Michael Weber, Ph.D.

The goals of “precision medicine” in cancer are (1) to identify the molecules that drive
the cancer and (2) develop “smart drugs” that block these drivers. These “smart drugs”
should stop the cancer but not be toxic. Many “smart drugs” have been developed, but
the cancer cells adapt and find escape routes. We get many hopeful “responses” to
therapy but disappointingly few “cures.” Our research identifies escape routes that
cancer cells use to evade death, and then uses additional drugs to block the escape
from treatment.

Our approach is already showing success in treating a blood cancer called Mantle Cell
Lymphoma. One of our combinations is causing complete responses in over half the
patients we treat. Unfortunately, many cases show resistance to our drugs, even
though the patients had never previously seen them. We are researching the ways that
cancer cells become resistant to these powerful drug combinations. Our goal is to
achieve deeper responses to therapy and turn the frequent “responses” into genuine
“cures.”

Hui Li, Ph.D.

Co-Funded with St. Baldrick’s Foundation

Alveolar rhabdomyosarcoma is one of the most common children tumors.  No effective therapy is available for advanced disease.  Poor understanding of the etiology of the tumor is partly responsible for the lack of advancement in treatment.  We are using tumor-signature events to study the cell of origin for the disease.  Our results may shed light on the development of the tumor, and potentially lead to better diagnostic and therapeutic tools. 

Michael Weber, Ph.D.

Funded by the 2015 Virginia Vine

“The Commonwealth Crushes Cancer” event

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.

Steven Grant, M.D.

Funded by the 2015 Virginia Vine

“The Commonwealth Crushes Cancer” event

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.

Mazhar Adli, Ph.D.

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.

Stephanie Sullivan, MD

Funded by the V Foundation’s Virginia Vine event

Endometrial cancer (EC) is the most common cancer of the female reproductive tract in the US. There has been an increase in the amount of this cancer and more women are dying of this than in the past. Black women are twice as likely to die from EC than white women. There are many possible reasons for this, one of which might be that Black women have different stressors than white women and this can change the way the immune system works with chemotherapy to fight cancer. Our center is leading a one- of-a-kind research study dedicated to Black women with EC to better understand if a new immunotherapy treatment works as well in Black women as it does in white women. We hope to look for markers that can help us predict if someone will respond to the new treatment or not. These biomarkers can be used to help women decide if a treatment is right for them and are likely to be different between Black and white women. We plan to look at three types of biomarkers: allostatic load (a measure of the impact of stress on the body), microbiome (different bacteria make up in our bodies), and cytokines (markers of how our immune system is working). We hope to find out if any of these biomarkers can help us predict which patients will respond to therapy and help improve outcomes for Black women. 

Daniel Lee, MD

Funded by the V Foundation’s Virginia Vine event

Chimeric antigen receptor (CAR) T-cells are immune cells from patients that are engineered to target and kill cancers (not normal tissue).  This is a new and exciting way to treat cancer. CARs have been wildly successful in treating children with leukemia that does not respond to any other therapy, saving many lives.  I ran one of the first clinical trials to show this.  Sadly, many patients experience severe or life-threatening side effects.  The only drug that helps is currently on national shortage.  This means some patients needing this lifesaving therapy may not get it.  Even if that drug was available, CAR therapy still needs to be safer.  We developed a chimeric inhibitory receptor (CIR) that we believe does just that.  When it is combined with a CAR it dramatically decreases the production of the side effect causing proteins called cytokines.  Importantly, it still kills tumors.  Funding from this grant will allow us to make more versions of the CIR that can put the brakes on CARs in different ways.  We will test the best ones in mice that have leukemia to confirm they still work.  Results from these experiments will allow us to start a clinical trial of CIR-containing CAR T-cells for patients with leukemia or lymphoma here at the University of Virginia using our new CAR T-cell manufacturing facility.  This unique approach to improving safety will have a dramatic impact on Virginians as well as all others with cancer who need life-saving CAR T-cell therapy. 

Francine Garrett-Bakelman, M.D., Ph.D.

V Scholar Plus Award – extended funding for exceptional V Scholars

Acute Myeloid Leukemia (AML) is the most common acute leukemia in adults. The majority of patients diagnosed are over the age of sixty and individuals in this age range experience poor response to treatment and worse clinical outcomes compared to younger patients. 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. The project proposed utilized data generated from AML patients older than 60 to identify RBM47 as a potential biomarker and driver of the disease. We will utilize data from another set of patients to confirm the association between the level of RBM47 in AML cells and clinical outcomes in these patients. Furthermore, in order to identify how RBM47 may contribute to the disease, we will determine what aspect(s) of AML biology RBM47 may regulate. Collectively, these findings will contribute to a body of knowledge for a long-term goal of identifying potential targetable mechanisms of disease that could be used to develop new and more effective treatments for AML patients over the age of sixty.

James Larner, M.D. & David Brautigan, Ph.D.

Funded by the V Foundation’s Virginia Vine event

Prostate cancer afflicts one in seven men and is their second leading cause of death, justifying development of more effective therapies. Prostate cancer depends on testosterone binding to and activating the androgen receptor (AR), which in turn promotes the growth of prostate cancer. Current therapies for prostate cancer are aimed at reducing AR activity, either by blocking the production of testosterone or through agents which compete with testosterone for binding to the AR. Our approach is depleting cancer cells of the AR protein by promoting its degradation. We will accomplish this by manipulating the pathways (either genetically or with drugs) which control protein degradation. Our preliminary data show that we can promote degradation of the AR in cells in test tubes. In this proposal we will test if we can promote AR degradation in mouse models of prostate cancer.

Michael Weber, Ph.D.

The goals of “precision medicine” in cancer are (1) to identify the molecules that drive
the cancer and (2) develop “smart drugs” that block these drivers. These “smart drugs”
should stop the cancer but not be toxic. Many “smart drugs” have been developed, but
the cancer cells adapt and find escape routes. We get many hopeful “responses” to
therapy but disappointingly few “cures.” Our research identifies escape routes that
cancer cells use to evade death, and then uses additional drugs to block the escape
from treatment.

Our approach is already showing success in treating a blood cancer called Mantle Cell
Lymphoma. One of our combinations is causing complete responses in over half the
patients we treat. Unfortunately, many cases show resistance to our drugs, even
though the patients had never previously seen them. We are researching the ways that
cancer cells become resistant to these powerful drug combinations. Our goal is to
achieve deeper responses to therapy and turn the frequent “responses” into genuine
“cures.”

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