Gynecologic cancers originate in the female reproductive organs, including the uterus, ovaries, cervix, fallopian tubes, vulva and vagina. More than 80,000 gynecologic cancers are diagnosed in the United States each year, and about half of these cases are endometrial (uterine) cancer. Ovarian cancer is the second-most common gynecologic malignancy in this country. More than 22,000 cases are diagnosed every year, and more than 16,000 people die from it annually.
Gynecologic cancer is a serious disease, but in the majority of cases it can be treated and cured.
At the OSUCCC – James, our treatment team is dedicated to providing excellent, research-based clinical care for women who have or are at risk for gynecologic cancer. Working closely together, our physicians and researchers are better able to translate scientific advances to innovative patient care.
Gynecologic cancers may be treated by surgical procedures, radiation therapy and/or chemotherapy. At the OSUCCC – James, our gynecologic cancer treatment team includes specially trained medical, surgical and radiation oncologists along with experts in clinical cancer genetics. A board certified gynecologic oncologist functions as each patient's primary care cancer physician during the diagnostic, treatment and follow-up phases of her care.
- Examine all molecular aspects of gynecologic cancer cells—genetic, epigenetic, RNA/protein, non-coding RNAs and biochemical—and integrate these features to improve cancer risk stratification and to more effectively direct targeted therapies toward each person’s unique cancer
- Develop preclinical and clinical immunotherapeutic approaches that bolster the human immune system’s innate ability to combat gynecologic cancer
- Devise targeted therapies to thwart gynecologic cancer-relevant kinase-signaling pathways
Clinical research on promising investigational treatments for gynecologic malignancies at the OSUCCC – James is supported by numerous grants both private and public, but particularly from the National Institutes of Health. Here are a few examples:
The Ohio State University as Network Lead Academic Participating Site for the NCI National Clinical Trials Network (NCTN) (1 U10 CA180850 01)
PI: Richard Goldberg, MD, physician-in-chief at the OSUCCC – James
Co-PI: David Cohn, MD, director of the Division of Gynecologic Oncology at Ohio State
- Provide infrastructure to support Ohio State’s participation in the scientific and clinical research activities of the NCI's NCTN Program as a Network Lead Academic Participating Site (NLAPS)
- Use this support to make scientific discoveries about tumor biology, find better treatments and augment quality of life for patients, thus improving outcomes across the spectrum of cancers affecting adults
- Investigate new therapeutic agents and their toxicities in phase I to II clinical trials
- Evaluate the efficacy and toxicity of novel combinations based on preclinical data to exploit drug combinations more effectively
- Develop multi-modal approaches using surgical, immunological and radiotherapeutic measures in optimal combinations
- Integrate experts in molecular genetics, biochemistry, pharmacology, immunology and biostatistics in the design and execution of therapeutic protocols
- Improve cancer outcomes through discovery and education of pre- and postdoctoral students, nurses, allied medical personnel and physicians
- Understand and exploit tumor heterogeneity to exploit the value of targeted therapies
- Improve management of cancer-related symptoms
Dissecting the Role of Stat3 and Targeting Ovarian Cancer (1 R01 CA176078 01A1)
PI: Selvendirian Karuppaiyah, PhD
- Further elucidate mechanisms of STAT3 activation in ovarian cancer and determine how this contributes to drug resistance
- Use an in vivo orthotopic ovarian cancer model to evaluate whether diarylidenyl piperidone (DAP) compounds can overcome hypoxia-related drug resistance and increased toxicity
- Advance the understanding of ovarian tumorigenesis and use this knowledge to improve treatment for ovarian cancer patients who develop hypoxia-mediated chemotherapy resistance
Mismatch Repair and Carcinogenesis (5 R01 CA067007 19)
PI: Richard Fishel, PhD
- Use newly developed methodologies to resolve the mechanism of MMR on naked DNA and then determine the function(s) of MMR components on physiologically relevant chromatin for comparison
- Enumerate the precise mechanism of human MMR using single-molecule analysis
- Determine functions of the human MMR proteins on physiologically relevant chromatin
- Examine the biophysical mechanism of homologous recombination suppression by MMR
- Apply results to determine the functional defects associated with missense mutation found in families with Lynch syndrome
Examples of Clinical Trials for Gynecologic Cancers
(OSU-13059) A Phase I, First-in-Human Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of IMGN853 in Adults With Ovarian Cancer and Other FOLR1-Positive Solid Tumors (NCT01609556)
PI: David O’Malley, MD
- Test the drug IMGN853 in treating patients with folate receptor 1 (FOLR-1)-positive ovarian and other solid tumors (FOLR-1 is a gene)
- Determine maximum tolerated dose and recommended phase II dose of IMGN853
(OSU-13151) Randomized Phase II Study of Intravenous 3-Aminopyridine-2-Carboxaldehyde Thiosemicarbazone (3-AP, Triapine® NSC #663249) Cisplatin-Radiochemotherapy Versus Intravenous Cisplatin-Radiochemotherapy in Women Diagnosed With Stage IB-IVA Cervical Cancer and Stage II-IVA Vaginal Cancer (NCT01835171)
U: John Hays, MD
- Determine the post-therapy three-month fludeoxyglucose F 18 (18F-FDG) positron emission tomography (PET)/computed tomography (CT) complete metabolic response of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) (triapine) radiochemotherapy
- Determine acute < 30-day adverse events of 3-AP radiochemotherapy by Common Terminology Criteria for Adverse Events (CTCAE), version 4
- Determine the late >= 30-day adverse events of 3-AP radiochemotherapy by CTCAE, version 4
- Determine post-therapy clinical response by Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1
- Determine the progression-free interval of 3-AP radiochemotherapy
- Determine peripheral blood methemoglobin proportion before and after 3-AP infusion (optional)
(OSU-13218) Randomized Controlled Study Comparing AEZS-108 With Doxorubicin as Second-Line Therapy for Locally Advanced, Recurrent or Metastatic Endometrial Cancer (NCT01767155)
PI: David O’Malley, MD
- Compare the efficacy and safety of the drugs AEZS-108 and doxorubicin. The study will include about 500 patients with endometrial (uterine) cancer resistant to platinum/taxane-based chemotherapy
- Compare the overall survival (OS) of patients treated with AEZS-108 to the OS of patients treated with doxorubicin.
Examples of Recent Clinical Research Accomplishments
Pelotonia ‘Idea Grant’ Supports Study of Drug Resistance in Ovarian Cancer. OSUCCC – James researchers received an “Idea Grant” supported by Pelotonia—an annual grassroots bicycle tour that raises millions of dollars for cancer research at Ohio State—to study ways of reversing drug resistance in patients with ovarian cancer. Chemotherapy kills cancer cells by damaging their DNA so badly the cells can’t repair it. Nonetheless, ovarian cancer recurs in up to 80 percent of patients after treatment with chemotherapy. But these researchers have found that a protein called histone deacetylase 10 (HDAC10) is part of a DNA repair system in cells. They believe this system allows some ovarian cancer cells to survive the damage inflicted by the platinum-based chemotherapy used to treat the disease. This grant will enable them to examine whether drugs called HDAC inhibitors will knock out the HDAC10-powered DNA repair system and make drug-resistant ovarian cancers respond once again to platinum-based chemotherapy. If successful, the project will lay the groundwork for a new treatment strategy that might prolong the lives and reduce the suffering of women with ovarian cancer. Grant awardees are Jeffrey Parvin, MD, PhD, and David Cohn, MD.
Statewide Screening Launched by Ohio State Has Lifesaving Potential. The OSUCCC – James has launched a statewide initiative to screen newly diagnosed colorectal cancer patients and their biological relatives for Lynch syndrome, a genetic condition that predisposes individuals to colorectal, uterine and ovarian cancers. The initiative—made possible through money raised by Pelotonia, an annual grassroots bicycle tour that raises money for cancer research at Ohio State—will identify family members who may be at risk of developing these cancers so they can take precautionary measures. The Ohio Colorectal Cancer Prevention Initiative is led by Heather Hampel, a certified genetic counselor at Ohio State. Hampel says about 3 percent of colorectal cancer cases result from Lynch syndrome, which is characterized by inherited mutations in one of four genes for DNA-repair proteins.
Study Shows Benefit of 3-Drug Regimen in Treating Recurrent Ovarian Cancer. A phase II study led by researchers at the OSUCCC – James found that a biweekly regimen involving the drugs gemcitabine, carboplatin and bevacizumab was effective for treating patients with platinum-sensitive recurrent ovarian, peritoneal or tubal cancer. The study, which involved 45 patients and was published in the journal Gynecologic Oncology, found that the three-drug regimen, administered at specific intervals, showed an improved response rate and progression-free survival over outcomes previously reported for patients receiving just a gemcitabine/carboplatin combination. The researchers contend that the three-drug combination should be further evaluated. Larry Copeland, MD, was senior author for the study.
Examples of Translational Research Accomplishments
Novel Agent Could Boost Treatment for Endometrial Cancer. An experimental agent designed by researchers at the OSUCCC – James decreased high levels of a protein that is overexpressed in endometrial (uterine) cancer, and the scientists believe the agent could serve as an adjunct targeted therapy for patients with this disease. Reporting in the journal Gynecologic Oncology, the investigators stated that treatment with HO-3867, a novel agent that inhibits the STAT3 protein, decreased the high levels of STAT3 Ser727 in endometrial cancer cells by inducing cell cycle arrest and apoptosis, or natural cell death. The preclinical study involved cell lines, human tumor samples and xenograft mice. Selvendiran Karuppaiyah, PhD, was corresponding author.
Study Reveals Useful Tool in Characterizing Endometrial Cancer. The National Cancer Institute’s Cancer Genome Atlas described DNA polymerase ɛ (POLE)-mutant tumors as a molecular subtype of endometrial (uterine) cancer with improved progression-free survival. A study led by OSUCCC – James researchers expanded on the Genome Atlas investigation and found that POLE mutations can be a useful tool in determining whether endometrial cancer is a result of sporadic or inherited predisposition to the disease. Paul Goodfellow, PhD, was corresponding author for the study, which was published in the journal Cancer (epub ahead of print).
MMR Protein Expression Study in Endometrial Cancer Finds Biological Associations. In a translational research study of mismatch repair (MMR) protein expression in 1,049 patients with endometrial (uterine) cancer, OSUCCC – James investigators sought to identify relationships among cancer outcome, weight (BMI) and other factors. They found that BMI showed statistically significant associations with MMR expression, tumor grade and stage among the study participants, and that obesity correlates with lower grade and stage endometrial cancer. A link between BMI and maintenance of the MMR system was not supported by the data. The study was published in the journal Gynecologic Oncology. Adrian A. Suarez, MD, was corresponding author.
HO-3867, a Safe STAT Inhibitor, is Selectively Cytotoxic to Ovarian Cancer. A preclinical study led by OSUCCC – James researchers and published in the journal Cancer Research offered proof-of-concept for an agent called HO-3867 as a selective STAT3 inhibitor to treat ovarian cancer and other solid tumors where STAT3 is widely upregulated. In their study abstract, the researchers state that STAT3 is well corroborated preclinically as a cancer therapeutic target, but they note that translational strategies for its blockade by small molecule inhibitors has been elusive. In this study, they reported the development of a class of bifunctional STAT3 inhibitors, based on conjugation of a diarylidenyl-piperidone (DAP) backbone to an N-hydroxypyrroline (-NOH) group, that exhibits minimal toxicity against normal cells and good oral bioavailability. Selvendiran Karuppaiyah, PhD, was corresponding author.
The Ohio State University College of Medicine Fellowship in Gynecologic Oncology, established in 2008, is a three-year program that includes one year of research followed by two years of clinical training. The goal of the fellowship program, led by Ritu Salani, MD, is to train gynecologic oncologists who are exemplary physicians to care for and provide consultation and comprehensive management to patients with gynecologic cancer.
This is accomplished through training fellows to be:
- Surgeons, who are able to manage a full range of technical surgical issues and complex medical problems that arise in women with gynecologic cancers
- Teachers, who can transmit the information learned during their fellowships to the patients they manage as well as to other medical personnel (i.e. obstetrician/gynecologists)
- Researchers, whose investigation of the clinical and basic scientific questions will lead to improved outcomes in women with gynecologic cancers.
The Ohio State University College of Medicine Gynecologic Oncology Faculty:
- Floor Backes, MD
- David Cohn, MD, Division Director
- Larry Copeland, MD
- Jeffrey Fowler, MD
- David O’Malley, MD
- Ritu Salani, MD, MBA, Fellowship Director
- Caroline Billingsley, MD, 3rd year (clinical), from Medical University of South Carolina
- Adam ElNaggar, MD, 2nd year (clinical) from University of Tennessee, Memphis
- JJ Wallbillich, MD, 2nd year (clinical) from University of Texas, Houston
- Kristin Bixel, MD, 1st year (research) from Beth Israel Deaconess Medical Center
- Blair Smith, MD, 1st year (research) from The Ohio State University
The research fellow is expected to either develop an independent research focus or integrate their interests into an existing collaborative research path within the Division of Gynecologic Oncology. Current basic science research projects include:
- Immunology and vaccine research in ovarian cancer (specifically peptide design and anti-angiogenic therapy, research by a faculty member in collaboration with PhD immunologist);
- Molecular biology of endometrial cancer (specifically DNA mismatch repair and epigenetic gene silencing, collaboration with PhD molecular biologists)
- Molecular profiling of ovarian cancer (specifically pharmacogenomics, collaboration with PhD molecular biologist)
- Cervical cancer susceptibility (specifically investigation of polymorphisms in TGFBR1)
The Division also has strong clinical research interests focusing on novel therapeutics as well as outcomes research focusing on population science and health disparities (collaboration with PhD population scientists). During the research year, whether the focus is on clinical or basic science, the education of the fellow will be in the development and execution of a research plan based on the scientific method. At Ohio State and through the Comprehensive Cancer Center, the Division has established extremely successful research collaborations that continue to expand. Throughout the fellowship, the fellows will perform mentored clinical research as projects evolve. Mentorship will be provided by the faculty who is supervising the research.
Fellows will be operating with faculty surgeons as the primary surgeon or first assistant, or as the primary surgeon with residents as the first assistant and the faculty member as the second assistant. Since each fellow enters their clinical fellowship years with varying levels of skill and previous experience, there is no formal progression of responsibility as the fellow advances from their junior to senior clinical year. Toward the end of the junior and through the senior clinical year, it is expected that, with experience, the fellow will assume more of a primary surgical role. The primary inpatient management will be the responsibility of the clinical fellows. The level of responsibility in patient management should be constant throughout the clinical fellowship years, but the amount of input from the faculty regarding daily management may vary based on the fellows’ prior experience.
Members of the Division of Gynecologic Oncology provide comprehensive services for patients diagnosed with gynecologic malignancies, including radical pelvic surgery, pelvic and vaginal reconstruction, advanced laparoscopic and robotic surgery, and care for complications of diseases and treatments. The following are some of the unique clinical services available in the Division:
- Minimally Invasive Surgery:
- Advanced laparoscopic surgery in gynecologic oncology has been performed at Ohio State since the 1990s, and continues to play a major role in the surgical management of gynecologic cancer patients.
- Robotic Surgery – Drs. Fowler, Cohn, O’Malley, Backes and Salani are certified to perform robotic surgery.
- Intraoperative radiation therapy (IORT): A dedicated linear accelerator in our cancer operating rooms makes it possible for selected patients to receive advanced radical pelvic surgeries in combination with intraoperative radiation therapy. This technique has been utilized in patients undergoing exenterative procedures, as well as those undergoing lymph node debulking for recurrent gynecologic cancers.
- Pelvic reconstructive surgery: Members of the division of gynecologic oncology perform these procedures, including myocutaneous vaginal reconstruction.
- Urologic and bowel surgeries: Faculty in the division of gynecologic oncology perform these procedures, which include continent urinary diversion.
Formal didactic education within the Division includes:
- Monthly morbidity and mortality review
- Monthly Departmental Journal Club
- Quarterly Divisional Journal Club
- Weekly Gynecologic Oncology Tumor Board
- Weekly Oncology Fellows’ Lecture Series
Ohio Medical License: The application process should be started immediately after you have been accepted as a fellow. It can take as long as 6 months for the Ohio Medical License process to be completed. Go to http://www.med.ohio.gov/ and you will also need a Federation Credentials Verification Service application (FCVS) http://www.fsmb.org/fcvs.html. Both of these websites are self explanatory with the license requirements and application.
Fellowship Coordinator: Jan Testa (firstname.lastname@example.org)
Prerequisites: Satisfactory completion of an ACGME approved OB/GYN residency program