Mary Philip, M.D., Ph.D.

Primary liver cancer is a leading cause of cancer death worldwide. Liver cancers are resistant to many cancer drugs. Our immune system has enormous power to find and destroy infectious microorganisms in our bodies, and scientists reasoned that immune cells such as T cells could also find and destroy cancer cells. Using a mouse model of liver cancer, we found that T cells could recognize cancer cells in the liver, however the T cells failed to kill the cancer cells. We discovered that interactions between liver cancer cells and T cells quickly restructured T cells’ DNA. DNA is the program that controls how cells respond and function.  The DNA restructuring in T cells took away the T cells’ ability to kill cancer cells. Our goal is to understand how the interaction between liver cancer cells and T cells makes T cells dysfunctional. We are working to develop a three-dimensional liver cancer model in cell culture dishes. We can add T cells to precisely study the earliest changes in T cells after they encounter a liver cancer cell. This will give us clues about why the T cells are shut down their anti-tumor function. We will then test DNA targeting strategies to see if they prevent T cells from becoming dysfunctional. Ultimately, these genetic targeting strategies can be used to activate T cell responses against cancer cells in patients with liver cancer. 

Dineo Khabele, M.D.

Funded by the Kay Yow Cancer Fund

The research supported in this proposal will impact patients with ovarian cancer.  Ovarian cancer is the most common cause of gynecologic cancer death.  Noninvasive imaging is critical for detecting disease and monitoring response to treatment.  However, current methods are inadequate and better approaches are urgently needed.  Our concept is that the protein cyclooxygenase-1 (COX-1), which is expressed at high amounts in ovarian cancer, can be used to detect and monitor the spread of disease and response to treatment.  We will test a first-of-its-kind COX-1 targeted PET molecule in mouse models of ovarian cancer.  Our study paves the way to clinical trials of a much-needed new imaging technique to benefit women diagnosed with ovarian cancer.

Jeffery Klco, M.D., Ph.D.

Funded by the Dick Vitale Gala

The overall purpose of our research project is to identify if there are patterns of genetic changes (i.e. mutations) that explain why some children with acute myeloid leukemia (AML) fail to effectively respond to chemotherapy and ultimately relapse. Relapsed disease is strongly associated with poor outcome and early death in children with AML. Frequently, when AMLs relapse they do so through the outgrowth of a cell population (subclone) that was present at a low level at the time of diagnosis. These subclones frequently have mutations that allow them grow better after therapy. Unfortunately, we have a poor understanding of these subclones in pediatric AML and methods to detect them and study them are lacking. The proposed studies in this grant will identify these mutations in a large group of relapsed pediatric AML and then address if sensitive approaches to detect mutations in patients after therapy will increase our ability to predict relapse. Currently our methods to predict relapse are not applicable to all cases and likely do not effectively capture all leukemic subclones for analysis. In the second part of this grant we propose a model system to introduce mutations that will allow us to more effectively study the subclonal complexity of AML to understand why some subclones are more resistant to chemotherapy. Collectively these studies will dramatically increase our understanding of pediatric AML with the long-term goal of pushing the outcomes of pediatric AML closer to pediatric ALL.

Christine Lovly, Ph.D.

Funded by The Hearst Foundation

Important advances have been made in therapeutically targeting molecularly defined subsets of lung cancer that depend on specific molecular alterations for tumor growth. Prime examples include tumors which harbor EGFR mutations or ALK translocations. Many other potential “driver mutations” have also been identified in lung cancer, yet therapeutically actionable alterations are still only found in approximately 50% of lung adenocarcinomas. The principal objective of this proposal is to define a novel molecular cohort of lung cancer characterized by the presence of a previously unreported EGFR exon 18-25 kinase domain duplication (EGFRKDD). This novel EGFR alteration was initially detected in the lung tumor specimen from a young male never smoker with metastatic lung adenocarcinoma. In our preliminary data, we have also detected EGFR-KDD in the tumors from other patients with lung cancer as well as from patients with brain cancer. The proposed research uses in vitro and in vivo models as well as patient-derived tumor samples and clinical data to study EGFR-KDD. Findings from these studies could potentially be immediately relevant and provide a new avenue for precision medicine in these notoriously difficult-to-treat malignancies because there are already several approved EGFR inhibitors in clinical use

Paul Northcott, Ph.D.

Funded by Vs. Cancer

Brain cancer is the leading cause of cancer-related death in children. Current therapies for medulloblastoma, the most common type of aggressive childhood brain cancer, cure 60-80% of patients from their disease, however, these treatments are non-specific, highly toxic, and impose devastating consequences on the developing child. Novel, rationally designed therapies informed by studying medulloblastoma in the laboratory and identifying the causes of this childhood cancer are desperately needed to improve patient outcome and quality of life for survivors and their families.

Studies outlined in this application aim to gain a better understanding of the genes responsible for a large subset of medulloblastoma patients whom are typically associated with an exceedingly poor clinical outcome. There are currently no effective therapies designed to specifically treat these high-risk patients and as such they are treated with standard protocols that carry with them considerable side-effects, effectively stealing any possibility of a normal ‘life after cancer’ for kids fortunate enough to survive.

Discoveries made using state-of-the-art technologies during my recent Post-Doctoral Fellowship revealed important new insight into the genes involved in these high-risk medulloblastoma patients.  The most compelling evidence from my analyses implicated a new gene – KBTBD4 – a gene not previously implicated in childhood brain cancer, nor in any other cancer type. The experiments outlined in this application will directly evaluate the role of this novel, frequently altered gene (most commonly affected gene in high-risk patients) in medulloblastoma and establish its potential as a future target of therapeutic intervention in high-risk patients.

Jun Yang, Ph.D.

Funded by the Dick Vitale Gala

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.

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