher stromal fractions portend worse clinical outcomes. In contrast, tumors infiltrated by CD8 T cells have better clinical outcomes. Hence, tumors behave differently based on the collective behavior of the microenvironment. We will leverage biotechnology advances in sequencing single cells to better understand the important determinants of the coevolution between the adaptive immune response and the tumor. By tracking the spatial geometry of cells in tumor samples we hope to better understand the TME and ultimately determine which genetic factors can be best exploited for therapeutic intervention.
Prostate cancer is the second leading cause of cancer-related death in American men, resulting in 29,480 fatalities last year. Death from prostate cancer most frequently occurs following the development of resistance to first- or second-line androgen deprivation therapy (ADT). As such, there is a critical need to discover early drivers of ADT resistance to help guide selection of patients for earlier intensification of therapy.
The majority of cancer biomarker research has focused, to date, on protein-coding genes, which are pieces of DNA that are converted to RNA and then converted to protein. Our team instead focuses on investigating long noncoding RNAs (lncRNAs), which are pieces of DNA that are converted to RNA but are not further converted to protein. These lncRNAs, which function as RNAs instead of proteins, represent an underexplored, but crucial, area of cancer biology. Our team recently identified over 45,000 novel lncRNAs, and determined that several lncRNAs, including one named SChLAP1, were better indicators of disease progression than conventional protein-coding genes.
Based on our initial findings, we hypothesize that lncRNAs serve as important mediators of treatment resistance in prostate cancer. The goals of this application are: 1) to investigate the mechanism by which our top candidate lncRNA, SChLAP1, promotes ADT resistance and 2) to determine if SChLAP1 and other lncRNAs can serve as predictive biomarkers to guide therapy selection in patients with aggressive prostate cancer, using tumor samples from a phase III clinical trial.
Funded in Collaboration With Stand Up To Cancer (SU2C)
The last two decades have seen the development of increasingly effective cancer therapies that target different aspects of tumors cells, including uncontrolled growth/survival, evasion of the immune system, hyper-activated signaling pathways and dysregulated gene expression programs. In a subset of cancers, including non-small cell lung cancer (NSCLC) with mutations in the epidermal growth factor receptor (EGFR), these therapies can lead to dramatic tumor regressions in a significant number of patients. However, in the majority of EGFR mutant lung cancer patients who respond to anti-cancer therapies, relapse usually occurs preventing long-term cures. We propose to investigate the reasons why cancer cells become resistant to treatment. We believe a tumor is made up of a number of different types of cells that can each respond differently to treatment. We hope to uncover and understand these differences by looking at genomic data taken from patients who are biopsied before treatment, during response to treatment, and when resistance emerges. We are also interested in understanding the role the immune system plays during cancer treatment. We’d like to understand if the tumor has developed ways to evade the immune system, and how we can promote the patient’s own immune system to fight back against the cancer. It is our hope that combining traditional drug treatment with newer immunotherapies will provide greater tumor regressions. Our goal is to create a deeper understanding of the make-up of a tumor in order to identify novel therapies to expand the survival of patients with NSCLC.
Funded in Collaboration With Stand Up To Cancer (SU2C)
The so called targeted therapies are effective in tumors that strictly depend on a given protein or cellular signaling (the target) for growth and survival. Hyperactivation of the PI3K pathway is frequent in breast cancers and its pharmacologic inhibition showed clinical responses. However, these molecules alone cannot elicit a durable inhibition of tumor growth because the tumor can adapt and compensate the inhibition of the pathway.
Thus, targeting these compensatory mechanisms in combination with the PI3K pathway would in principle lead to stronger and more durable antitumor activity.
In this proposal we aim to validate in the laboratory theoretical predictions of successful drug combinations. These predictions are obtained from mathematical models developed from what is currently known about the perturbations of the PI3K/AKT signaling network in response to different inhibitors of the pathway. In addition, we plan to test therapeutic combinations based on genomic analyses from tissue samples of breast cancer patients treated with PI3K inhibitors.
Taken together, our results should provide the rationale to test novel and more effective therapeutic options for patients with hyperactivation of the PI3K pathway.