Combination Strategy Could Hold Promise for Ovarian Cancer

 Johns Hopkins Kimmel Cancer Center researchers demonstrated that mice with ovarian cancer that received drugs to reactivate dormant genes along with other drugs that activate the immune system had a greater reduction of tumor burden and significantly longer survival than those that received any of the drugs alone.

The study already spurred a clinical trial in ovarian cancer patients. The investigators, led by graduate student Meredith Stone, Ph.D.; postdoctoral fellow Kate Chiappinelli, Ph.D.; and senior author Cynthia Zahnow, Ph.D., believe it could lead to a new way to attack ovarian cancer by strengthening the body’s natural immune response against these tumors. It was published in the Dec. 4, 2017, issue of the Proceedings of the National Academy of Sciences.

Ovarian cancer is currently the leading cause of death from gynecological malignancies in the U.S. “We’ve taken two types of therapies that aren’t very effective in ovarian cancer and put them together to make them better at revving up the immune system and attacking the tumor,” says Zahnow, associate professor of oncology at the Johns Hopkins Kimmel Cancer Center.

Zahnow says that a class of immunotherapy drugs known as checkpoint inhibitors, currently being studied at the Bloomberg~Kimmel Institute for Cancer Immunotherapy, helps the immune system recognize cancers and fight them off. The drugs have shown success in treating melanoma, nonsmall cell lung cancer and renal cell cancers, but they have had only modest effects on ovarian cancer.

Similarly, another class of drugs known as epigenetic therapies has been used to treat some types of cancer by turning on genes that have been silenced— either by the presence of chemical tags, known as methyl groups, or by being wound too tightly around protein spools, known as histones—but these drugs haven’t been effective against ovarian cancer either.

Zahnow and her colleagues became inspired to investigate a new way to treat ovarian cancer by two recent publications from their group that showed epigenetic drugs turn on immune signaling in ovarian, breast and colon cancer cells (Li et al., Oncotarget 2014). These immune genes are activated when epigenetic therapy turns on segments of ancient retroviruses that activate type 1 interferon signaling in the cells (Chiappinelli et al., Cell 2015).  Stone, Chiappinelli and Zahnow wanted to know if this increase in immune signaling could lead to the recruitment of tumor killing immune cells to the cancer.

Zahnow and her colleagues worked with a mouse model of the disease in which mouse ovarian cancer cells are injected into the animals’ abdomens to mimic human disease. These cells eventually develop into hundreds of small tumors, which cause fluid to collect within the abdomen, a condition known as ascites. Floating in this fluid is a milieu of both cancer and immune cells, offering a convenient way to keep tabs on both the tumor and the animals’ immune response.

The researchers started by pretreating the ovarian cancer cells outside of the animal in a culture dish with a DNA methyltransferase inhibitor (a drug that knocks methyl groups from DNA) called 5-azacytidine (AZA). After injecting these cells into mice, the researchers found that animals receiving the pretreated cells had significantly decreased ascites or tumor burden and significantly more cancer-fighting immune cells in the ascites fluid compared to those injected with untreated cells. These cells also had increased activity in a variety of genes related to immune response. Pretreating these cells with histone deacetylase inhibitors (HDACis), which help DNA uncoil from histones, didn’t affect the animals’ ascites or boost their immune response.

These early findings suggested that changes in gene activity induced by AZA cause the tumor cells themselves to summon immune cells to their location. In addition, when the researchers transplanted untreated cells into mice and treated the animals with both AZA and an HDACi, significantly more immune cells were in the ascites fluid, suggesting that the HDACi was acting on the animals’ immune systems. These mice also had decreased ascites, lower tumor burden and longer survival than mice that received just AZA.

When the researchers treated the mice with both AZA and an HDACi, along with an immune checkpoint inhibitor, they got the greatest response—the highest decreases in ascites and tumor burden, and the longest survival. Further experiments using immunocompromised mice showed that the immune system is pivotal to the action of these drugs, rather than the drugs themselves acting directly to kill tumor cells.

“We think that AZA and the HDACis are bringing the soldiers, or immune cells, to the battle. But the checkpoint inhibitor is giving them the weapons to fight,” says Zahnow, who also collaborated with epigenetics scientist Stephen Baylin, M.D., on this project.

The preclinical data generated through this study is already being used to help patients with ovarian cancer through an ongoing clinical trial to test the effectiveness of combining AZA and a checkpoint inhibitor. Future trials may add an HDACi to determine if it affects outcomes.

“Combining epigenetic therapy and a checkpoint blocker leads to the greatest reduction in tumor burden and increase in survival in our mouse model and may hold the greatest promise for our patients,” says Zahnow.

Risk-reducing mastectomy questioned for BRCA mutation carriers with prior ovarian cancer

Mutations in the BRCA gene correspond to a higher lifetime risk of developing breast and ovarian cancers, and many women who carry these mutations consider undergoing mastectomy or removal of the ovaries and fallopian tubes as preventive measures.

But for the subset of women with BRCA mutations who have already had ovarian cancer, risk-reducing mastectomy might not be worth the price tag. New research from the Duke Cancer Institute finds that for many women in this unique group, prophylactic mastectomy does not produce a substantial survival gain and is not cost-effective.

The finding is especially noteworthy because of updated National Comprehensive Cancer Network guidelines recommending that many women with ovarian cancer be considered for genetic testing regardless of family history. Now, more than ever before, some women with ovarian cancer are also learning that they carry a BRCA mutation.

“Risk-reducing mastectomy is costly and can require many months of follow-up and recovery,” said Charlotte Gamble, M.D., the study’s lead author and a resident physician at Duke University School of Medicine. “Our results emphasize that prophylactic mastectomy should be used selectively in women with both a BRCA mutation and a history of ovarian cancer.”

In the study, published online July 11 in the journal Annals of Surgical Oncology, Gamble and co-researchers constructed a statistical model comparing risk-reducing mastectomy to breast cancer screening, including mammogram and MRI. The model incorporated clinical factors such as the age at ovarian cancer diagnosis, time between ovarian cancer diagnosis and risk-reducing mastectomy, BRCA mutation status, cancer survival rates and treatment costs. Risk-reducing mastectomy was compared to breast cancer screening performed every six months following ovarian cancer diagnosis.

The study’s authors also considered a cost-effectiveness measurement called the incremental cost effectiveness ratio. Healthcare interventions where this ratio is less than $100,000 per year of life saved are commonly considered cost-effective in medical literature. The authors used the same threshold in this study.

According to the authors’ analysis, the benefit of risk-reducing mastectomy over screening alone largely depended on the patient’s age at the time of her ovarian cancer diagnosis and time to mastectomy:

For women diagnosed at any age with BRCA 1 and 2 gene mutations and within the first four years after ovarian cancer diagnosis, mastectomy was associated with a negligible gain in survival and was therefore not found to be cost-effective;

For women diagnosed at age 60 or older, regardless of time since ovarian cancer diagnosis, the gain in survival months was also negligible and the procedure was not cost-effective;

For women diagnosed at age 40 to 50 with BRCA 1 and 2 mutations and at least five years after an ovarian cancer diagnosis, the procedure was associated with a survival benefit of two to five months compared to screening and found to be cost-effective.

“Our study provides clarity on how a woman’s age and timing of a risk-reducing mastectomy after an ovarian cancer diagnosis impact the benefit of this procedure,” Gamble said. “Within the first five years, nobody benefited from risk-reducing mastectomy and after that threshold, survival gains were seen mostly in the youngest, healthiest ovarian cancer patients.”

“There is no right or wrong answer on how to manage breast cancer risk in this unique population,” added senior author Rachel Greenup, M.D., assistant professor of surgery at Duke. “However, we hope that our findings provide guidance to women and their doctors deciding if and when prophylactic mastectomy is beneficial following ovarian cancer treatment.”

New Clinical Trial Combines Two Methods to Defeat Ovarian Cancer

New clinical trial offers combination therapy to directly kill cancer cells and teach the immune system to keep them from coming back.

Fewer than half of women diagnosed with ovarian cancer live for five years or more. Sarah Adams, MD, hopes her new clinical trial will change this outcome. Adams recently opened a clinical trial at The University of New Mexico Comprehensive Cancer Center to test a new approach to defeat ovarian cancer. The clinical trial treats women whose ovarian cancer results from mutated BRCA genes. It uses one drug that kills the ovarian cancer cells and another that boosts the immune system in response to the dying cancer cells.

Ovarian cancer has unclear symptoms and no screening tests that catch it in its early stages. Often, ovarian cancer spreads to other organs before a woman even knows she has it. Surgery and chemotherapy can help women at the beginning of their treatment, and this gave Adams the idea for her new approach.

As a gynecologic oncologist, Adams performs surgery and prescribes chemotherapy for women with cancers of the female reproductive organs. Adams also conducts research. Her research suggested that women with BRCA-related ovarian cancer responded better to some chemotherapy drugs. Others’ research showed that other chemotherapy drugs not only kill cancer cells but also make the immune system more sensitive to them. Adams’ new treatment combines these approaches into what she thinks may be a powerful way to win against ovarian cancer.

BRCA is a set of genes we all carry. Each gene contains the instructions to produce a protein. BRCA proteins help DNA to repair itself when both of its strands break and completely split the molecule in two. If the BRCA genes are mutated, or changed, the resulting proteins do not work properly and the cell cannot repair its DNA. It dies unless it can resort to other repair methods.

Cells with mutated BRCA genes resort to using a DNA-repair protein called PARP. Adams’ therapy uses a type of drug called a PARP inhibitor, which keeps the PARP protein from its repair work. “If you knock out BRCA,” says Adams, “the cell can still live. If you knock out PARP, the cell can still live. But if you knock out both, the cell dies.”

The PARP inhibitor does not affect non-cancerous cells because they have working BRCA proteins to repair DNA. “It’s specific to cancer cells so it’s nicely targeted and there’s minimal toxicity,” says Adams. The therapy is also easy to dispense. “It’s a pill that people take orally,” she says.

Adams’ therapy combines the PARP inhibitor with a specific antibody. An antibody is a protein that attaches to a target cell. The antibody in Adams’ therapy helps one type of immune cell, called a T-cell, to find and devour ovarian tumor cells. Untreated ovarian tumors often produce chemical signals that keep T-cells away. But, the PAPR inhibitor combined with the antibody alert the entire immune system to the ovarian cancer cells.

Once the immune system can find the ovarian cancer cells, it can rid the body of them if the PARP inhibitor doesn’t kill them first. And because the immune system can remember how to respond to ovarian cancer cells, it can continue to rid the body of them if the cancer tries to come back. Adams hopes that this effect will give women long-lasting protection.

The clinical trial is currently open to women with BRCA1 or BRCA2 mutations. Either parent can pass these BRCA mutations to their children. People with BRCA mutations have a higher risk of getting breast and ovarian cancers and may have relatives who had these cancers at young ages.

In pre-clinical studies, this combination therapy got rid of tumors and helped mice to live longer. The clinical trial now makes the therapy available to women with BRCA gene mutations whose ovarian cancer has returned. “I’m very excited about the results we’ve seen so far,” says Adams, “and hopeful that this regimen can achieve long-term benefit for women with ovarian cancer.” Adams’s ultimate goal is to expand the therapy to help all women with ovarian cancer.

New Ovarian Cancer Immunotherapy Study Poses Question: Can Microbiome Influence Treatment Response?

Roswell Park Study with pembrolizumab in untried combination is first ovarian cancer clinical trial to incorporate gut flora analysis

A new clinical study underway at Roswell Park Cancer Institute is the first to test the combination of the immunotherapy pembrolizumab with two other drugs as treatment for recurrent epithelial ovarian cancer, and is also the first ovarian cancer clinical trial to incorporate analysis of patients’ microbiomes — the bacteria present in the human gut and other organs.

This new study, led by Principal Investigator Emese Zsiros, MD, PhD, FACOG, Assistant Professor of Oncology in Roswell Park’s Department of Gynecologic Oncology and Center for Immunotherapy, is a phase II clinical trial that will enroll approximately 40 patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, and will evaluate the impact of the combination of the PD1-targeting antibody pembrolizumab (Keytruda) with intravenous bevacizumab (Avastin) and oral cyclophosphamide (Cytoxan) on antitumor immune responses and on progression-free survival.

Pembrolizumab has been approved by the U.S. Food and Drug Administration for treatment of advanced melanoma, some metastatic non-small cell lung cancers and recurrent squamous cell head/neck carcinoma, but has only been tested in a small number of ovarian cancer patients, as a single drug and showing modest response. The investigators say a strong scientific rationale supports their hypothesis that the combination of pembrolizumab with two other drugs that have already been approved to treat ovarian cancer — bevacizumab and low-dose oral cyclophosphamide — may have much broader benefit for patients.

“Our biggest hope is that by trying these three drugs in combination, we can significantly extend the lives of patients with recurrent ovarian cancer. We also hope to minimize the side effects associated with chemotherapy drugs, and to markedly improve the quality of our patients’ lives,” says Dr. Zsiros. “We will be looking at potential biomarkers that will tell us who can most benefit from this therapy combination and to better understand how cancer cells and immune cells communicate with one another so that we can design better medications to kill cancer efficiently.“

As part of this study, the clinical team will analyze blood, tumor, stool, vaginal and skin microbiome samples, looking to identify possible associations between these markers with clinical outcomes and tumor response. The study, which is supported by a grant from Merck & Co. Inc., maker of pembrolizumab, will be one of the first to analyze these bacteria to determine possible associations with response to immunotherapeutic agents in patients with cancer.

“We’re looking at how to improve our immune defenses to cancer, but we’re looking at it from a variety of angles,” says Dr. Zsiros. “There’s a whole new area of research suggesting that what’s going on in our gut, our gut flora, has a huge influence on your overall health and happiness, and this study will extend that work into some new directions.”

According to the National Cancer Institute, epithelial ovarian cancer is one of the most common gynecologic malignancies, and is the fifth most frequent cause of cancer death in women.

 

Yale Researchers Find Genes Behind Aggressive Ovarian And Endometrial Cancers

In a major breakthrough for ovarian and uterine cancers, Yale researchers have defined the genetic landscape of rare, highly aggressive tumors called carcinosarcomas (CSs), pointing the way to possible new treatments.

The findings are published in the Oct. 10 online early edition of Proceedings of the National Academy of Sciences.

Endometrial and ovarian cancers are the most prevalent gynecologic tumors in women, with over 76,160 newly diagnosed cases and about 14,270 deaths in 2015 in the United States alone. Although CSs comprise only 2%-5% of all uterine malignancies and 1%-2% of all ovarian tumors, they are responsible for a disproportionate number of deaths due to their high biologic aggressiveness and resistance to standard treatments, such as radiation and chemotherapy.

The collaborative research team — which included experts in gynecological cancer, genomics, pathology and computational biology— performed a comprehensive genetic analysis of ovarian and endometrial CSs. The team collected tumors from 68 women affected with ovarian and uterine CSs to try to determine the molecular basis of the tumor’s aggressive behavior. They sequenced all the genes from the tumors and identified mutations that are crucial for these tumors to grow. The team also studied the copy number variations — genes that are not mutated but are amplified in the tumors to give them a growth advantage over normal tissues.

“We identified a number of new genes that are frequently mutated in CS,” said senior author Alessandro Santin, M.D., professor of obstetrics, gynecology and reproductive sciences at Yale School of Medicine, and program leader of the gynecological cancers research program at Smilow Cancer Hospital at Yale-New Haven and a member of Yale Cancer Center.

“In addition to mutations in cancer genes previously identified in uterine and ovarian carcinomas, we found an excess of mutations in genes encoding specific groups of proteins, which may potentially explain their mixed tissue characteristics,” said Santin.

“We’ve established unequivocally the common genetic origin of these tumors as epithelial tumors,” he added. “Importantly, by studying the genetics of both the carcinomatous and sarcomatous elements of these tumors, we demonstrated that the transition from carcinoma to sarcoma, which represents one of the main characteristics of these tumors, may happen at different times during the evolution of these cancers.”

Liquid Biopsies Offer Hope for Earlier Treatment, Better Tracking of Ovarian Cancer

Researchers at the Mayo Clinic Center for Individualized Medicine have found a promising new way to monitor and treat recurrence of ovarian cancer — a hard-to-detect disease that claims many lives. New research from George Vasmatzis, Ph.D., of the Department of Laboratory Medicine and Pathology at Mayo Clinic, finds liquid biopsies from blood tests and DNA sequencing can detect a return of ovarian cancer long before a tumor reappears. That could lead to earlier intervention and more effective, individualized treatment. Dr. Vasmatzis’ research on the “Quantification of Somatic Chromosomal Rearrangements in Circulating Cell-free DNA From Ovarian Cancers” is published in the July 20 edition of Scientific Reports.

“With liquid biopsies, we don’t have to wait for tumor growth to get a DNA sample,” says Dr. Vasmatzis. “This important discovery makes it possible for us detect recurrence of the disease earlier than other diagnostic methods. We can repeat liquid biopsies to monitor the progression of the cancer. That gives hope of a better treatment plan over time.”

The study was done on 10 patients in advanced stages of ovarian cancer. Blood was drawn before and after surgery. Investigators compared DNA from the liquid blood biopsies to DNA tissue samples from the tumor, using mate-pair sequencing — an inexpensive whole exome sequencing that can reveal genetic changes that contribute to tumor growth.

“In this study, the blood drawn before and after surgery and the surgical tissue was used to identify DNA fragments with abnormal junctions that can only be seen in this patient’s tumor DNA,” explains Dr. Vasmatzis. “Next-generation mate-pair sequencing was used to identify specific DNA changes of the tumor to create an individualized monitoring panel for liquid biopsy. This allows us to shape treatment to the individual patient rather than using a standard treatment that may not work for everyone.”

When post-surgery DNA matched that of the tumor, patients were later found to have had a recurrence of ovarian cancer. However, when the post-surgery DNA did not match the DNA of the tumor, patients were found to be in remission.

Ovarian cancer has one of the highest death rates of all gynecological cancers, because the tumor often cannot be detected until the late stages. Most patients go into remission after initial treatment, but the tumor returns 75 percent of the time. The next stage of ovarian cancer that develops typically does not respond to chemotherapy. More than 21,000 women in the U.S. were diagnosed with ovarian cancer, and 14,000 women died of the disease in 2015.

Research Explains the Role of the Gene BRCA1 in DNA Repair

Scientists at the University of Birmingham are a step closer to understanding the role of the gene BRCA1. Changes in this gene are associated with a high risk of developing breast and ovarian cancer.

The research, published in Nature Structural and Molecular Biology, explains how the gene encourages the attachment of the protein, ubiquitin, to other proteins and plays a vital role in DNA repair.

Should the results be confirmed by further studies, it is possible that patients with certain genetic changes in BRCA1 could be identified as being at higher risk of breast and ovarian cancer.

The gene BRCA1 makes a protein that can attach ubiquitin, which helps to regulate processes in the body, to other proteins. However little was known about the importance of this activity in DNA repair.

The new research has found that this attachment of ubiquitin by BRCA1, its ‘ubiquitin ligase activity’, is needed for a specific type of DNA repair that is ‘error-free’, known as homologous recombination. It is known that cells without this type of DNA repair can develop mutations leading to cancer development. Cells lacking the BRCA1 ubiquitin ligase activity were found to be sensitive to certain DNA damaging agents that need homologous recombination in for repair.

Dr Jo Morris, lead author from the University of Birmingham, explained, “We know that loss of BRCA1 is associated with a high risk of breast cancer, so getting to grips with understanding this gene has been a major aim of breast cancer research. This study may explain why some cancer predisposing mutations are found in the front part of the BRCA1 gene – the part that allows it to function as a ubiquitin ligase.”

The team sought to identify how BRCA1 manages to perform the ubiquitin attachment role, and found that it relies on a part of a partner protein, called BARD1.

Using changed versions of BARD1, and leaving the BRCA1 protein untouched, they were able to identify the attachment function of BRCA1 and show that it is needed for the cell response to, and proper repair of, DNA damage.

Dr Morris added, “Our finding that BRCA1 has several independent functions in DNA repair has implications for treatment. Clinicians are currently worried that breast cancer patients with low or absent BRCA1 may become resistant to therapeutic agents such as Olaparib. Our data show that cancer cells without BRCA1 have more than one “Achilles heel”, and so there are more ways to target cancers and therefore to prevent tumours becoming resistant to treatment.”