Facilitate the transition of projects from the laboratory to the clinic. Translational researchers seek to apply basic knowledge of cancer and bring the benefits of the new basic-level understandings to patients more quickly and efficiently. These grants are $600,000, three-year commitments
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.
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.
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.
Neuroblastoma is the most common extracranial solid tumor of childhood. Amplification of the MYCN proto-oncogene occurs commonly in high-risk neuroblastoma and marks a particularly aggressive and lethal form of the disease. We and others have described an array of highly targeted inhibitors to block kinases both upstream and downstream of MYCN in neuroblastoma. Among these targeted inhibitors, we have recently described a novel conformation disrupting inhibitor of Aurora Kinase A which potently induces MYCN degradation through an allosteric change in Aurora Kinase A. Because these inhibitors target distinct members of the MYCN pathway, we hypothesize that they will have nonoverlapping toxicities and that combinations of MYCN targeted therapies will more potently block MYCN. In Aim 1 of this proposal we will rigorously test combinations of MYCN targeted therapies for pre-clinical efficacy with the goal of rapidly translating combinations into patients with neuroblastoma. In Aim 2 of this proposal we will develop our novel conformation disrupting Aurora Kinase inhibitor to “dial out” toxic Aurora Kinase A activity and finesse more potent MYCN degradation in neuroblastoma to optimize therapeutic efficacy. Successful completion of this proposal will result in direct and rapid translation of therapeutic combinations of MYCN targeted therapies into children with neuroblastoma and provide new clinical grade drug candidates for conformation disrupting Aurora Kinase A inhibitors.
Lung cancer is the top cancer killer in the United States and worldwide, claiming over 1.5 million lives in 2012, according to the World Health Organization. The purpose of our research project is to understand how patients’ genetic ancestry contributes to the likelihood of acquiring specific harmful changes in DNA (“mutations”) in lung cells that lead to lung cancer. Mutations in the EGFR gene are important because EGFR mutations often cause lung cancer, especially in non-smokers. Significantly, patients whose lung cancers have EGFR mutations benefit from drugs targeting mutant EGFR, including gefitinib, erlotinib, and afatinib. Mutations in EGFR occur more frequently in lung cancer patients of East Asian or Latin American origin but the basis for this observation is a mystery, especially because these mutations are not inherited but arise after birth. Here, we propose to analyze DNA from 1500 Latin American lung cancer patients, to understand whether and how their genetic makeup leads to increased risk of developing EGFR-mutant lung cancer.
By defining the basis of increased risk of EGFR mutant lung cancer in Latin American populations, we could enable the use of effective existing treatments in this population. Additionally, if we can find a genetic marker for susceptibility to EGFR mutation, we could facilitate the screening, early detection and early EGFR-targeted therapy of lung cancer in at-risk populations. We therefore believe that our research plan could lead not only to an improved intellectual understanding of lung cancer but to improved outcomes for lung cancer patients from susceptible populations.
Mutations in the KRAS gene are one of the most frequent genetic alterations found in lung cancer, a disease that is associated with the highest cancer-related morality rate in the US. Despite their prevalence, we still do not have an effective therapeutic intervention to target lung cancers harboring KRAS mutations. In this application we will investigate novel approaches to inhibit the function of this protein in patient-derived (or ‘avatar’) models of lung cancer and then translate the most promising findings to early phase clinical trials.
The global burden of cancer, severe pathology bottlenecks in underserved regions, and evolving medical knowledge increase the need for inexpensive and rapid diagnostic approaches for point-of-care use. We developed a low-cost imaging module (D3), mountable onto standard smartphones, that exploits holography to detect and profile tumors using scant clinical samples. Cells are decorated with plastic beads coated with antibodies against various cancer markers. Recorded holograms (inherently noisy and undecipherable images) are transmitted wirelessly to a remote server via a secure, encrypted cloud service. Results are rapidly reconstructed and returned to the end user’s smartphone screen along with a diagnostic readout. Pilot testing of human biopsies demonstrated protein profiling capabilities comparable to gold standard methods and excellent diagnostic accuracies compared to expert pathology interpretation. To render the platform poised for global field testing, we propose to optimize D3 to achieve simultaneous, multiple marker testing along a spectrum of field conditions using scant samples. We will then inaugurate this next generation platform and pilot its global oncology reach by tackling a key unmet need – early breast cancer detection in Botswana. Testing for key markers in breast cancer specimens is universal practice in developed regions yet rarely performed elsewhere due to highly inadequate resources. Instead, empiric treatment with anti-estrogens occurs leading to over/under treatment and significant drug-drug interactions (e.g. reduced HIV medication levels). D3 could position itself as a key early detection tool in global regions, enabling judicious and personalized treatment and increased biological insight.
Colorectal cancer is the second leading cause of cancer deaths in the United State, with African Americans having a significantly higher risk of developing colorectal cancer and of dying from colorectal cancer than do Caucasians. This study is based on the recent milestone publication from our team finding that 41% of colorectal cancers from African Americans are molecularly distinct from colorectal cancers from Caucasians, with African American colorectal cancers bearing mutations in certain genes that are never or rarely mutated in Caucasian colorectal cancers (dubbed: African American Colorectal Cancer, or AACC, genes). This proposal will examine whether AACC genes are similarly targeted for mutation in cancers from African Americans that live in different regions of the country; whether AACC gene mutations are associated with more aggressive colon cancer behavior; whether cancers with AACC gene mutations appear different under the microscope; whether AACC gene mutations show molecular footprints of exposures to environmental carcinogens; and whether mutations of AACC genes preferentially target genes that are inherited from African versus from Caucasian forebearers. We further will develop functional models for two AACC genes (EPHA6 and FLCN) that are mutated exclusively in African Americans and will test effects of these mutations on the ability of cancer cells to grow and to metastasize. We moreover will determine if the presence of these mutations turns on any signaling pathways whose activation would render these cancers sensitive to treatment with new types of anti-cancer drugs that are designed to target and shut down specific cancer-associated signaling pathways.
Acute lymphoblastic leukemia (ALL) is an aggressive cancer of the blood and a leading cause of disease-related death in children and adolescents. Cure rates of ALL have improved over the last decade thanks to innovative therapies, but it came at the cost of often severe toxicity associated with chemotherapy that can have long-lasting debilitating effects on children. The goal of our research is to move from the “sledgehammer” delivery of chemotherapy to “surgical precision” personalized ALL therapy, to minimize side effects and improve survival. We have recently discovered genetic factors (variations of our genetic make-up, DNA) that strongly influence the way thiopurine (an important anti-leukemic drug) is processed in patients, and we found that 80% of severe toxicity of this drug is due to genetic defects in two genes. Therefore, we reason that 1) patients should be tested for these DNA variations before ALL therapy starts, and 2) the genetic test results can be used to tailor chemotherapy for each patient to avoid toxicity, an approach also known as pharmacogenetics-based precision medicine. To achieve this goal, we have assembled an outstanding group of basic scientists and clinicians in 5 countries with diverse expertise, to preform comprehensive research in laboratory as well as clinical research in clinical trials of ALL. If funded, this work is likely to have immediate impact in the way we treat children and adults with ALL, demonstrating the importance genetics-guided precision medicine in cancer in general.
