Michael Pacold, Ph.D, M.D.

Funded by the Hearst Foundation

Tumors that spread to the brain, called brain metastases, are the cause of death of half of patients with metastatic melanoma. The metabolic environment of the brain is uniquely low in two amino acids, serine and glycine, which carry messages between nerve cells. This ensures accurate nerve cell communication, but should prevent or slow the growth of tumors, as tumor cells need large amounts of serine and glycine to make DNA and proteins to divide and grow. Yet, tumors can spread to the brain, and are incurable once they have done so.

We hypothesize that tumors metabolically adapt to the brain’s metabolic environment by increasing their ability to make serine and its product glycine, and that blocking the production of serine should either attenuate the development of brain metastases or help treat existing brain metastases. We will determine if serine synthesis is increased in brain metastases, and if tumor cells adapt to, or are selected for, the environment of the brain by increasing their production of serine and glycine. In addition, we have developed small molecules that inhibit serine synthesis, and will test these compounds in mouse models of melanoma brain metastases with the goal of reducing their initiation or growth. These studies will demonstrate that targeting the serine synthesis pathway might be useful in treating melanoma brain metastases and offer proof of concept that small molecule inhibitors of serine synthesis might be effective in treating patients with melanoma brain metastases and brain metastases from other tumors.

Lauren McCullough, Ph.D.

Funded by Hooters of America, LLC

Breast cancer is the most common cancer diagnosed among US women. The discovery and treatment of breast cancers has improved, but survival differences continue. African-American women have greater deaths across all types of breast cancer. While many social, economic, lifestyle, and biologic factors contribute to survival differences, we believe that fat and its impact on the cancer environment is an important factor. More African-American women are obese than Whites, and obesity has been linked to increased odds of breast cancer occurring again, spreading to other locations, and death. In older women (>50 years), most of the hormones that drive breast cancer are from total body fat. But, certain changes specific to breast fat may influence breast cancer. Early data show that one of these changes may be the development of crown-like structures (CLS). CLS of the breast (CLS-B) has been linked to greater inflammation, hormones, and poor survival among White women. We believe that CLS-B are more common in African-American than White women across body size, and that they are related to worse survival leading to the observed differences by race. This award would support the first study of obesity, CLS-B presence, and related outcomes in group of African-American and similar White women being treated for breast cancer (400 women total). Our study will advance the understanding of obesity and the breast cancer environment, as well as explain the value of CLS-B as a predictor of treatment response, breast cancer outcomes, and possible driver of differences among African-American women.

Ling Li, Ph.D.

Each year, around 10,000 patients with Acute Myeloid Leukemia (AML) in the US will die from the disease. About a quarter of AML patients have a particular change in the FLT3 gene. This change leads to a lower chance of surviving the disease. This genetic change causes a FLT3 protein to be defective. Drugs such as tyrosine kinase inhibitors (TKIs) are used to treat the effects of abnormal FLT3 protein (FLT3-ITD). However, they are not very effective.

A particular type of cancer cells called leukemia stem cells (LSCs) is not removed by drugs like TKIs. Researchers think LSCs are responsible for the disease coming back in people with AML. Thus, LSCs with FLT3-ITD are considered responsible for resistance to TKI treatment. Understanding why LSCs are resistant to TKIs will allow us to target these stem cells, and possibly cure people.

FLT3-ITD signals can be changed by modifying the protein in different ways such as methylation. Our studies found a link between methylation of FLT3-ITD and LSC resistance to TKI treatment. Thus, we think that FLT3-ITD methylation helps these stem cells resist drug treatment. We want to understand better how methylation helps LSCs survive. Also, we will test whether a lower amount of methylated FLT3-ITD protein leads to fewer cancer stem cells in test animals. Targeting protein methylation could lead to new ways to treat people with FLT3-ITD leukemia.

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.

Elda Grabocka, Ph.D.

Funded in memory of Patty Molloy.

Pancreatic cancer is one of the most lethal cancers and has a five-year survival rate of ~9%. This outcome is largely due to limitations in current diagnostic strategies as well a lack of effective therapies. Thus, there is a dire need to better understand this disease. Recent studies in cancer research have indicated a causal relationship between the capacity of cancer cells to cope with stress and cancer progression and therapy resistance. Pancreatic tumors are driven by a gene called KRAS that is mutated in 95% of all human pancreatic cancers. We have recently found that one critical process driven by mutant KRAS is the formation of stress granules. Stress granules serve as a protective mechanism from chemotherapeutic agents, which kill cancer cells by inducing stress. In this proposal, my laboratory will determine the role of stress granules in the drug resistance of KRAS-driven pancreatic cancer, and develop strategies to block stress granules as a therapeutic tool. This approach has not been explored and could provide impactful insight for the treatment of this disease.

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

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.

Mohammad Fallahi-Sichani, Ph.D.

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.

Nadya Dimitrova, Ph.D.

First year of this grant was funded in part by UNICO, in memory of Carl Esposito

Lung cancer is the leading cause of cancer deaths worldwide in men and women, with adenocarcinoma being the most prevalent subtype of non-cell lung cancer in the US. The National Cancer Institute estimates that, in 2016 alone, over 220,000 Americans were diagnosed with lung cancer and close to 160,000 Americans died of their disease. These dismal numbers have not changed significantly over the past decade. Thus, despite enormous advances in our understanding of many of the genetic, epigenetic, and immune events that underlie lung cancer development, a vast amount of knowledge remains to be amassed in order to improve human health. The experiments outlined in this proposal aim to elucidate how an understudied class of genes, called long noncoding RNAs (lncRNAs), participates in lung cancer development and may be harnessed for therapeutic applications. Specifically, we propose innovative approaches to investigate a set of lncRNAs downstream of the key tumor suppressor protein p53. By selecting this pathway, our intent is to dissect a molecular network, which represents a known barrier to lung adenocarcinoma progression, allowing us to discover and characterize lncRNAs that may modulate the transition to advanced and metastatic disease. Our ultimate goal is two-fold – first, to open new avenues in how we explore the significance of lncRNAs in disease states, such as lung cancer, for which few effective treatment options exist, and second, to make the first strides towards deciphering the regulatory code of lncRNAs, thus expanding the druggable space in cancer and ultimately improving patient outcomes.

Gina DeNicola, Ph.D.

Lung cancer accounts for the largest number of cancer deaths for both men and women. While there have been recent advances in treatment options for patients having lung tumors that have specific mutations, or by harnessing patients own immune systems, the vast majority of patients with advanced tumors will not respond to these treatments or they will relapse following an initial response. A common feature of lung tumors is their increased production of antioxidants, which promote their growth and survival and which contribute to resistance to therapies. The DeNicola lab studies how the production of antioxidants by lung tumor cells affects these processes, and how blocking antioxidant production inhibits tumor formation and progression.

We recently found that many lung tumors increase their levels of an antioxidant protein called NNT, which was not previously associated with lung cancer. Notably, studies of the DeNicola lab show that if NNT is not present, lung tumors cannot form. In these V Foundation Scholar studies, we will define how NNT is regulated in lung cancer cells, and will develop strategies to block the function of NNT.  In addition, we seek to understand how NNT promotes tumor formation. These studies will provide an improved understanding of NNT, and will allow us to design better therapies for lung cancers that have increased NNT levels.

John Cunningham, Ph.D.

Nucleotides are the building blocks of our genetic material and must be replicated every time a cell divides. Chemotherapeutic drugs interfering with nucleotide metabolism exploit this requirement and are a valuable weapon in the oncologist’s arsenal. However, the cytotoxic properties which make these compounds so efficacious in killing cancer cells also wreak havoc on normal proliferating cells and tissues. In order to create the next generation of drugs that inhibit nucleotide metabolism, we must identify novel targets that are specifically required by cancer cell, but not normal cell, proliferation and survival. My discoveries have identified one such target – the enzyme phosphoribosyl pyrophosphate synthetase 2 (PRPS2). PRPS2, and its paralog PRPS1, generate a critical precursor necessary for producing all nucleotides and function as a ‘molecular throttle’ capable of increasing or decreasing the rate at which these genetic building blocks are made. While targeting this metabolic enzyme represents a powerful approach to stymie nucleotide production, the redundancy afforded by the existence of two distinct forms of the same enzyme also presents a phenomenal opportunity for selectively killing cancer cells. In line with this, I have demonstrated that PRPS2, but not PRPS1, is specifically upregulated and required by cancer cells. This is in contrast to normal cells and developing organisms which require PRPS1, but not PRPS2. This proposal seeks to unravel the molecular basis for this selectivity through use of novel mouse models and structure/function studies, thus pinpointing a putative mechanism of action and developing a rational basis for future drug development.

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