This year's funding goes to Guang Yao, PhD and Wenxin Zheng, MD who will study "Molecular Mechanism of Tubal Secretory Cell Expansion and Biomarkers for Ovarian Cancer Early Detection."
Women's pelvic serous cancer (PSC) constitutes serous carcinomas of the ovary, fallopian tube and peritoneum. It is now known that the majority of women's PSCs are derived from fallopian tubal epithelial cells. Such understanding has gradually shifted the research focus from the ovary or the ovarian surface epithelia to the tubal epithelial cells. Two different types of epithelial cells are present in tubal mucosa: one with cilia and the other one without. The overgrowth of the tubal cells without cilia serves as a latent precancer or a common pathway prior to the development into ovarian serous cancer.
The combined efforts from Drs. Yao and Zheng are expected to uncover the mystery of the growth advantages of the cells without cilia in the fallopian tubes of PSC patients. Such understanding will help us to develop a novel way of ovarian cancer early detection and prevention.
About the researchers:
Guang Yao, PhD
A cell biologist whose expertise is cancer pathway and analysis at the molecular and system level.
Wenxin Zheng, MD
A physician scientist and an internationally recognized gynecologic pathologist who has contributed multiple original research works in the field of gynecologic oncology and gynecologic pathology.
Mark D. “Marty” Pagel, PhD: Measuring tumor acidity in ovarian cancer patients using non-invasive CEST MRI
This study looks into a non-invasive method that uses magnetic resonance imaging to measure the acid content in tumors during pre-clinical studies. In this study, Dr. Pagel and his team of researchers aims to demonstrate that their clinical imaging method can diagnose tumors with high-acid and low-acid content in patients with ovarian cancer. Determining if a patient's tumor has a high acid content can help the patient and physician to select the best chemotherapy, leading to "personalized medicine" for each individual patient.
Kimberly McDermott, PhD: Dr. McDermott: Are primary cilia a predictive marker for hedgehog drug therapeutic efficacy?
The objective of this study is to determine if the presence of primary cilia on Basal Cell Carcinoma is predictive of responsiveness to treatment with an SMO Inhibitor called GDC-0449. This drug is currently in clinical trials for a number of different cancers including Basal Cell Carcinoma and if our study is successful the use of primary cilia as a marker to predict drug efficacy would allow physicians to target treatment specifically to patients that are most likely to respond positively to the drug.
Amanda Baker, PharmD, PhD
Investigating hypoxia in ovarian cancer using Hypoxyprobe(™)-1, a diagnostic biomarker for guiding hypoxia-targeted therapies
Hypoxia, a deficiency in the amount of oxygen reaching the tissues, is a common feature of many solid tumor types and is strongly associated with aggressive disease and chemotherapy and radiation resistance. The incidence of hypoxia in ovarian tumors has not been widely investigated.
In tumor tissues obtained from patients participating in this study, the investigator will assess the percentage of ovarian tumor cells that are growing in hypoxic conditions by using an investigational diagnostic chemical probe called Hypoxyprobe(™)-1. These results will be compared with a molecular biomarker of hypoxia called HIF-1α. The information gained from this new BTE study will provide evidence to guide the clinical investigation of hypoxia-directed therapies in ovarian cancer. The tumor tissue obtained as part of this study will also be a valuable resource for investigating how hypoxia contributes to traditional chemotherapy resistance.
In 2010, the five grants involved testing novel therapies, understanding biological processes, developing innovative diagnostic tools and using gene expression signatures to predict treatment response. The diseases of focus are ovarian cancer, cervical cancer and breast cancer.
Graeme J. Dougherty, PhD
Shona T. Dougherty, MB, ChB, PhD
Pro-apoptotic molecular therapy of ovarian cancer
This study will explore the therapeutic potential of a novel ovarian cancer treatment that exploits the secretion by tumor cells of a particular soluble molecule. The molecule, known as vascular endothelial cell growth factor (VEGF), plays an important role in the formation of the blood vessels that support tumor growth. Using genetic engineering techniques, we have generated an artificial receptor that causes cells to die upon binding of VEGF. A specially modified non-infectious virus will be used to introduce and express this receptor in ovarian tumors and the effect on tumor survival will be determined. Particular emphasis will be placed on ensuring that the approach is safe and that various normal cell types are not harmed as a result of treatment. Such studies are essential prior to the initiation of planned clinical trials.
Arthur F. Gmitro, PhD
Andrew R. Rouse, PhD
Confocal Microlaparoscope for Imaging the Fallopian Tube
Currently there is no way to detect early stage ovarian cancer and most cases are diagnosed at advanced stages when treatment options are limited and prognosis is poor. This study aims to develop a small and flexible endoscope that provides real-time cellular-level images of tissues inside the abdominal cavity. The device will image early-stage ovarian cancer on the surface of the ovary as well as inside the fallopian tube, where many ovarian cancers are thought to arise. Such a device would be used during a laparoscopic procedure to diagnose early-stage ovarian cancer and may provide an effective way to screen women at high risk of developing the disease.
Samuel K. Campos, PhD
Unraveling the Inhibitory Mechanisms of Bacitracin on HPV16 Infection
Human papillomavirus (HPV) infections are associated with more than 99 percent of all cervical cancers and therefore represent a significant cause of worldwide morbidity and mortality among women, especially in developing countries. Despite being the causative agents of cervical cancers, the molecular mechanisms involved in host cell invasion are poorly understood for oncogenic HPVs. We have observed that Bacitracin, an FDA approved antibiotic commonly available in over-the-counter ointments, blocks HPV infection perhaps by inhibiting a class of enzymes that may play a role in HPV-host cell invasion. Understanding the inhibitory mechanisms of this compound will expand our knowledge of HPV-host cell interactions and identify potential targets for the development of HPV antivirals and prophylactics.
Julie E. Lang, MD, FACS
Isolation and Gene Expression Profiling of Circulating Tumor Cells in Breast Cancer
Circulating tumor cells (CTCs) are rare cancer cells shed into the blood stream of breast cancer patients. In a prospective clinical study enrolling 120 newly diagnosed breast cancer patients, we will obtain a tube of blood and a small piece of tumor tissue from surgery. The purpose of our study is to determine if CTCs are cancer stem cells. We will use a novel technique we developed that permits isolating rare CTCs and studying their molecular biology. We will also study if a CTC gene expression signature may be defined for patients with locally advanced breast cancer that predicts for response to treatment. As CTCs may explain why disease recurs despite aggressive treatment of breast cancer, this novel approach has potential to determine if studying CTCs can help guide physicians in making treatment decisions for breast cancer patients.
Russell S. Witte, PhD
Spectroscopic Photoacoustic Imaging of Molecular Expression in Metastatic Breast Cancer
Our long-term goal is to develop novel imaging tools and complementary contrast agents to noninvasively monitor the tumor microenvironment and improve treatment strategies for breast cancer patients. Because detection of just one cell surface receptor is generally an incomplete diagnosis of metastatic breast cancer, we will develop a photoacoustic imaging system and targeted contrast agents to simultaneously map expression of multiple surface receptors. This will dramatically enhance our existing pre-clinical imaging platform already capable of tracking a tumor’s growth and vascular network in three dimensions. Photoacoustic imaging is a safe, highly sensitive real-time technology that potentially provides powerful diagnostic and theranostic capability during routine ultrasound breast exams.
2009-10 Grant Award Winners
Setsuko K. Chambers, MD; Patrick W. Mantyh, PhD, JD
A Model for Human Breast Cancer-induced Bone Pain
Breast cancer, more so than most solid tumors, has the predilection to metastasize to bone, resulting in bone pain, bone destruction and frequently bone fracture, all of which can severely impact the quality of life and functional status of the patient. The goal of this proposal is to develop the first preclinical model to explore the mechanisms and factors that drive human breast cancer-induced bone pain and breast cancer growth in bone. We will focus on therapies that target tyrosine receptor kinases which drive bone pain and metastases. This study fosters a unique collaboration between a physician/scientist (Chambers), who is both a clinician and a tumor biologist, and a neurobiologist (Mantyh) who studies and developed the first preclinical model of cancer pain. By having both these investigators focus on the same platform we have the potential to synergistically interact to develop novel and more effective therapies that control cancer pain and reduce the progression of cancer.
Vince Guerriero, PhD
A Paradigm Shift Leads to a New Treatment for Breast Cancer
Breast cancer is the most common malignancy for women throughout the industrialized world. In general, most individuals with cancer do not die from the tumor in the primary site, but rather from local invasion and/or distant metastasis. This research takes on the challenge of developing a new revolutionary treatment for primary and metastatic breast cancer. The hypothesis is that expression of a specific protein on the tumor cell surface protects these cells from the patients’ immune system and therefore protects the tumor from elimination. This hypothesis will be tested by blocking the specific protein on the tumor surface using another protein. This will allow an immune response to ensue, which will destroy the tumor. Using a protein that will bind specifically to the surface of tumor cells and remove inhibition of the immune system against those cells has far reaching implications in the development of new treatments for breast cancer.
Ana Maria Lopez, MD, MPH
Assessment of Clinical Efficacy Utilizing Telepathology for Paps
This study aims to use technology to improve the ability to detect premalignant cells, in the hope that cervical cancer may be prevented. Though cervical cancer is treatable - and when detected early, is curable - detection of premalignant disease is the most clinically-effective and cost-effective outcome. This study will assess the role and accuracy of telepathology - using telecommunication technology to transmit a digital image to a pathologist - in cervical cancer screening. By eliminating the need for glass slides, breakage and loss of clinical material would not be a concern. Further, as a digital image, the clinical material may be easily and rapidly transmitted electronically for primary or second-opinion reads, which may be of greatest benefit to women in underserved, rural or remote areas and in developing countries. Finally, the digitized images allow for the addition of annotations, which may facilitate communication between consultants and may be helpful with education.
Kimberly McDermott, PhD
The Role of Primary Cilia in Breast Cancer Progression
Cilia - membrane-enclosed organelles that project from the surface of a cell - are found on a number of cell types in the mammary gland including epithelial cells, the precursor cells of cancer. Mutations in genes involved in ciliary assembly and function cause abnormal cellular functions such as loss of cellular polarity, which is a hallmark of cancer progression. We hypothesize that loss of primary cilia causes loss of polarity in cancer cells. This study should provide significant advances towards our understanding of the events involved in initiation of breast cancer. Furthermore, results obtained from these studies can be applied to future studies focused on understanding how primary cilia can be used in unique strategies for diagnosis and treatment of breast cancer.
Mark Nelson, PhD; Todd Vanderah, PhD; Patrick Mantyh, PhD, JD
Control of Breast Cancer Bone Metastasis by CB2 Receptor Agonist
Bone is one of the most common sites of metastasis in human breast cancer. Bone metastases cause cancer-related pain, pathologic fractures, hypercalcemia, neurological defects and immobility, which severely affect the quality of life in breast cancer patients. Conventional therapies do not allow a curative outcome for breast cancer bone metastasis. Therefore, determining factors that regulate the growth of breast cancer in the bone microenvironment is essential for the development of novel therapeutics for bone metastasis. To accomplish our goals, outstanding investigators from the departments of Pathology and Pharmacology will utilize both preclinical and basic research studies to focus on the therapeutic effects of cannabinoid receptor 2 (CB2) agonist. These studies are sure to result in new modalities of treating breast patients with bone metastases with the possibility of being used in patients with other bone cancers.
Marlys Witte, MD; Baldassarre Stea, MD, PhD
Radiation Damage and Radioprotection from Lymphedema and Other Vascular Complications in Women’s Cancers: An In Vitro and Clinical Observational Study
Radiation therapy (RT) to a cancer mass, or to the area surrounding draining cancer-containing lymph nodes, is a commonly used and important component of current therapy for breast and other female pelvic cancers. Among acute complications is lymphedema, a hardened type of tissue fluid swelling that progresses over time and involves the arms, legs and surrounding tissues. Due to removal or obstruction of lymphatic vessels and lymph nodes, lymphedema is a common, disabling, lifelong problem that impairs functional status, diminishes quality of life and occasionally threatens both limb and life. This study seeks to retain RT’s value in curing early cancer and controlling more advanced disease while preventing or minimizing delayed RT complications including lymphedema by testing the effectiveness of amifostine, an FDA-approved radioprotective agent. This will lay the groundwork for a clinical trial of amifostine by establishing an accurate baseline of lymphedema incidence in patients with breast cancer and other female pelvic cancers undergoing RT at the Arizona Cancer Center. The potential impact of this translational project worldwide on survivorship and quality of life of the large number of patients who are at risk for lymphedema is substantial.
Wenxin Zheng, MD
Detection of Endometrial Serous Carcinoma in its Early Form or Precancer Stage
Endometrial cancers can be basically divided into two categories: non-aggressive and aggressive. The aggressive endometrial cancer constitutes the majority of cancer deaths in postmenopausal women and there is currently no good method to cure or control it. This project aims to detect the aggressive type of endometrial cancer in its early form or precancer stage using a non-invasive cytology-based immunoassay. Clinical detection in its early form or precancer stage will provide us an outstanding opportunity to control or even prevent the disease.