Aberrant chromatin regulation is a hallmark of multiple developmental diseases including cancer. Various chromatin marks such as DNA methylation and histone modifications, known as “epigenetic marks”, are implicated in the dynamic regulation of chromatin structure and lineage specific gene expression. Epigenetic regulators are recurrently mutated in cancer. The reversible nature of epigenetic marks holds great therapeutic promise. Therefore much effort is devoted to developing small molecule epigenetic inhibitors however such approaches are targeting the entire genome, causing multiple unintended side effects. I am proposing to develop tools that enable locus-specific manipulation of chromatin structure and function. Bu using such locus specific epigenetic engineering tools, I aim to alter aberrantly regulated local epigenetic modifications at specifically targeted genomic region.
Funded by Virginia Vine 2016
“Precision medicine” aims to develop better treatments by understanding the molecular causes of disease. This is essential in cancer because each type (breast, brain, or blood cancer, for example) represents dozens of different kinds of cancer at the molecular level. And each of these different molecular sub-types requires different treatments.
Based on research of the past twenty years, we understand a great deal about what drives cancers. Many drugs have been devised that specifically target these causes – molecular “smart bombs.” However, the cancer cells rapidly adapt and find escape routes. Drugs that seem to work ultimately fail. We get many hopeful responses but few cures.
Our research seeks to identify and block these escape routes. We look at the molecular changes inside cancer cells after drugs are applied, and we then use other drugs to “slam the door” so the cancer cannot escape treatment. Our approach is already proving successful: We are testing one of these combinations in people to treat Mantle Cell Lymphoma. We propose to look at similar cancers that might benefit from this approach. We also want to better understand ways that cancer cells might escape from our combination treatments. Our goal is to improve responses to therapy and turn temporary responses into real cures.
Funded by Virginia Vine 2016
The promise of cancer therapies that target the mutationally activated “drivers” of malignant behavior is that highly selective drugs can be developed that will be effective with minimal side effects. However, that promise has not been achieved because most cancers rapidly develop resistance to these targeted therapies. Recent experience with the leukemias and lymphomas that respond to the drug ibrutinib provide a sobering example of both the successes and disappointments of these targeted approaches. Whereas many patients with malignancies of B-cells (Chronic Lymphocytic Leukemia (CLL), Mantle Cell Lymphoma (MCL) or Diffuse Large B-Cell Lymphoma (DLBCL)) show a beneficial response to treatment with ibrutinib, the responses are generally incomplete and often are not durable. The goal of the collaborative research proposal from UVA and VCU is to elucidate the important mechanisms of intrinsic and adaptive resistance to therapies for B-cell malignancies, and use this understanding to develop RATIONAL combinations of drugs that target both the driver of malignancy and the resistance mechanisms. The two groups have over the past few years taken complementary approaches to tackling this problem, and some of these discoveries are now entering clinical trial. The UVA and VCU groups will utilize materials from these clinical trials, as well as preclinical models and patient samples to develop tools to match patients with the most appropriate drug combinations, and to develop additional combinations of targeted therapies that will have deeper and more long-lasting benefits.
V Scholar Plus Award- extended funding for exceptional V Scholars
Gene regulation is vital for our health and abnormal regulations lead to many diseases, including cancer. There are two mechanisms that control genes: Genetic info and epigenetic. Genetic alterations are stable and we cannot target them. However, epigenetic is dynamic as it changes over time. Epigenetic can control gene expression in tissues. It is the loss of this control that causes cancer. In cancer, only select genes are abnormal while the rest are normal. We need to target only abnormal genes. Current therapy is based on chemicals that target all of the genes in the cell. Thus they have side effects. This proposal develops a novel tool that can target a specific gene. Thus, it can correct an aberrant gene only. The tool also has strong therapeutic potential. This will be very valuable for basic research.
“Precision medicine” aims to develop better treatments by understanding the molecular causes of disease. This is essential in cancer because each type (breast, brain, or blood cancer, for example) represents dozens of different kinds of cancer at the molecular level. And each of these different molecular sub-types requires different treatments.
Based on research of the past twenty years, we understand a great deal about what drives cancers. Many drugs have been devised that specifically target these causes – molecular “smart bombs.” However, the cancer cells rapidly adapt and find escape routes. Drugs that seem to work ultimately fail. We get many hopeful responses but few cures.
Our research seeks to identify and block these escape routes. We look at the molecular changes inside cancer cells after drugs are applied, and we then use other drugs to “slam the door” so the cancer cannot escape treatment. Our approach is already proving successful: We are testing one of these combinations in people to treat Mantle Cell Lymphoma. We propose to look at similar cancers that might benefit from this approach. We also want to better understand ways that cancer cells might escape from our combination treatments. Our goal is to improve responses to therapy and turn temporary responses into real cures.
Mailing List
