- Organizing the Heterogeneity in High-Grade Serous Ovarian Cancer by Mass Cytometry
- Genetic Profiling in the Australian Ovarian Cancer Study
- Premalignant Expression Signature in BRCA-1-mediated Ovarian Cancer
- Understanding Ovarian Cancer Risk Factors
- New Agents for Taxol-Resistant Ovarian Carcinoma
The OCRP Teal Innovator Award supports a highly recognized, visionary individual with the funding and the freedom to focus his creativity, innovation, and leadership on high-risk ideas that could significantly impact ovarian cancer research or patient care. The first recipient of this unique award mechanism, Dr. Garry Nolan, of Stanford University, hypothesizes that there are underlying "currents" of biology and pathology across tumors. Dr. Nolan envisions creating a unifying picture of ovarian cancer systems biology that facilitates real and long-term changes in the understanding of this disease and brings about changes to treatment modalities.
Dr. Nolan's research team is focused on validating a new adaptation of flow cytometry (called mass cytometry) to study complex samples, such as human tumors, at the single-cell level. This technique allows them to trace the lineages and reconstruct the family tree of ovarian cancers. Dr. Nolan and his team previously found that a common family tree is formed across samples from 40 different ovarian cancer patients, and the researchers will now extend their studies to more ovarian cancer samples to determine which cells are the best to target for a therapy to be most effective for each patient. Establishing whether there are different responses of each branch of the "family tree" to important clinical drugs is a priority of this research. It is expected that deep proteomic profiling of single cells enabled by single-cell mass cytometry will have enormous impact by providing a far more detailed characterization of this disease on a patient by patient basis than currently exists. The potential impact of this research includes choosing optimal therapeutic outcomes for each patient based on the particulars of their individual cancer or in finding leads for the development of new targeted agents against cells in a cancer that are not acted upon by conventional therapies. This work may also result in new approaches for early detection of ovarian cancer.
With regard to this exciting and paradigm-changing research, Dr. Nolan has stated, "My laboratory and those of our collaborators are firmly committed to a large-scale effort in this malignancy. Basically, our message is that cancers can be organized, can be mapped, and we can finally understand which cells a given drug has activity against and map this to the molecular biology of the disease. We hope that our work can overcome one or both of the major barriers (deeper classification and early detection) to improving therapeutic outcome for ovarian cancer patients."
One of the forefronts of ovarian cancer research is focused on identifying and understanding the different subtypes of this cancer, with the goal of effectively tailoring treatments. Dr. David Bowtell is involved in multiple projects that are aimed at this essential question.
One of the most well-defined risk factors for ovarian cancer is an inherited germline mutation in either the BRCA1 or BRCA2 genes. It is therefore important to characterize the clinical, pathological, family history, and molecular factors that can predict BRCA1/2 mutations and understand the effect of BRCA1/2 mutations on ovarian cancer treatment outcomes. Drs. Gillian Mitchell and David Bowtell, recipients of a FY07 Translational Research Partnership Award, evaluated the frequency and impact of germline BRCA1/2 mutations in 1,001 population-based ovarian cancer cases. The research, led by Ph.D. student Ms. Kathryn Alsop, leveraged existing samples and case information from the FY00 OCRP-funded Australian Ovarian Cancer Study (AOCS). BRCA1/2 mutations were identified in 14% of the 1,001 samples from women with invasive non-mucinous ovarian tumors, similar to that reported previously by Canadian researchers. Importantly, the AOCS researchers found that BRCA1/2 germline mutations were predominantly restricted to high-grade serous cancers, where the combined frequency was 22.7%. Almost half the women carrying BRCA1/2 mutations did not have a significant family history of breast or ovarian cancer. These findings challenge the current practice of offering genetic testing only to women with a positive family history of breast or ovarian cancer.
Very detailed clinical information was associated with the AOCS samples, allowing researchers to compare responses to first and second lines of chemotherapy in carriers and non-carriers. Enhanced responses to platinum and non-platinum based chemotherapy were seen in mutation carriers in both first- and second-line treatments. The researcher's findings have important implications for use of conventional chemotherapy in mutation carriers and the design of clinical trials in women with high-grade serous cancer.
In another study using ovarian high-grade serous cancer samples from the AOCS, Dr. Bowtell and research fellow Dr. Prue Cowin investigated matched tumor samples from women pre- and post-treatment. A variation in copy number of DNA (the duplication or deletion of parts of chromosomes) previously shown in ovarian cancer was found in these samples. After relapse, patients who had neither hereditary nor spontaneous BRCA1 mutations and were initially sensitive to therapy but were resistant after relapse (S-R) had a greater increase in copy number variation compared to patients who were always resistant to therapy (R-R).
Examining the locations of these copy changes that were distinct to the 11 patients in the S-R group compared to the R-R patients, the investigators found that 4 of these 11 patients had a loss of chromosome section 2q21.2, particularly in the region of the low-density lipoprotein receptor-related protein 1B (LRP1B). Mutations in this gene have been found in other solid tumors. In addition, in this S-R group, a significant reduction in LRP1B expression was seen from the original tumor or ascites samples compared to the ascites sample taking during the resistant relapse. This was confirmed in an independent validation using 92 primary tumor and 43 recurrent ascites samples from women with high grade serous ovarian carcinoma. Experiments in cell lines found that addition of LRP1B to cells with low expression reduced cell growth rates and increased sensitivity to liposomal doxorubicin, with no change noted in response to normal doxorubicin. "Silencing" this gene in cells had the opposite effect. As the expression of LRP1B was detectable from cells obtained from ascites fluid, it is a potential target to identify women who are likely resistant to liposomal doxorubicin before they are ever treated for a relapse.
Cowin PA, George J, Fereday S, Loehrer E, Van Loo P, Cullinane C, Etemadmoghadam D, Ftouni S, Galletta L, Anglesio MS, Hendley J, Bowes L, Sheppard KE, Christie EL, Australian Ovarian Cancer Study, Pearson R B, Harnett PR, Heinzelmann-Schwarz V, Friedlander M, McNally O, Quinn M, Campbell P, deFazio A , and Bowtell DDL. 2012. LRP1B deletion in high-grade serous ovarian cancers is associated with acquired chemotherapy resistance to liposomal doxorubicin. Cancer Research 72(16):4060-4073.
Alsop K, Fereday S, Meldrum C, deFazio A, Emmanuel C, George J, Dobrovic A, Birrer MJ, Webb PM, Stewart C, Friedlander M, Fox S, Bowtell D, and Mitchell G. 2012. BRCA mutation frequency and patterns of treatment response in BRCA mutation-positive women with ovarian cancer: A report from the Australian Ovarian Cancer Study Group. Journal of Clinical Oncology 30(21):2654-2663.
With their OCRP Translational Research Partnership Award, which the DoD granted in FY07, laboratory scientist Anton Krumm and clinician Elizabeth Swisher, of the University of Washington, brought their collaborative efforts to the study of pre-malignant and epigenetic alterations in fallopian tube epithelium (a potential site of origin for epithelial ovarian cancer) in women with BRCA1 mutations. Drs. Swisher and Krumm observed that women with BRCA1 mutations have a 50% lifetime risk of ovarian cancer; they hypothesized that fallopian tube epithelium tissue from women with BRCA1 mutations would have a unique gene expression profile reflective of early changes in the fallopian tube that lead to the development of ovarian cancer. Over the course of their award, Swisher and Krumm discovered a potential BRCA1 pre-neoplastic gene expression signature profile for BRCA1 serous carcinoma that may identify early changes in BRCA1-mediate ovarian carcinogenesis. Since completion of their award, the researchers have validated candidate genes as important in early premalignant changes in BRCA1-mutated normal fallopian tube, thus improving our understanding of the molecular events associated with the early events of ovarian and fallopian tube carcinogenesis. The investigators are currently exploring how this gene expression signature profile can be applied to achieve early detection of the disease or used to identify potential candidates for risk-reducing surgery. In follow-up studies of the general population, the investigators are hoping to determine the fraction of ovarian cancers that arise from the fallopian tube lining and, of those, how many have a familial risk for the disease. These studies are bringing us closer to understanding the origin of ovarian cancer, a critical contribution toward improving both screening and prevention of this deadly disease.
Press JZ, Wurz K, Norquist BM, Lee MK, Pennil C, Garcia R, Welcsh P, Goff BA, Swisher EM. 2010. Identification of a preneoplastic gene expression profile in tubal epithelium of BRCA1 mutation carriers. Neoplasia 12(12):993-1002.
Thomas BJ, Rubio ED, Krumm N, Broin PO, Bomsztyk K, Welcsh P, Greally JM, Golden AA, Krumm A. 2011. Allele-specific transcriptional elongation regulates monoallelic expression of the IGF2BP1 gene. Epigenetics & Chromatin 4:14.
Dr. Terry is a member of the DOD OCRP's Ovarian Cancer Academy. The Ovarian Cancer Academy is a virtual career development and research training platform providing mentoring, networking, peer support, and collaborative opportunities for talented, highly committed junior faculty. Her research is focused on understanding ovarian cancer risk factors by etiologic pathway. Based on measurements from pathology reports, she and her colleagues have classified more than 1,700 cases from the New England Case Control Study and the Nurses' Health Study into dominant tumors (likely of ovarian origin) defined as those restricted to one side or with one side that is two times greater than the other and nondominant (likely tubal origin). They have found that dominant tumors are more strongly associated with multiparity, tubal ligation, and endometriosis, whereas nondominant tumors are more strongly associated with a family history of ovarian cancer and genetic variation in a telomere-associated protein, TERT. Results from Dr. Terry's work provide a better understanding of ovarian cancer risk factors, which is important for prevention.
Primary diagnosis of ovarian cancer often occurs at late stages of the disease, when metastasis has already occurred. After surgical debulking (removal of a portion of the tumor), adjuvant chemotherapy treatment with platinum and/or taxane compounds often produces high initial response rates, followed by high relapse rates, with patients exhibiting a drug-resistant form of disease correlating with poor probability of 5-year survival. Previous clinical trials showed improved survival rates, in patients with low-volume disease, when these drugs were administered intraperitoneally rather than intravenously. Several types of tumors, including ovarian, express significant amounts of the CD44 family of cell surface proteins, and Dr. Jim Klostergaard, of the University of Texas M. D. Anderson Cancer Center, hypothesized that they would provide an effective target to allow for localization of therapies to tumors, thus lowering overall toxicity. Dr. Klostergaard received a New Investigator Award from the fiscal year 2000 Department of Defense Ovarian Cancer Research Program to test hyaluronic acid (HA), the natural ligand for CD44, as a backbone for paclitaxel (TXL) prodrugs.
Dr. Klostergaard prepared HA-TXL and analyzed its toxicity and antitumor activity in two CD44+ human ovarian carcinoma xenograft mouse models. He was able to establish that a small intraperitoneal dose of this HA-based prodrug, below the maximum tolerated dose, reduced or eliminated tumor burden and prolonged survival when compared to controls. His current work in several human ovarian cancer models, including those that are taxane-resistant, indicates that frequent low doses of targeted HA-TXL are more effective than a systemic treatment based on the maximum tolerated dose and is under revision for publication in Clinical Cancer Research. This validates the potential for CD44-HA interactions to be used in the targeted delivery of anticancer agents specifically to cancer cells.
Auzenne E, Ghosh SC, Khodadadian M, Rivera B, Farquhar D, Price RE, Ravoori M, Kundra V, Freedman RS, and Klostergaard J. 2007. Hyaluronic acid-paclitaxel: Antitumor efficacy against CD44(+) human ovarian carcinoma xenografts. Neoplasia 9:479-486.