Research Profiles
Cancer Center faculty are dedicated to excellence in patient care, community outreach, education and research. Research efforts are particularly important because they are the keys to finding new treatment and curative therapies. Here are examples of current research projects.
Bone Marrow | Breast Cancer | Esophageal Cancer | Gynecologic Oncology
Head and Neck Cancer | Imaging | Minimally Invasive Gastrointestinal Surgery
Pancreato-Biliary Cancer | Pharmacology and Toxicology | Radiation Oncology
Thoracic Tumors | Pituitary Cancer | Colon Cancer
Blood and Marrow Transplantation
At least 80 research studies are being conducted at the International Bone Marrow Transplant Registry/Autologous Blood and Marrow Transplant Registry (IBMTR/ABMTR) Statistical Center using data reported by more than 500 participating centers. These studies address important issues in improving the outcome of hematopoietic stem cell transplantation and cancer treatment.
Mary M. Horowitz, MD, MS, Medical College of Wisconsin oncologist and scientific director of the IBMTR/ABMTR, and Douglas Rizzo, MD, Medical College of Wisconsin hematologist/oncologist, are collaborating with investigators at Northwestern University in Chicago and the University of Florida in a National Cancer Institute funded study of quality of life among transplant survivors and their spouses.
Christopher N. Bredeson, MD, MS, FRCPC, Medical College of Wisconsin hematologist/oncologist, received funding from the American Cancer Society and the Froedtert & Medical College Cancer Center to form a multi-institution clinical trial comparing non-myeloablative stem cell transplant strategies for low grade lymphoma and chronic lymphocytic leukemia.
William Drobyski, MD, Medical College of Wisconsin specialist in neoplastic diseases, is participating in research involving the use of murine models to understand and reduce the severity of the major complication of allogeneic bone marrow transplantation, namely graft versus host disease. His research also focuses on using these same models to develop new approaches to improve grafting of donor marrow and reduce the risk of disease recurrence after bone marrow transplantation. The National Institutes of Health funds these studies.
Breast Cancer
Sally Twining, PhD, Medical College of Wisconsin biochemist, is studying the interaction between Maspin (a tumor suppressor synthesized by normal breast epithelial cells) and a binding molecule found on the outer membrane of breast tumor cells. Using this information, molecules may be developed for potential therapeutic intervention in breast and prostate cancer.
Alonzo Walker, MD, associate professor of surgical oncology at the Medical College of Wisconsin, is chief of surgical oncology, and is the institutional program leader for the American College of Surgeons Oncology Group clinical trial on sentinel lymph node biopsy in breast cancer. The trial is experiencing excellent survival.
Christopher Chitambar, MD, professor of medicine (hematology/oncology) at the Medical College of Wisconsin, is investigating iron proteins and the hemochromatosis (HFE) gene in breast cancer.
Dr. Chitambar's research is focused on how iron and iron proteins promote abnormal cell growth that may lead to cancer. HFE is a common inherited disorder characterized by iron overload that results in organ damage leading to significant morbidty and mortality. It was discovered that a mutation of the HFE gene leads to iron overload.
His research is analyzing HFE function in tumor growth and tumor response to chemotherapy and is building on preliminary data by focusing on cervical and breast cancer. This project will provide new information about HFE in iron-dependent tumor growth and may reveal a role for HFE as a factor in the cellular responsiveness to cancer killing drugs.
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Fritz Sieber, PhD, professor of pediatrics at the Medical College of Wisconsin, is focusing on cytotoxic Se(0)-protein conjugates for the treatment of breast cancer.
High-dose chemotherapy and bone marrow transplantation have failed to significantly improve long-term survival rates in women with high-risk and metastatic breast cancer. The prevailing opinion is that currently used high-dose chemotherapy regimens fail to eradicate the tumor in the patient in a majority of cases.
One problem with the currently used chemotherapy regimens is that they rely mostly on drugs that were originally developed for the treatment of leukemias and lymphomas. Solid tumors such as breast cancer have growth characteristics that are very different from those of leukemias and lymphomas, and may, therefore, require different drugs.
A new class of anti-cancer drugs consists of two components, a protein and pure selenium. The proteins that are used for this purpose are molecules that are bound and internalized by tumor cells that have small quantities of selenium attached to them. The proteins can, therefore, act as Trojan horses and transport selenium into tumor cells.
Esophageal Cancer
Reza Shaker, MD, Medical College of Wisconsin gastroenterologist/hepatologist and director of the Froedtert & Medical College Digestive Disease Center, is principal investigator of a study analyzing genetic reasons that chronic gastroesophageal reflux disease (chronic heartburn) can lead to cancer of the esophagus. A grant from the Dr. Ralph and Marion C. Falk Medical Research Trust is allowing Dr. Shaker and his associates to break new ground in the genetics behind this problem.
Gynecologic Oncology
Janet L. Osborne, MD, Medical College of Wisconsin gynecologic oncologist, has clinical interests in gynecologic cancers (ovary, endometrium, cervix, vulva), gestational trophoblastic disease, radical surgery, cancer prevention and screening, and chemotherapy for treatment of gynecologic malignancies.
A major research focus continues on the role of glutathione in chemotherapy and radiation resistance. Current studies involve the assessment of glutathione levels in normal and malignant ovarian and cervical specimens, as well as the ability to alter glutathione resistance through use of a glutathione-depleting drug.
Other research efforts include the Gynecologic Oncology Interdisciplinary Group study entitled "Proton magnetic resonance spectroscopy: A non-invasive modality to differentiate recurrent disease, fibrosis, and necrosis following definitive irradiation for cervical cancer." Encouraging preliminary data indicate magnetic resonance spectroscopy may enhance the ability to detect cancer before and after treatment with radiation.
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Head and Neck Cancer
The Head and Neck Cancer Program is a collaborative effort of physicians and a dentist in Otolaryngology (Bruce H. Campbell, MD, FACS), Radiation Oncology (Christopher Schultz, MD, Roger Byhardt, MD, FACR, and Beth Gore, MD), Medical Oncology (Paul Ritch, MD, and Stuart Wong, MD), Radiology (Michelle Smith, MD), Plastic and Reconstructive Surgery (James Sanger, MD, and William Dzwierzynski, MD) and Oral Surgery (Steven Sewall, DDS).
Imaging
James E. Youker, MD, Medical College of Wisconsin radiologist and chairman of radiology, announced the pending installation of the first positron emission tomography (PET) scanner, which will soon be upgraded to PET/CT scan technology as part of a major new clinical program in oncologic diagnosis and imaging.
William Rilling, MD, Medical College of Wisconsin interventional radiologist, has been actively working with radiofrequency ablation and chemo embolization of liver neoplasms.
Minimally Invasive Gastrointestinal Surgery
Dennis Blom, MD, Medical College of Wisconsin surgeon, has joined the faculty of the Department of Surgery. Dr. Blom has special interest in gastrointestinal cancer surgery using laparoscopic techniques.
Pancreato-Biliary Cancer
The pancreatic service study group participated in a multi-institutional study analyzing whether Vapreotide prevents pancreatic fistulas following pancreatic surgery. Paul Grippo, PhD, has joined the Medical College of Wisconsin Department of Surgery as a post-doctoral fellow working on pancreatic cancer.
Pancreatic cancer leads to about 29,000 deaths annually in the United States, usually within the first year following diagnosis. No therapies have proven effective at altering this dismal outlook.
To design new therapies against pancreatic cancer, Dr. Grippo and his associates are studying how this disease originates and develops and how to prevent pancreatic cancer formation and spread.
Kras is an altered regulatory gene that can be detected even in early stages of pancreatic cancers. Kras is normally involved in regulating cell growth. Inappropriate Kras activation is thought to contribute to pancreatic cancer formation.
To study early events in pancreatic cancer and evaluate new therapies, the researchers generated mice that express mutated Kras and develop small pockets of cancer cells in their pancreas. The researchers propose to attack these cancer cells by stimulating the immune system to target and kill these cancer cells.
By targeting mouse cells to mutant Kras before and after mutant Kras expression, the researchers can determine the preventative and therapeutic potential of Kras vaccines, respectively. Results from these studies will help design effective, generally applicable vaccines against pancreatic cancer. Ultimately, other cancer immunotherapies can be evaluated by targeting mutant Kras in this mouse system.
William Rilling, MD, Medical College of Wisconsin interventional radiologist, and Edward Quebbeman, MD, PhD, Medical College of Wisconsin surgeon, are using radiofrequency ablation in a clinical program to treat liver tumors.
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Pharmacology and Toxicology
Representatives from the Pharmacology and Toxicology Department have published numerous papers over the last year focusing on basic research into pharmacologic anti-cancer agents.
Colleen Lawton, MD, FACR, Medical College of Wisconsin radiation oncologist, is co-author of several reports presented at the American Society for Therapeutic Radiology and Oncology. These studies reveal the positive effect of treating prostate cancer with hormones, plus external beam radiation.
William See, MD, Medical College of Wisconsin chief of urology, along with Yoshiki Iwamoto, PhD, is studying the impact of surgical wounding on the biology of prostate cancer.
They have determined that post-surgical wound fluid significantly inhibits the growth of a hormonally independent, human prostate cancer cell line. These results suggest surgical wound fluid has a selective, growth-inhibitory effect on the type of prostate cancer cells that result in patient deaths. Further studies are underway to determine the mechanism through which this effect occurs.
Physicians at the Froedtert & Medical College Cancer Center are using extremely cold temperatures to kill prostate cancer cells.
Robert Donnell, MD, MS, Medical College of Wisconsin urologist, and William See, MD, pioneered the use of freezing for prostate cancer in Wisconsin. The freezing process (cryosurgery) provides the highest cure rate with the highest safety profile for men in whom prostate cancer has recurred following treatment with radiation therapy or radioactive seeds.
Cryosurgery is also available to men who refuse surgery and/or radiation treatment. This new technology uses liquid argon to produce temperatures of –70 degrees to –110 degrees F to kill tumor cells. Cryosurgery is associated with a shorter recovery time than most other treatments for prostate cancer and, unlike other treatments, cryosurgery can be repeated if necessary.
Frank Begun, MD, MS, Medical College of Wisconsin urologist, uses laparoscopy, a technique where surgery is performed using a small telescope, to treat kidney tumors. Laparoscopy can often be combined with cryosurgery (which freezes only the tumor) allowing physicians to save the remaining normal kidney tissue.
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Radiation Oncology
In 2000, the Froedtert & Medical College Cancer Center became the first in southeastern Wisconsin to use Intensity Modulated Radiation Therapy (IMRT). Because conventional radiation treatment techniques target the tumor, plus a wide margin of normal tissues, the radiation dose must be limited to the level non-cancerous tissues can tolerate.
IMRT allows escalation of the cancer dose without increasing the risk to normal tissues, because the dose can be tightly conformed to the tumor. In IMRT, the radiation treatment approach is inversely planned by complex computer algorithms, which can quickly analyze an almost infinite number of approaches to treating the tumor.
It is now clear that IMRT can more safely deliver higher doses of irradiation than conventional radiation techniques. Early clinical trials have demonstrated improved tumor control with higher radiation doses. These results are being confirmed by a National Institutes of Health funded multi-institution trial in which Froedtert Hospital is a participant.
Thoracic Tumors
A trial to evaluate the use of preoperative chemo-radiation with a Cox-2 inhibitor thought to have anti-angiogenetic properties in certain patients with non-small cell cancer of the lung has been approved and funded.
A retrospective study of Stage I and II non-small-cell lung cancer was carried out during the past year. This study showed a significant correlation between co-morbidities and outcome for patients treated with surgery or radiation therapy. The manuscript is in press for the International Journal of Radiation Oncology, Biology, and Physics.
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Pituitary Cancer
Bahiru Gametchu, PhD, associate professor of pediatrics (hematology/oncology) at the Medical College of Wisconsin, is studying signal transduction pathways initiated via plasma membrane receptor for estrogen receptor-a.
Because estrogens (E2) support breast tumor cell growth, understanding how this process works has been the goal of clinicians trying to devise prevention and treatment blueprints. Dr. Gametchu has previously identified a sub-population of GH3/B6 pituitary tumor cells which bear a new form of the estrogen receptor-a (mERa) on their plasma membranes, in addition to the classical intracellular receptor. These membrane estrogen receptors (MERs) mediate nongenomic responses to estrogen, and respond to protein-conjugated estradiol (which cannot enter cells rapidly).
It is likely that the membrane receptor form of estrogen receptor-a can begin signal transduction leading to cell multiplication when hormone is bound to it. Measurement of receptors responsible for starting responses leading to tumor cell growth will improve clinical selection of patients who will benefit from hormone-targeted therapies.
Colon Cancer
Parvaneh Raffiee, PhD, assistant professor of surgery (transplant surgery) at the Medical College of Wisconsin, is studying the effect of ionizing radiation on human intestinal microvascular endothelial cells.
Tissue specific microvascular endothelial cells lining capillaries and venules, play a central role in multiple physiologic processes including inflammation, wound healing, embryogenesis and hemostasis. Overwhelming evidence now suggests that the growth of new microvessels, or angiogenesis, plays a key role in solid tumor progression as rapidly growing neoplastic cells require an increased nutrient supply that must be delivered through neovascularization.
Other pioneering work has demonstrated that tumor growth is angiogenesis dependent, and angiogenesis is essential for tumors to grow larger than 1 mm, the maximum distance for oxygen transport and nutrient diffusion. Assuming that tumor growth and metastasis requires neovascularization, then specifically targeting the proliferation of microvascular beds may emerge as an attractive therapeutic strategy.
Recent investigation has demonstrated that angiogenesis is a common feature in colorectal cancer, and over expression of the angiogenic cytokine vascular endothelial growth factor (VEGF) has been demonstrated in 36 of 36 tumors analyzed in one study. Thus, investigation of angiogenesis and tumor microvascular endothelium in colorectal cancer is a promising area for defining tumor biology as well as devising forms of anti-angiogenic adjuvant cancer therapy.
The Medical College of Wisconsin scientists have focused on the microvascular biology of human intestinal inflammation, and have developed novel protocols for the routine in vitro isolation and culture of human intestinal microvascular endothelial cells (HIMEC) from surgically resected small and large intestine. The researchers have recently succeeded in culturing microvascular endothelial cells from colorectal adenocarcinomas, as well as matched normal colon.
In this research, Dr. Raffiee is extending his investigation into human intestinal microvascular angiogenesis, to formally define the signaling pathways and mechanisms which underlie the growth and proliferation of human intestinal microvascular endothelial cells. He also wants to determine the effect of ionizing radiation on the microvascular endothelial cells from the large intestine.
Andrey Sorokin, PhD, assistant professor of medicine (nephrology) at the Medical College of Wisconsin, is studying the molecular mechanisms involved in treating patients with relapsing prostate cancer.
The treatment of patients with relapsing prostate cancer is usually disappointing, with chemotherapy having little or no effect due to high resistance to programmed cell death (apoptosis) of metastatic prostate cancer cells. Dr. Sorokin's research is addressing the molecular mechanisms of this resistance.
He is testing the hypothesis, that the presence of protein called cyclooxygenase-2 is the cause of resistance to apoptosis of prostate cancer cells. The rationale for these studies is derived from his previous work, demonstrating that decreasing cyclooxygenase-2 activity makes prostate cancer cells more sensitive to apoptotic agents and that cyclooxygenase-2 protein increased synthesis of proteins with known anti-apoptotic properties, thus promoting survival of cancer cells.
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