Thank You for Supporting Cancer Research | A Message from the V Foundation
Read moreState: New York
Linda Van Aelst, Ph.D.
Dimitar Nikolov, Ph.D.
Funded by Cannata Marketing and Konica Minolta USA
In memory of Cyrus R. Tyler
Rolf Freter, M.D., Ph.D.
Daniel Hochhauser, M.D., Ph.D.
Raul Rabadan, Ph.D., Junfei Zhao, Ph.D.
Funded in Collaboration With
Stand Up To Cancer (SU2C)
Tumors across different patients can be understood as independent evolutionary processes of clonal Darwinian evolution under distinct therapeutic evolutionary pressures. Different therapeutic strategies disrupt evolution in distinct ways allowing the inference of the order and co-mutation patterns specifically associated to these therapies. Inferring evolutionary patterns from large cross-sectional and longitudinal therapy specific cohorts will identify specific mechanisms of drug resistance, the genetic background of these mechanisms and will inform the dynamic model of the main routes of drug evasion.
First, using CAT(0) phylogenetic spaces, we will learn the statistics of phylogenetic processes associated specific drug mechanisms in breast cancer and melanoma. We conjecture that undisrupted evolutionary processes follow linear patterns and that specific therapies generate distinct branching patterns associated to number of alterations needed for relapse and effective size of the resistant population. Second, the highly branched processes associated to therapy allow to reconstruct the genetic alterations of ancestral clones allowing to order the genetic alterations. Combining cross-sectional information, one can elucidate the main routes of drug resistance, what alterations are selected under specific therapy and which is the mutational background in which they arise. As genomic data from clinical studies will be arriving we will generate first evolutionary models and integrate the results with the networks from dynamic modeling. By combining genomic data of longitudinal studies with state of the art network inference, we aim to uncover the main mechanisms of drug resistance and design combinatorial approaches.
Je Lee, Ph.D.
Pancreatic cancer is one of the most deadly diseases in the U.S. It is hard to diagnose early, and it does not respond to treatments when discovered late. Therefore, new methods for early diagnosis and prevention are critical. Currently, our approach to finding cancer biomarkers relies on technologies that lack spatial or temporal resolution for discriminating individual cells and tumor regions. In fact, much of our analyses are based on average measurements from the mixed population of different cell types within the tumor tissue. This means that each biomarker has to be validated in multiple experimental and pre-clinical settings through very time-consuming and expensive processes, severely hampering our ability to discover diagnostic or therapeutic biomarkers. We developed a novel method to image and sequence DNA and RNA genome-wide without extracting them from the tissue, and the nucleic acid sequence is visualized directly under the microscope. Therefore, we combine positional features associated with cancer progression and molecular or genetic features associated with cancer clonal evolution. Our proposal will determine genetic sequences associated with each pixel of cancer tissue images to generate a map of genetic alteration and biomarkers as a function of the tissue landscape. If successful, our proposal could signal a new approach to discovering genetic biomarkers using specific architectural hallmarks of cancer, rather than average gene expression differences between heterogeneous tissues.
Kira Gritsman, M.D., Ph.D.
Acute myeloid leukemia (AML) is a devastating disease with poor survival. The standard treatments of chemotherapy and/or stem cell transplantation are not specific, and are toxic to blood cells, resulting in severe treatment-related complications for patients. Leukemias are composed of rapidly dividing “blast” cells, and the more rare “leukemic stem cells” (LSCs). These LSCs can lead to resistance and relapse, because they can evade chemotherapy. To achieve long-term remissions in AML and prevent relapse, we need to find more specific ways to kill LSCs.
The enzyme PI3 kinase (PI3K), which can modify proteins inside the cell, is more active in leukemic cells than in normal cells. However, PI3K is also important in normal blood cells. We identified a strategy to specifically kill leukemic cells by blocking specific components of PI3K called “isoforms”, which can sometimes substitute for each other in normal blood cells. We will determine whether this therapeutic strategy can also be used to kill LSCs.
Leukemic cells can also evade chemotherapy by hiding in their bone marrow microenvironment, the “niche”. Niche cells and leukemic cells “talk” to each other by sending signals back and forth, which can protect leukemic cells from chemotherapy. Cells need PI3K to process such signals. Inhibition of PI3K in niche cells could potentially kill leukemic cells by short-circuiting this crosstalk with the niche. We have found that PI3K in the niche cells is important for blood development. We will now examine whether inhibition of PI3K in the niche can compromise leukemic growth and progression.
Jedd Wolchok, M.D., Ph.D. & John Moral, M.D.
Funded in Collaboration With
Stand Up To Cancer (SU2C)
Pancreatic cancer is a lethal disease. 95% of patients die within 5 years of diagnosis, despite our best current treatments including surgery, chemotherapy, and radiation. By 2020, pancreatic cancer is projected to become the second leading cause of cancer death in the United States. Novel strategies to combat this deadly disease are urgently needed.
T-cells are highly specialized cells of the immune system designed to protect the human body from infections and cancer. In the past decade, we have discovered that T-cells recognize proteins that only cancers make, identifying cancers as foreign, triggering T-cells to kill cancers. Cancers however are equipped with strategies to escape T-cells. Our group has recently identified a drug paricalcitol that eliminates barriers that tumors have developed to block T-cell attack. Our preliminary findings demonstrate that this drug increases T-cell numbers within tumors by greater than 10 fold. These results are promising as it allows us to further boost T-cells with other drugs, and increase the ability of T-cells to kill tumors.
Our proposed research will delve deep into understanding the specific proteins on tumors that T-cell recognize, the specifics of how tumors create barriers to block T-cells, and combining paricalcitol with other drugs that boost T-cells in a clinical trial. Our proposals allow us to gain a deeper understanding of the biology of T-cells in pancreatic tumors so that we may develop better treatments to improve outcomes in patients.
Piro Lito, M.D., Ph.D.
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.
