Almost all of our knowledge about cancer and medicine is about the proteins that are encoded by only 2% of human genome (the DNA that is contained in our chromosomes and carries the program for making our cells and controlling them). However, in the recent years the scientific world has been transformed by the revelation that significant parts of our genome are expressed as molecules called long noncoding RNAs (lncRNAs), which do not code any proteins, but nevertheless play critical roles in normal and diseased conditions. LncRNAs are critical for gliomas, reveal novel molecular mechanisms of cancer progression and are new targets for therapy. LncRNAs are expressed in different subtypes of gliomas at higher or lower levels compared to the surrounding normal brain, and this makes them useful as novel markers that may help in diagnosis and in predicting outcome for the patient. So far only a few lncRNAs associated with gliomas have been functionally characterized, and even less is known about their mechanisms of action and their usefulness as markers. In this collaboration between Drs. Dutta and Abounader we will focus on novel lncRNAs- H19, LINC00152 and several TUCRs, that are differentially expressed in gliomas and that influence the way a glioma behaves. Our objective is to determine the mechanisms by which these RNAs affect glioma biology, get a comprehensive catalog of all TUCRs that are differently expressed in gliomas and to determine whether targeting these lncRNAs will be therapeutic for gliomas.
Funded by the Stuart Scott Memorial Cancer Research Fund
Acute Myeloid Leukemia (AML) is a blood cancer that affects individuals of all ages. AML is the most common form of acute leukemia in adults. The incidence of the disease increases with age, with the majority of patients being diagnosed over the age of sixty. With aging, the disease does not respond as readily to treatments. Despite advances in the field, clinical outcomes for AML patients over the age of sixty remain poor. To improve upon current treatment options for AML patients over the age of sixty, it is essential to better understand the mechanisms that drive the disease in these patients and determine which patients benefit from current treatments. The project proposed will identify molecular features that characterize patients over the age of sixty and determine how to predict which patients benefit from current treatments and what potential mechanisms drive the disease in individuals over the age of sixty.
Tumor cells carrying driver oncogenes such as mutated BRAF, EGFR and EML4-ALK appear to sustain an oncogene addiction state, in which growth and survival are highly dependent on the continued activity of the oncogenic pathway. The discovery of such dependencies has informed drug development strategies for a variety of cancers. However, patient responses to therapeutic inhibitors of oncogene action are often incomplete and limited by drug resistance. Although genetic factors in resistance are part of the story, emerging evidence suggests that tissue-specific epigenetic mechanisms and reprograming following oncogene inhibition can induce adapted states where there is reduced dependence on the oncogenic activity. These epigenetic states generate heterogeneous sub-populations of drug-tolerant cells that not only limit drug effectiveness, but also constitute a reservoir from which genetically resistant clones are ultimately selected and contribute to disease progression. This represents a major challenge facing development and use of targeted therapies for a variety of cancers. Our research aims at addressing this problem for BRAF-mutant tumors. We are proposing an integrated strategy to dissect the poorly understood epigenetic states at the single-cell level, identify their key regulators, and predict and test efficient ways to block the heterogeneous populations of drug-resistant cells and maximize tumor cell killing. Our findings will help us utilize targeted therapeutics more generally, more precisely, and more effectively to cure cancer.
Acute leukemias (acute myeloid leukemia—AML and acute lymphoid leukemia—ALL) are lifethreatening cancers of the blood responsible for 40% of all childhood cancer deaths. For those who survive, life-altering side effects from conventional therapy are common. Despite progressively improved survival, these circumstances are far from ideal. To achieve better outcomes with fewer side effects, we need new treatments that target mechanisms of leukemia cell survival. By focusing on these adaptations we have discovered an “Achilles heel” in leukemia cell survival. We discovered that leukemia cells depend upon a partnership between two proteins, Growth Factor Independence-1 (GFI1) and Lysine Specific Demethylase-1 (LSD1) in order to survive. The GFI1—LSD1 complex promotes leukemia cell survival by blocking genes that cause cell death. Leukemia cells cannot survive without GFI1, even if LSD1 is present, nor can they survive without LSD1 even if GFI1 is present. This suggests that inhibitors of the GFI1—LSD1 axis can trigger leukemia cell death. To this end, we developed a new drug (SP-2577) that selectively inhibits LSD1, overriding pro-survival effects of the GFI1—LSD1 axis and triggering death of AML and ALL cells. Notably, SP-2577 causes death of leukemia cells that are resistant to other drugs currently used to treat leukemia, and thus may provide a treatment for patients with relapsed disease. Our proposal tests the addition of SP-2577 to established treatment regimens for patients with relapsed AML or ALL and validates markers of SP-2577 “on target” activity for future multi-institutional clinical trials.
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.
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.
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