Dr. Elizabeth S. Yeh
A Novel Targeted Approach for Triple-negative Breast Cancer
Elizabeth S. Yeh
Assistant Professor of Cell and Molecular Pharmacology and Experimental Therapeutics
General Audience Summary
Triple-negative breast cancer (TNBC) is defined by the absence of specific clinical markers called estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Beyond chemotherapy there are no drugs that are given to TNBC patients on a routine basis.
This is a major concern because this type of breast cancer is typically more aggressive thus, finding an effective treatment is crucial. Our group has characterized a molecule called, HUNK, that we have evidence to suggest is a candidate for drug targeting. Therefore, we propose to test HUNK as a target for TNBC.
Elizabeth Yeh, Assistant Professor of Cell and Molecular Pharmacology, investigates mechanisms that drive the etiology and progression of breast cancer in order to identify curative treatments for this disease.
Dr. Yeh performed her graduate training in the lab of Dr. Anthony Means at Duke University in the Department of Pharmacology. In Dr. Means’ lab I developed a core understanding of intracellular signaling and its relationship to cell biology. Following, Dr. Yeh did her postdoctoral training in the lab of Dr. Lewis Chodosh at University of Pennsylvania where she gained a foundation for translating cellular signaling into preclinical studies in mouse models.
While at the University of Pennsylvania, Dr. Yeh worked with Dr. Lewis Chodosh, who identified a novel AMPK-related protein called Hormonally Up-regulated Neu-associated Kinase (HUNK), whose function has been determined to be critical in the etiology and progression of human breast cancer.
Dr. Yeh’s work demonstrated that HUNK promotes the survival of breast cancer cells, further suggesting that this molecule could be a therapeutic target. In Dr. Yeh’s continued study of this molecule at Medical University of South Carolina, her lab is working to elucidate the intracellular mechanisms by which HUNK regulates survival signaling through the growth factor receptor, EGFR, a molecule that is commonly overrepresented in human breast cancer.
Dr. Mildred Acevedo-Duncan
Understanding the role of PKC-i in cancercell proliferation
Mildred Acevedo-Duncan, P.H.D
Principal Investigator, Merit Review Program (James A. Haley Veterans’ Hospital), Associate Professor of Chemistry (University of South Florida)
The lifetime probability of developing cancer is one in two for men and one in three for women. Additionally, there will be approximately 310,010 cancer death in men and 275,710 cancer deaths in women in 2013.
Certain cancers are highly lethal tumors SEQ CHAPTER \h \r 1due to the emergence of therapy-resistant cancer cells. To address this health issue, we propose to investigate how a drug (ICA-1) against an enzyme named protein kinase C-iota (PKC-i) decreases cancer proliferation. The rationale for understanding how ICA-1 interacts with PKC-i to affect cell proliferation during cell growth and development is that PKC-i has been linked with the rapid growth rates of malignant cells. PKC-i attaches a phosphate group to proteins called substrates in a process called phosphorylation.
Once the phosphate group is donated by PKC-i, the substrate carries out its intended function. This function may involve regulation of the cell cycle (either increasing or decreasing the rate), cell proliferation, and cell survival. The cell cycle comprises all of the life stages of cells, and these stages are the basis for cell division, cell multiplication and cell proliferation. Therefore, large uncontrolled quantities of a PKC-i that stimulates the cell cycle may phosphorylate too many substrates and cause uncontrolled cell growth and cancer formation.
The objectives of our research project are to measure the levels of PKC-i in different types of cancer specimens, to determine how ICA-1 regulates the in-vitro and in-vivo cancer cell proliferation through the PKC-i/Cdk7/cdk2, PKC-i/BAD and PKC-i/IKKalpha/beta pathways, and to further elucidate these pathways. Thereafter, we hope to block PKC-i with ICA-1 to halt tumor proliferation and even destroy the tumor. We believe this will be a successful approach to battle cancer because our own research has shown that PKC-i is physiologically associated with these substrates that control cell proliferation and cell survival. Additionally, ICA-1 and an inhibitor of PKC-i production (PKC-i siRNA) decrease the proliferation of cancer cells in-vitro. Hence, we envision that this research may help patients who have overexpressed PKC-i in their cancers.
Our hypothesis is that a novel PKC-i inhibitor (ICA-1) can inhibit cancer cell proliferation. This research investigates the relationship between the cell proliferation and a gene that promotes cancer (oncogene; PKC-i) in non-tumorigenic cells and different types of cancer cells to determine if PKC-i phosphorylates and activates cell proliferation proteins. This research is important because it addresses the processes controlling cell proliferation. Information gained from this research will make a significant contribution by providing fundamental understanding of the mechanisms of cellular regulation, which can be applied to malignancy systems. The inclusion of non-tumorigenic cells will permit us to determine if genetic over-production of PKC-i protein in non-malignant cells initiates malignant characteristics. Our understanding of the role of PKC-i in cancer cell proliferation will enhance future studies by allowing us to develop new strategies for the treatment of cancer.
We anticipate that within the next 15 years, patients whose cancer tumors overproduce PKC-i may be treated with drugs (ICA-1) that block the function of PKC-i. These drugs will be called anti-PKC-i chemo-therapeutic drugs and the therapy will be called anti-PKC-i therapy. For this concept to become a reality, it is necessary to demonstrate how PKC-i regulates the cell proliferation mechanisms. Additionally, it is necessary to block the proliferation of the cancer cells with chemicals that inhibit PKC-i (ICA-1) function. Finally, similar experiments will need to be performed in animals with cancer cells and in patients through clinical trials.
We have identified a novel PKC-i drug named ICA-1 that will be tested in-vitro and in-vivo in the proposed research. This research will contribute to advancing the field of research by deciphering a method to inhibit PKC-i in cancer cells. Additionally, we will establish if PKC-i controls cell proliferation and if PKC-i inhibitors (ICA-1) can stop the proliferation of cancer cells.
Results from this study have potential clinical applications for anti-PKC-i therapy in patients with overexpressed PKC-i, which would be an important advancement for personalized medicine.
Dr. Lili Yang
Stem Cell-Engineered Invariant Natural Killer T Cells for Cancer Immunotherapy
Lili Yang, PhD
Member of the UCLA Broad Stem Cell Research Center
General Audience Summary
Recruited to UCLA from Caltech in January 2013, Lili Yang, PhD, is a talented member of the UCLA Broad Stem Cell Research Center who is at the beginning of her independent research career.
A large contribution from Save the ta-tas® via the Concern Foundation is providing the much needed resources for Dr. Yang to initiate a project that will establish stem cell-engineered natural killer T cell therapy for breast cancer, and open the door to exploring its broader therapeutic potential for melanoma, prostate cancer, lung cancer, and leukemia.
This project aims to develop a novel immunotherapy for breast cancer through genetically engineering hematopoietic stem cells (HSCs) to produce invariant natural killer T (iNKT) cells targeting breast cancer.
Because of the longevity and self-renewal of HSCs, this new therapy has the potential to provide breast cancer patients with therapeutic levels of engineered killer cells for a lifetime.
Dr. Matthew Pratt
Funding made possible by a generous donation from ICING Stores. Visit ICING Stores – www.icing.com.
Investigation of glycosylation in cancer metabolism
Dr. Matthew Pratt
What influenced you to explore this area of research?
This is the first question, but somehow also the most difficult. The honest answer is that I followed where the science lead. I am an organic chemist by training, and one of the goals of my lab is the creation of chemical tools that will allow us and others to approach biological problems that have been otherwise difficult to address. One of these chemical tools is aimed at the visualization and identification of a specific type of glycosylation that is altered in cancer. Application of that tool in my lab lead us to the investigation of glycosylation in cancer metabolism and let’s hope the rest is history….
How were you funded up to this point?
In addition to funding from the Concern Foundation, the research in my lab has been funded by the University of Southern California, the American Cancer Society, and most recently by the Damon Runyon-Rachleff Innovation Award from the Damon Runyon Cancer Research Foundation.
How do you envision the study progressing?
We are trying to understand some basic, yet fundamental cancer biology. In contrast to normal cells in our adult bodies, cancer cells have a very different metabolism. Most of our adult cells, for example muscle cells, use the nutrients they take in to generate energy to perform their jobs. In this example, muscle cells would use carbohydrates such as glucose to generate energy to move us around. In contrast, cancer cells behave more like embryonic cells. They use the nutrients they take in for not only energy but also to generate “cellular building-blocks” that allow them to make copies of themselves. Additionally, the metabolism of cancer cells can change depending on the cancer cell environment, and this adaptability is key to tumor progression and survival. We are investigating one pathway that we hypothesize contributes to the ability of cancer cells to sense their environment and alter their metabolism accordingly. Specifically, we are studying the modification of cancer-associated metabolic enzymes by a carbohydrate in a process termed glycosylation. We hope that if we can understand this process, it will open opportunities to prevent cancer from changing its metabolism, leading to cancer cell death.
How many people does it take to consider it a viable clinical trial?
We are still at a fundamental scientific discovery stage in our research, but hope to uncover new opportunities for cancer targets and encourage the development of new types of drugs.
Can you explain Glycosylation in more depth?
Glycosylation simply refers to the physical attachment of a carbohydrate to another biomolecule (e.g. proteins, lipids, etc.). The type of glycosylation that we are studying is the addition of a single carbohydrates called N-acetyl-glucosamine, which is called O-GlcNAc for short. O-GlcNAc is added to proteins on the inside of all cells and can change the activity of those proteins to generate a range of biological outcomes. What makes it particularly interesting to us is that the amounts of O-GlcNAc addition are intimately linked to nutrient availability and metabolism, making it an interesting player in cancer metabolism.
What will it mean if your hypothesis is validated and where will you go with this information?
We hypothesize that O-GlcNAc addition in cancer cells acts as a nutrient sensor and contributes to the adaptability of cancer metabolism. If this holds true, we plan to move to animal experiments to test if O-GlcNAc addition is important for tumor formation and then think about ways to exploit O-GlcNAc to prevent cancers from changing their metabolism in response to their environment. Additionally, we hope to use the process of discovery to continue to develop new chemical tools to study O-GlcNAc and metabolism, hopefully enabling new experiments to be performed by the cancer research community.
What do you like to do for fun outside the laboratory?
There’s something outside the laboratory? In all seriousness though, science is my major passion, but I do enjoy good beers, good tacos, and good friends and family outside of lab.
Dr. Smita Bhatia
Development of second cancers directly related to the treatment of the primary cancer
Dr. Smita Bhatia
Professor and Chair, Department of Population Science
Who is Dr. Smita Bhatia?
With more people surviving their initial cancer diagnoses it has become important that we must also focus on the patients post treatment to try to mitigate any long term complications. Dr. Smita Bhatia at City of Hope has undertaken the study of second cancers.
There will be 20 million cancer survivors in the U.S. by 2020, representing 6% of the entire population. This number has tripled since 1971 and is growing at the rate of 2% per year. Treatment used to treat the primary cancer can result in devastating and crippling long-term complications.
Development of second cancers directly related to the treatment of the primary cancer is one of the most devastating events experienced by cancer survivors. Dr. Smita Bhatia, Professor and Chair, Department of Population Sciences has undertaken a study of second cancers because:
- Second cancers are the most common cause of mortality in cancer survivors (other than that due to recurrence of primary cancer)
- A clear relationship exists between second cancers and treatment with chemotherapy and radiation used to treat the primary cancer
- There is a critical need to understand this devastating outcome at the molecular level such that innovative treatments and prevention strategies can be planned
- Findings from this study can be extended to help understand why cancer happens in the first place
Why is Dr. Bhatia’s research important?
Dr. Bhatia is utilizing a case-control study design, by harnessing the resources offered by the Children’s Oncology Group (a consortium of 200 members institutions across the country, with a commitment to cure childhood cancer, and improve the quality of life of the cancer survivors), as well as at the level of a single institution treating large numbers of patients with adult-onset cancer (City of Hope), and, to our knowledge, this study is unparalleled in its magnitude and detail in any other setting. Thus, this study will be able to identify cancer survivors who are at high risk of second cancers because of their unique genetic makeup. Currently, 131 COG member institutions are participating in this study, in addition to patients undergoing hematopoietic cell transplantation at City of Hope.
Individuals exposed to radiation and chemotherapy are vulnerable to long-lasting organ toxicity; the very young because their organs are developing and the elderly because of organ senescence. In addition, genetic predisposition and its interaction with therapeutic exposures can potentially exacerbate the toxic effect of treatment on normal tissues and organ systems. Thus, it becomes imperative to understand the individual variability in: i) the internal dose of the therapeutic agent; ii) the biologically effective dose; iii) the alterations in structure or function of the tissue or organ; and iv) the consequent development of preclinical disease, in order to understand the pathogenesis of therapy-related complications, and also develop a better idea of the individual susceptibility.
Dr. Bhatia believes the research could find much-needed answers and is thankful for the funding provided by Concern Foundation. Findings from this research could identify patients at risk – such that alternative modes of therapy could be offered to this population and the second concerns prevented.
Dr. Eva González-Suárez
González-Suárez, P.H.D in Molecular Biology
National Center of Biotechnology, Extraordinary Award Winner by the Universidad Autonoma de Madrid, Spain
Who is Dr. Eva González-Suárez?
Eva González-Suárez is a PhD in Molecular Biology and Extraordinary Award Winner by the Universidad Autónoma de Madrid, Spain (2003). She got her bachelor degree in Chemistry and her master degree in Biochemistry at the Universidad de Oviedo, Asturias, a small town in a rainy, mountainous region at the north of Spain. Her interest in the cancer field began when she was still a college student and attended a local cancer meeting organized in her hometown. She met Dr. Blasco and became fascinated by the novel discoveries on the telomerase field.
First she worked as a summer student in Blasco´s lab and as soon as completing her degree she moved to Madrid and started her doctorate work on telomerase at the National Center of Biotechnology, at the time, the most prestigious research center in Spain. Her research aimed to elucidate the role of telomerase in tumorigenesis and aging. Telomerase elongates the extremes of the chromosomes, the telomeres allowing cell division without compromising genetic information. Most tumor cells use this mechanism in order to proliferate indefinitely.
The results of her work can be summarized in two main discoveries:
- In the absence of telomerase, when telomeres are strikingly short, tumors are abolished or dramatically reduced (González-Suárez et al., Nat Genetics, 2000 and Can Res, 2003).
- Telomerase overexpression, even in the presence of long telomeres, results in a higher incidence of spontaneous and induced tumors (González-Suárez et al. EMBO J, 2001, Mol Cel Biol, 2002) but extends maximum longevity due to a lower incidence of senile lesions (González-Suárez et al., Oncogene, 2005).
She received several awards for this work including Young Investigator 2003 “Severo Ochoa” Award, Best Doctorate Thesis 2003 and Juan Abelló Pascual II Award 2003. After this successful experience Dr. González-Suárez was ready for new challenges.
She was offered a postdoctoral position at the Oncology department of Amgen Inc. in Seattle, WA, USA. First, it was a great opportunity to join one of the most prestigious biotech companies in the world and, on the other hand, living in Washington was for Eva like going back “home” as it rains nearly as much as in Asturias and the mountains are gorgeous to hike!
The main project developed by Dr. González-Suárez in Amgen was the characterization of the role of RANK and RANKL in mammary gland development and tumorigenesis. Amgen as developed a monoclonal antibody against RANKL, Denosumab, that is being used for the treatment of osteoporosis and bone metastasis. Breast cancer has a high incidence of bone metastasis and some preliminary data suggested that RANKL may also play a role on mammary epithelial cells (MECs) that Eva decided to explore. Her results demonstrated that RANK signaling activation in MECs promotes proliferation, impairs terminal differentiation (González-Suárez et al., MCB, 2007) and increases the susceptibility to mammary tumors in her research. These results suggest that RANKL plays a role in mammary tumor initiation and progression and may indicate that blocking RANKL may be effective, not only for the treatment of bone metastasis but could also impact the primary breast tumor site. Amgen is currently investigating this line of research. After this work and numberless hikes in the northwest Dr. González-Suárez decided to face her biggest challenge, to lead her own research group.
In 2008 she joined the newly created Cancer Epigenetics and Biology Program of the Bellvitge Institute for Biomedical Research (IDIBELL) in Barcelona, Spain, as a Young Investigator. She is now discovering the Pyrenees and the Mediterranean coast and working in close contact with clinicians, oncologists and pathologists as her laboratory is located in a hospital. Her current research lines are within the mammary gland biology and breast cancer field, particularly in understanding the events that drive transformation of the mammary epithelial cells and metastasis and the stem cell pathways that become deregulated during carcinogenesis. She is investigating the RANKL pathway and its impact on breast cancer development using primary cells and clinical samples, with the aim to find new resistance mechanisms to current therapies and identify novel targets to treat breast cancer.
Why is Dr. González-Suárez’s research important?
Breast cancer is the most common malignancy among females in the western world, resulting in approximately half a million deaths annually mainly due to metastatic disease. Current therapies for breast cancer include local treatments (surgery and radiation) and systemic treatments, mainly chemotherapy and directed therapies against hormones or Her2, an oncogen that is over expressed or amplified in 30% of breast tumors. These therapies are in many cases not effective because intrinsic or acquired resistance, and tumors often relapse leading to metastatic disease. Therefore, it is essential to identify new therapeutic targets. Metastasis to the bone is a common complication of breast cancer (65-70%). RANKL and its receptor RANK play a critical role during bone remodeling as signaling through this pathway is essential for osteoclast differentiation. In physiological conditions there is a perfect balance between bone resorption by the osteoclasts and bone generation by the osteoblasts. A deregulation of this balance towards the osteoclasts occurs during osteoporosis and bone metastasis. Numerous lines of evidence indicate that blocking RANK/RANKL interaction effectively prevents or reduces tumor-induce bone lesions. Our goal now is to elucidate the role of RANK and RANKL in human mammary epithelial cells and breast cancer and in the clinical setting.
This project has benefits in the short term, as an antibody against RANKL for the treatment of bone metastasis has already been developed. If we demonstrate that RANK activation promotes breast cancer initiation and tumor progression in humans, RANKL inhibition will be beneficial not only for the treatment of bone pathologies, but will also impact primary tumor initiation and progression. In addition, studying cooperation of RANKL and other signaling pathways will provide insights into new combined therapies that allow circumvallation of tumor resistance and successful eradication of tumors.
Understanding the role of PKC-i in cancercell proliferation
Andrea Dorfleutner, P.H.D
Research Assistant Professor at the Feinberg School of Medicine at Northwestern University
Who Is Andrea Dorfleutner?
I was born and raised in Vienna, the capital of Austria, where I got my masters degree in Cell Biology, Genetics and Immunology from the University of Vienna in 1999. However, for my PhD thesis I decided to leave my home country and work on a collaborative research project between the University of Vienna and The Scripps Research Institute in La Jolla, California. During this time I was awarded a graduate fellowship from the Austrian Academy of Sciences and at the completion of the project I graduated with honors from the University of Vienna.
In 2003 I was offered a postdoctoral position at the Mary Babb Randolph Cancer Center in Morgantown, WV, where I started to work on a protein that is associated with the actin cytoskeleton of cells. I discovered that this protein, called AFAP1 is highly expressed in breast cancer cells that have the capability to move around and metastasize. However, in normal breast epithelial cells or breast cancer cells that do not metastasize this protein is barely detectable. I found this very fascinating and ever since I am trying to answer the question on if and how a single protein could make such a huge difference. In addition I am intrigued to figure out if a treatment targeting this protein could some day prevent breast cancer metastasis, which is the main cause of mortality in breast cancer.
In 2007 I moved to Chicago and was offered a research assistant professor position at the Feinberg School of Medicine at Northwestern University, which is giving me the opportunity to establish my own research lab. This is very exciting and I am facing new challenges every day. I am now studying how AFAP1 is able to facilitate cell movement and metastasis and aim to identify a strategy to interrupt this process, which might lead to the development of novel breast cancer treatment strategies that prevent breast cancer cell metastasis and therefore better survival for women that are diagnosed with breast cancer.
Why is Andrea Dorfleutner’s research important?
Breast cancer is the most common and fatal type of cancer among women in the US. It develops when normal cells within the breast tissue change and develop malignant properties, such as uncontrolled growth, invasion and destruction of adjacent tissues, and spread to other locations in the body, called metastasis. While non-metastasizing breast cancer is not life-threatening, patients with metastasizing breast cancer have a five-year survival rate of only 20%. In addition, patients with non-metastasizing breast cancer are at risk of developing metastasizing breast cancer. Only 1-5% of women have metastatic disease at the time of breast cancer diagnosis. Therefore an early treatment that blocks metastasis would dramatically change the outcome or most patients and increase their chance for remission. Metastases account for the majority of patient’s deaths due to cancer, and yet current treatments are mainly focusing on preventing primary tumor growth. Thus understanding the metastatic process is of utmost importance and is highly significant for the development of novel treatments.
In order to metastasize, tumor cells have to move away from the primary tumor and invade surrounding tissues. They traffic to distant sites, interact with extracellular matrix and organ tissues and form a secondary tumor. These processes are highly dynamic and require adjustments of the cell shape as well as the adhesive and motile properties of tumor cells, which are controlled by the actin cytoskeleton. Dynamic actin cytoskeletal changes involve the recruitment and modification of actin binding proteins. Therefore we aim to contribute to a better understanding of the molecular mechanisms involved in dynamic actin remodeling in metastasizing breast cancer cells in order to identify novel strategies for breast cancer treatments that prevent cancer cell metastasis.
We recently identified that high expression of the actin binding and crosslinking protein AFAP1 correlates with the ability of breast and prostate cancer cells to invade and metastasize. In the absence of AFAP1, breast cancer cells show a reduced capacity to attach to a substrate, indicating that AFAP1 expression is required for the attachment phase of metastasis. In addition, AFAP1 is phosphorylated upon breast cancer cell adhesion, and we hypothesize that this protein modification changes it’s actin binding and crosslinking properties in order to allow the dynamic actin remodeling required for metastasis.
Therefore we propose to investigate 1) the mechanism of AFAP1 phosphorylation and 2) the functional consequences of AFAP1 phosphorylation on cellular processes of breast cancer metastasis: cell attachment, migration and invasion. Delineating the function of AFAP1 in breast cancer cell metastasis might enable the development of novel therapies in the future, which disrupt the function of AFAP1 and subsequently prevent breast cancer metastasis, thus resulting in a higher survival rate of breast cancer patients.
Understanding the molecular mechanism of inflammation and how chronic inflammation is linked to cancer.
The focus of our lab is to understand the molecular mechanism of inflammation and how chronic inflammation is linked to cancer. A main interest is the production of the pro-inflammatory mediator interleukin-1 beta (IL-1b). This protein, which initiates and perpetuates inflammatory reactions, is primarily produced by macrophages, which are a specific type of white blood cell. Normally, IL-1b is important to promote acute, self-limiting inflammatory reactions to eliminate infections and to promote wound healing. However, chronic and excessive production of IL-1b contributes to human diseases, including cancer.
True malignancy begins, once tumor cells begin to invade surrounding tissue and eventually break from the primary tumor to establish metastases at secondary sites. Macrophages are actively recruited by cancer cells into the tumor microenvironment. Although, macrophages are capable to kill tumor cells, they become frequently manipulated by cancer cells to support tumor growth by providing the needed cytokines, proteases and growth factors for cancer cells to become malignant, and are referred to as tumor-associated macrophages. More than 15% of all cancers are known to arise from chronic inflammation, including breast, cervical and ovarian cancer. Thus, there is focus on blocking macrophages and inflammation as cancer treatment. IL-1b from macrophages is required for the invasiveness of tumor cells and metastasis and high IL-1b levels within tumors are associated with more aggressive tumors and bad prognosis, and include breast, colon, lung, head and neck cancer and melanoma. Anti-IL-1b therapy is investigated for cancer patients.
We study the molecular mechanism by which macrophages produce IL-1b and how one can block chronic and excessive IL-1b production. We identified 3 novel proteins in human macrophages that can inhibit IL-1b generation and are currently investigating their role in breast cancer metastasis. In particular we are studying their contribution to the generation of IL-1b in macrophages, their contribution to the recruitment of macrophages to primary tumor sites/cancer cells and cancer cell metastasis.