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: (1) second cancers are the most common cause of mortality in cancer survivors (other than that due to recurrence of primary cancer); (2) a clear relationship exists between second cancers and treatment with chemotherapy and radiation used to treat the primary cancer; (3) There is a critical need to understand this devastating outcome at the molecular level such that innovative treatments and prevention strategies can be planned; (4) 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.

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: 1) 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) and 2) 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.

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.

Who is Christian Stehlik?

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.