Advances Spring 2011 Issue. In the United States, ovarian cancer remains the deadliest of all gynecologic malignancies and the fifth leading cause of cancer death for women. The lack of an adequate early-detection screening assay is a major factor in the high fatality rate. More than 75 percent of cases present with advanced-stage disease; of these patients, fewer than 30 percent have five-year disease-free survival rates or are cured.
Genetic Profiling Uncovers New Therapeutic Approaches to Ovarian Cancer
In the United States, ovarian cancer remains the deadliest of all gynecologic malignancies and the fifth leading cause of cancer death for women. The lack of an adequate early-detection screening assay is a major factor in the high fatality rate. More than 75 percent of cases present with advanced-stage disease; of these patients, fewer than 30 percent have five-year disease-free survival rates or are cured.
75%: the percentage of cases that present with advanced-stage disease, at which point five-year survival rates are less than 30 percent
Despite apparent differences in histologic types and grades of tumors of the ovary, standard therapies have historically treated all epithelial ovarian cancers the same: Patients have undergone surgical cytoreduction followed by platinum-based chemotherapy. Approximately 80 percent of advanced-stage ovarian cancers initially respond to this therapy, achieving a complete remission; but most recur, and patients, though living for five years or more, die with drug-resistant tumors.
Given these challenges, physicians and researchers have recognized the need to understand the biology of these tumors as the critical first step toward developing novel therapeutic approaches. Prior to joining the Massachusetts General Hospital Cancer Center in late 2008, Michael J. Birrer, MD, PhD, began leading a series of collaborative studies based at the National Cancer Institute (NCI), where he was deputy chief of the Cell and Cancer Biology Branch. Dr. Birrer, who is now director of Medical Gynecologic Oncology at the Cancer Center, began working in 2003 with NCI colleagues, along with researchers at Brigham and Women’s Hospital, Harvard Medical School, Harvard School of Public Health, and Memorial Sloan-Kettering Cancer Center to systematically examine the genomic profile of ovarian epithelial tumors. Using laser capture microdissection to pull out the epithelial component of the tumors, the investigators isolated the stroma for high-density transcription profiling analysis.
The studies revealed that malignancies long considered clinically and morphologically indistinguishable are, in fact, biologically different diseases. Different histologic subtypes and grades of tumors may all originate in the ovary, but they have diverse patterns of gene expression. Buried in those patterns, researchers have discovered activated pathways and novel therapeutic targets. This work is fundamentally changing the treatment of ovarian cancer, moving the field from homogenous treatment approaches to more individualized therapies.
Differentiating Tumors by Grade
Translational Research Laboratory (TRL) technicians evaluating gene copy numbers by FISH in advanced-stage ovarian cancer.
A 2005 study by Dr. Birrer and his colleagues contributed to this strategic shift by examining the genomic composition of serous tumors of different tumor grades. (Serous cancers are the most common histologic subtype of ovarian tumors and account for approximately 70 percent of diagnosed cases.) This seminal study examined gene expression patterns for large numbers of tumors.
The findings revealed that low-grade serous tumors are an entirely distinct cancer from high-grade serous carcinomas. Even more significant, this study pointed the way toward more tailored therapies for patients with low-grade tumors. The profiling data and sequencing analysis indicated that activation of the MAP kinase pathway is an important feature of these tumors. Today, the Cancer Center is conducting trials using a single-agent MEK-inhibitor for recurrent low-grade tumors due to the nodal position of MEK in the MAP kinase pathway.
Characterizing Histologic Subtypes of Ovarian Cancers
As with tumor grade, genetic profiling suggests that endometrioid, clear cell, and mucinous tumors, which represent about 20 percent of all ovarian cancers, are biologically distinct from serous invasive tumors—and are associated with specific activated pathways that can be therapeutically targeted.
The team of researchers systematically examined the genomic profile of ovarian epithelial tumors. Using laser capture microdissection to pull out the epithelial component of the tumors, the investigators isolated the stroma for high-density transcription profiling analysis. The studies revealed that malignancies long considered clinically and morphologically indistinguishable are, in fact, biologically different diseases.
In another 2005 study, Dr. Birrer and others published clear evidence of these biological distinctions among histologic subtypes. The study examined clear cell, serous, and endometrioid cancers of the ovary and endometrium, as well as renal clear cell cancers. The results showed that clear cell tumors were distinct from serous ovarian carcinomas and could not be statistically distinguished from clear cell tumors originating in other organs, such as the kidney.
In a study to be published in 2011, Dr. Birrer and colleagues have identified differentially expressed genes and molecular signatures that present alternative therapeutic targets for treatment of clear cell tumors. They found that, unlike serous cancers, clear cell tumors have a unique ability to survive under stress conditions and continue to grow prolifically in low-oxygen and low-glucose environments. This capability derives from the tumors’ strong angiogenic signaling pathway involving upregulation of HIF 1 alpha, VEGF, and PGF and their ability to mobilize large quantities of energy-producing glycogen through activation of the enolase-mediated metabolic pathway.
Based on this discovery, Mass General Cancer Center investigators are now developing alternative therapies, such as using anti-angiogenic agents to starve the blood supply to clear cell tumors and using mTOR inhibitors to block their metabolism. Two such trials are now ongoing at the Cancer Center.
Investigators have made comparable strides in profiling mucinous tumors. A 2006 study by Dr. Birrer and researchers at NCI, Harvard Medical School, and the Harvard School of Public Health was the first to demonstrate that mucinous low malignant potential (LMP) tumors are genetically distinct from serous LMP tumors. They do not behave in the same benign manner as serous LMPs and are strongly associated with invasive serous adenocarcinomas.
The study had clear clinical implications for the pathologist and the physician, indicating that any mucinous tumor should be closely examined, as a seemingly benign borderline tumor could well have an invasive component. Expression profiling has further differentiated these tumors from serous ovarian cancer, suggesting that patients with mucinous cancers of the ovary should be treated with regimens other than carboplatin and taxol.
Cancer Center investigators are now leading an international trial for the Gynecologic Oncology Group of one such therapy using bevacizumab, an anti-angiogenic agent, in combination with the chemotherapy drug XelOx for advanced stage mucinous cancer.
Addressing Serous Tumors
Gene expression analysis of endometrial and ovarian tumors: A) Nonoverlapping gene expression profiles of endometrial and ovarian papillary serous tumors. B) Nonoverlapping gene expression profiles of endometrial and ovarian endometrioid tumors. C) Overlapping gene expression profiles of endometrial and ovarian clear cell tumors. D) Overlapping gene expression profiles of endometrial, ovarian, and renal clear cell tumors.
High-grade invasive serous cancers cause the majority of ovarian cancer deaths. Investigation is now under way at the Cancer Center to analyze these tumors, nearly 98 percent of which have p53 mutations (with many exhibiting abnormalities in the BRCA1 pathway as well), so that they typically exhibit significant DNA repair deficiencies. Such high-grade invasive serous cancers are grossly aneuploid (abnormal number of chromosomes) with a variety of chromosomal abnormalities and copy number differences that preclude straightforward clustering. Still, Cancer Center investigators have succeeded in identifying other molecular signatures that allow for the classification of subsets of serous tumors and point the way toward tailored therapeutics.
In 2008, researchers published a study generating a specific list of differentially expressed genes in serous malignancies distinguishing those patients with poor prognoses from those with good prognoses. Within those genes, the study found a number of pathways involving a variety of potential therapeutic targets.
A separate study led by Dr. Birrer and published in Cancer Cell that examined a large number of microdissected high-grade serous tumors identified a tumor-associated angiogenesis pathway. Within this pathway is a series of genes associated with angiogenesis, the most prominent being microfibril-associated glycoprotein-2 (MAGP-2). This pathway is highly expressed among a subset of serous cancers associated with poor prognosis. Tumors that exhibit overexpression of this pathway and the MAGP-2 gene have more blood vessels feeding the tumor than usual (which may explain why patients with these tumors do so poorly). Cancer Center investigators are now working to better characterize this signaling pathway to create a monoclonal antibody that can attack it. Ultimately, the work may provide vital therapeutics to treat patients with the poorest prognoses.
Inhibition of Poly(ADP-ribose) polymerase, or PARP, is proving to be the foundation of a variety of new targeted therapeutic approaches. A number of recent breast and ovarian cancer trials suggest that PARP inhibitors are particularly effective at treating cancer in patients with BRCA1 and BRCA2 mutations.
The researchers who are focused on the seemingly homogeneous group of high-grade serous tumors are also exploring inhibition of poly(ADP-ribose) polymerase, or PARP, which is proving to be the foundation of a variety of new targeted therapeutic approaches.
McGill University researchers in Montreal published a Human Genetics paper in 2008 that estimated that roughly 10 percent of all ovarian cancers arise in women with germline mutations of BRCA1 and BRCA2. Several years ago, investigators with the Institute of Cancer Research in London found that cells in culture with BRCA1 and BRCA2 abnormalities rely heavily on a unique repair system that is mediated by PARP, a member of a complex of DNA enzymes that repairs single-strand breaks. The work suggested that if PARP can be inhibited, the cells accumulate single-strand breaks, and over time these become double-strand breaks, which then require homologous recombination. Since homologous recombination is mediated by BRCA1 and BRCA2, cancer cells with BRCA mutations and inhibited PARP cannot efficiently repair these breaks, and they ultimately die.
This work has spawned a number of recent breast and ovarian cancer trials suggesting that PARP inhibitors are particularly effective at treating cancer in patients with BRCA1 and BRCA2 mutations. Research conducted at the Mass General Cancer Center, Beth Israel Deaconess Medical Center, and elsewhere suggests that these therapies may offer benefits for breast and ovarian cancer even beyond this subset of patients. A substantial portion of ovarian cancer patients with no germline mutation of the BRCA1 or BRCA2 genes have abnormal DNA repair function, and recently published work from several centers suggests that ovarian cancers, including those without BRCA1 or BRCA2 mutations, are highly responsive to PARP inhibitors. A Cancer Center team led by Dr. Birrer is now conducting trials of new PARP-based regimens in ovarian cancer patients.
One such set of Cancer Center trials will test a new PARP inhibitor agent (BiPar 201) plus carboplatin and gemcitabine among both platinum-sensitive and platinum-resistant patients. The chemotherapy drugs introduce single- and double-strand DNA breaks, and the PARP-inhibitor agent blocks repair of those breaks, in an attempt to promote tumor cell death.
Mass General investigators are profiling ovarian cancer cell lines with and without BRCA mutations in the hope of finding a BRCA1-like signature. It is anticipated that this work will allow physicians to identify a larger percentage of patients with high-grade serous tumors who can benefit from a PARP inhibitor coupled with chemotherapy.
A New Frontier in the Treatment of Ovarian Cancer
This work with PARP inhibitors, and the Cancer Center’s genetic profiling efforts, exemplify the new clinical paradigm of tailored therapeutics in the management of ovarian cancers. The next stage will be to validate these activated pathways, particularly in high-grade serous tumors, in a much larger number of specimens. The Cancer Center is part of an international effort to test several thousand formalin-fixed, paraffin-embedded materials from clinical trial specimens. Mass General investigators hope their ability to identify genomic tumor signatures will translate into useful prognostic information that will enable them to select the appropriate therapy for particular patients.
Ultimately, these Mass General Cancer Center efforts will help bring powerful new approaches to the understanding of ovarian malignancies, and new hope to patients of this historically intractable disease.
|Michael J. Birrer, MD, PhD
|Richard T. Penson, MD, MRCP
Massachusetts General Hospital Cancer Center
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