V Scholar Archives - Page 59 of 62

Ruoning Wang, Ph.D.

Funded by the Dick Vitale Gala in Memory of Eddie Livingston

Interaction of immune system with tumor is a complex and dynamic process, which dictates tumour initiation, progression and responses to therapy. Mounting evidence indicates that strengthening the amplitude and quality of T cell-mediated adaptive response is one of the most promising approaches to enhance therapeutic anti-tumor immunity. Functional and effective immune response requires a metabolic rewiring of immune cells to meet their energetic and anabolic demands. As such, tumor microenvironment represents a dramatic example of metabolic derangement, where the highly metabolic demanding tumor cells may compromise the function of some immune cells by competing nutrients (a form of intercellular competition), meanwhile may support the function of other immune cells by forming a metabolic symbiosis (a form of intercellular collaboration). Here, we propose to decipher the metabolic communications between tumor cells and immune system and understand how such communications impact on anti-tumor immunity.

Megan McNerney, M.D., Ph.D.

Each year, in the U.S. alone, over 50,000 people are diagnosed with myeloid cancers of the blood. Some myeloid cancers have been found to lose all or a portion of chromosome 7 [-7/del(7q)], and these cases are particularly difficult to treat. The overall survival for these patients is less than one year. -7/del(7q) also occurs in half of therapy-related myeloid neoplasms/cancers (t-MN). t-MN arise as a side effect of chemotherapy/radiation and occur in u to 8% of cancer survivors. There is clearly an urgent need to develop better therapies for -7/del(7q) disease. It has long been thought that one or more genes on chromosome 7 prevents cancer growth – “tumor suppressor genes.” I used genomic technologies and animal models to map this tumor suppressor gene, implicating CUX1. The long-term goal of the current proposal is to improve the outcome for patients with this type of disease. This proposal is designed to accomplish this by identifying CUX1-regulated pathways that may be potential drug targets as well as establish animal models for future use in preclinical therapy development. The contribution of the proposed research is expected to bhe characterization of the biological outcomes and altered pathways caused by CUX1 loss–the first step toward developing therapies. The significance of this work is not limited to leukemia; CUX1 is mutated in endrometial cancer, gastric cancer, and melanoma, among other tumors. Thus, the understanding of CUX1 function in myeloid disease may guide our knowledge of the role of CUX1 in other cancers.

Karen Sandell Sfanos, Ph.D.

Human-associated bacterial communities (e.g., the “microbiome”) are an integral part of the healthy human body, yet pathogenic shifts leading to increased and/or decreased diversity in the healthy-state microbiome composition are linked to disease development. We hypothesize that prostate infections that result from pathogenic shifts in the urinary tract microbiome contribute to prostate cancer development. As such, we aim to investigate associations between altered urogenital microbiome signatures and the presence of prostate cancer and/or high grade disease. Furthermore, we aim to correlate urinary tract microbiome signatures to prostatic inflammation in prostate cancer patients, as we hypothesize that microorganisms that may contribute to prostate cancer etiology do so via the induction of chronic inflammation in the prostate. These studies can be coupled to ongoing studies in our laboratory aimed at the identification of microbial signatures in prostate cancer tissues, and ongoing efforts to identify causal microorganisms in prostate cancer etiology. The proposed research project will represent an essential initial study linking urinary tract microbiome to genitourinary disease. Whereas the project is primarily focused on prostate cancer, this work may lay the important groundwork for additional studies linking urinary tract microbiome to other genitourinary malignancies such as kidney, urothelial, or bladder cancer.

Yong Zhang, Ph.D.

A set of proteins are highly active in cancer. They can add small groups to a series of target proteins. These uncommon additions are often linked with tumors found in breast, liver, and other tissues. To date, it is still unclear how those aberrant proteins cause cancer. To answer this question, it is crucial to know all the targets that they act on in live cancer cells. But no method has been made available to resolve this key issue. In this project we are aimed to create an innovative platform to achieve this goal. Our research plan will use chemistry and biotechnology to make new tools for target identification. A particular member in this group will be chosen for this work. Because it shows much higher activities in diverse types of cancer. The full range of targets for this protein in live cancer cells will be clearly assigned for each specific type of cells. Moreover, the patterns, levels, and time courses of such additions in live cells can be directly viewed and precisely measured by our creative approach. These findings will lead to unveil the interaction networks of this cancerous protein to guide our further studies. The fundamental knowledge obtained from this work will advance our understanding of cancer. Importantly, it will foster the development of new approaches for cancer detection and treatment.

Yanzhong Yang, M.D., Ph.D.

Prostate cancer is the second most frequently diagnosed cancer worldwide. In the US,
more than 230,000 cases are diagnosed yearly, affecting 1 in 7 men. If detected early,
the cure rate for these cancers is high – nearly all patients will be disease-free after five
years. However, in patients whose cancers either re-appear after treatment or spread to
other organs, therapies are limited mainly to symptomatic relief. Patients diagnosed at
this stage usually live no longer than 20 months. Therefore, a major challenge in treating
advanced prostate cancer is that the standard therapies, including radiation and
medicine, are not effective in killing these cancer cells.

A small proportion of tumor cells, known as cancer stem cells (CSCs), is particularly
important in promoting cancer, because they 1) can give rise to an entire tumor from a
single cell, and 2) are more resistant to treatment than other tumor cells. Efforts to
identify and then kill CSCs hold the key to effective prostate cancer treatment. The goal
of our work is to define the molecular mechanisms that drive growth of prostate cancer
CSCs. Once identified, those factors could serve as “biomarkers” or diagnostics. In
addition, drugs could be designed to target those factors as a way of blocking tumor
growth.

Ian Watson, Ph.D.

Skin melanoma is one of the fastest rising cancers. It is also the deadliest form of skin cancer. Sun and UV exposure are major risk factors for the development of melanoma. This is due to the fact that UV rays can change the DNA of normal cells. These DNA changes, called mutations, can turn a normal cell into a cancer cell. My research focuses on identifying UV-induced mutations in melanoma. In this proposal, I will test which of these mutations cause melanoma using a new research tool. I will determine which mutations affect the response to melanoma therapies used in the clinic. My work may help explain why some patients respond to certain treatments and others do not. This is information is important to know. It will allow doctors to prescribe drugs that are most likely to work for a specific patient. Ultimately, I will use findings from this proposal to develop new therapeutic strategies to treat melanoma.

Jennifer Trowbridge, Ph.D.

Funded by the Hearst Foundation

Acute myeloid leukemia (AML) is an aggressive blood cancer where <30% of all patients are long-term survivors and >11,000 patients die per year in the United States alone. Treatment of AML has changed little in the past two decades, and is ineffective in curing patients of their disease, as the majority will relapse within five years.

Doctors and scientists recently investigated the DNA of AML patients and found that many patients contain mutations in a gene called DNA methyltransferase 3A (DNMT3A). Strikingly, many healthy adults also have DNMT3A mutations in their blood cells. This suggests that additional mutations (not just DNMT3A alone) are required to develop AML. Currently, scientists and doctors have a poor understanding of why and how mutations in DNMT3A frequently, but not always, lead to the development of blood cancer. This is important to understand for two reasons. First, to develop new ways to assess risk of AML in healthy people with DNMT3A mutations. Second, to create new therapies that stop DNMT3A-mutant cells from causing AML to recur after treatment.

Our work focuses on the initial changes that drive cancer development or relapse. Therefore, we cannot directly use AML patients samples that already contain many mutations. I propose to use new mouse models precisely engineered to carry mutations found in human AML patients. My research will use these models to show why and how AML develops from mutations in DNMT3A.

Eric Snyder, M.D., Ph.D.

Cancer treatment is being improved by ever more specific drugs. But, there is growing proof that cancers growing in different parts of the body do not react to the same drugs, even if the tumor has the same mutation. For example, a lung tumor may respond when given a drug, but a tumor with the same mutation from another part of the body may not react in the same way. Some lung tumors can look a lot like healthy lung tissue, but some look like a completely different tissue. My lab has developed a mouse model of lung cancer that lets us change the state of the tumor from looking like one from the lungs to the stomach. We have shown that this change can happen in human lung cancer too. We will see if this change affects how lung tumors respond to targeted therapy. We will then use this knowledge to improve lung cancer treatment.

Jianfei Qi, Ph.D.

Prostate cancer is a common cause of death among men. Current treatment includes hormone therapy that targets the androgen receptor (AR). The AR promotes the growth of prostate cancer. Unfortunately, prostate cancer cells remain resistant to current therapy. This is partly due to the formation of active forms of AR. We need to understand how active forms of AR arise. Thus, we can discover therapies that will not become resistant to treatment. The JMJD1A protein plays an important role in this process. In this study we will look at how JMJD1A promotes the generation of active AR forms. JMJD1A may regulate several other proteins (e.g. HUWE1, c-Myc and HNRNPA1) to do this. We will block the expression of these proteins to see if prostate cancer cells become sensitive to hormone therapy. Our experiments include cell culture and mouse tumor models. Our study will stimulate the interest to develop inhibitors that block the activity of JMJD1A or the proteins it regulates. The inhibitors will serve as effective therapies for prostate cancer.

Yuliya Pylayeva-Gupta, Ph.D.

Pancreatic cancer is a very aggressive disease. It is the 4th leading cause of cancer deaths in the USA. Only 6% of patients who can undergo surgery will survive past five years. Late diagnosis and lack of good treatment options are some of the reasons for this outcome. Recent progress in cancer immune therapy showed effect in cancers such as relapsed leukemia and metastatic melanoma. Unfortunately, immune therapy was not effective in patients with pancreatic cancer. One explanation for this result is that pancreatic cancer blocks immune responses against cancer. Thus, understanding how cancer promotes immune suppression is vital to our ability to treat this deadly disease. Our initial work has revealed that B cells promote growth of pancreatic cancer. However, it is not clear how B cells promote cancer growth, and how targeting these cells can benefit patients. We propose to understand how B cells function in pancreatic cancer. The goal of this research project is to find new targets that can block immune suppression in pancreatic cancer. Using both mouse models of pancreatic cancer and patient samples, we hope to identify B cell based targets in pancreatic cancer. We ultimately hope to translate our findings into effective therapies that may also work with existing immune therapy treatments.