Scientists at Yale School of Medicine design a virus to treat ovarian cancer
A new Yale study showed that certain genetically modified viruses can cure ovarian cancer in mice. It may be of use in the treatment of ovarian cancer in humans.
Researchers at the Yale School of Medicine have tested a chimeric virus — containing genes from two different viruses — that can selectively infect and kill ovarian cancer cells in mice. Their findings represent a potential breakthrough in the long-term treatment of ovarian cancer in humans. The study was published in the journal Virology on Nov. 12, two weeks after the death of the paper’s lead author Anthony Van den Pol, former professor of neurosurgery and psychiatry at Yale.
“Every year, around 20,000 women are diagnosed with ovarian cancer, which is a smaller number compared to cancer types such as breast cancer,” said Gil Mor, the scientific director of the C.S. Mott Center for Human Growth and Development at Wayne State University and a co-author of the paper. “However, unfortunately only around 4,000 of those women can survive the disease.”
The main reason behind the lethality of ovarian cancer is the lack of treatments preventing the recurrence of the disease. In 80 percent of cases, patients who respond positively to chemotherapy still experience a return of the disease, according to Mor. He explained that once the cancer comes back and begins to spread, there is little that doctors can do.
The inspiration for the study was born out of a collaboration between Van den Pol and Mor many years ago, when they worked in adjacent labs at the Yale School of Medicine. Van den Pol, a research scientist in the Neurosurgery Department, had concentrated his research on the long-term treatment of brain tumors. Mor, on the other hand, had been working on treatments for ovarian cancer. The two scientists decided to collaborate to find an alternative treatment for ovarian cancer through oncolytic viruses, which selectively infect and kill cancer cells.
In the experiment’s in vitro phase, in which the research takes place in laboratory tubes or petri dishes without a living component, researchers made a virus called Lassa-VSV in the laboratory. Lassa-VSV consists of three parts: the Lassa virus, the vesicular stomatitis virus, or VSV, and a fluorescent label to facilitate tracing, according to Nazli Albayrak, a scientist who was involved in the in vitro phase. During this phase, the team infected different ovarian cancer cell lines, eventually choosing the ones that were infected most frequently to proceed with the research.
Then, after deciding on the cell line, the team injected tumor cells into the bodies of the mice, the paper explains. As the tumor cells began to replicate, the team then injected the Lassa-VSV virus into the tumor clusters. They observed that the virus infected the tumor cells very effectively yet did not harm the healthy cells that were present in other parts of the mice.
In gynecologic oncology, patients who are suffering from ovarian cancer are currently provided with chemotherapeutic agents after their surgeries. However, as Mor and Albayrak also mentioned, chemotherapeutic agents are not a cure for these patients.
This observation prompted the researchers to compare the effectiveness of chemotherapeutic agents and the Lassa-VSV chimeric virus in clearing tumor cells from the mice’s bodies. They found that the virus was able to get rid of more cancer cells than the chemotherapy treatment and do so without harming healthy mouse cells. Albayrak also noted that the mice treated with the Lassa-VSV virus lived approximately four times longer than those treated with chemotherapeutic agents.
Vaagn Andikyan, assistant professor at the School of Medicine who also works in gynecologic oncology, said that this form of treatment could be more effective in treating cancer in humans and be a prevalent option in the future.
“It is a very intriguing, very unique approach to ovarian cancer, and this approach may be applicable for several other malignancies,” Andikyan said.
Andikyan works with the standard treatment of ovarian cancer, a field that is rapidly changing through new drugs and new treatment procedures. He said that this paper’s approach to treating ovarian cancer is promising to him.
According to Mor, if the clinical phases — in which human subjects are involved — prove to be successful, many people can benefit greatly from the researchers’ discovery. This approach may even lead to the discovery of a vaccine against tumors and even in different cancer types, Andikyan said.
Van den Pol died on Oct. 28, the day on which the team’s paper was accepted to Virology, a pioneer journal in the field. Mor said that the team would miss Van den Pol and continue to honor him in their future research. Albayrak and Mor noted that they did not know Van den Pol had a condition until receiving news of his death.
“He was a very private person, and we knew that he did not feel well, but we never realized the magnitude of his disease,” Mor said.
The team and Van den Pol’s colleagues at the Yale School of Medicinewere saddened by the news, yet the team is hopeful about the discovery they recently made and will continue to include Van der Pol as an author in their future studies. Ovarian cancer is the fifth-most deadly cancer among women, according to the American Cancer Society.
Surgical treatment of ovarian cancer during the COVID 19 pandemic
Ovarian cancer patients may be at greater risk during the pandemic
Surgery can be done safely, but doctors may recommend postponement and using chemotherapy first, depending on local COVID-19 conditions and the specifics of your cancer
Ovarian cancer patients should follow the same CDC recommendations as the general population: staying home, social distancing, frequent handwashing, avoiding touching the face
The COVID-19 pandemic makes many people feel at-risk and vulnerable, but there are special considerations for cancer patients—especially cancer patients facing surgery. “In general cancer patients do fall into a high-risk group,” says Dr. Marta Crispens, a gynecologic oncologist with Vanderbilt University Medical Center in Nashville. Dr. Crispens performs ovarian cancer surgery as well as surgery for other gynecological malignancies. “And because of our surgical expertise, gynecologic oncologists also serve as backup for general gynecologists who have difficult cases, or sometimes for obstetricians who are dealing with challenging obstetrical cases that involve cancer.”
While women with ovarian cancer may be at increased risk of complications from infection with the new coronavirus, the precautions that are recommended are the same ones that the CDC encourages the general population to follow. “That includes physical distancing, staying home, good hand hygiene, avoiding touching your face,” says Dr. Crispens. “All the things that the CDC is recommending for the population at large should be done even more vigorously in the cancer population.”
The additional risks from COVID-19 are even more concerning when a patient is facing surgery, as most ovarian cancer patients do, whether after the initial diagnosis or as part of continuing treatment. The initial surgery after diagnosis is especially important both for staging the cancer–determining how advanced it is–and removing visible tumors. While doctors usually recommend surgery within a few weeks of an ovarian cancer diagnosis, the pandemic makes that decision less clearcut. A patient and her doctor must decide whether the need for surgery is urgent enough that it should be performed immediately, taking all possible precautions to avoid infection with the coronavirus. Or whether it’s safe to postpone surgery, using chemotherapy or other treatments to control the cancer until the pandemic has subsided.
There are cases when surgical delay is the medically optimal course. For instance, patients who have other medical conditions may need to get those treated and under control before surgery can be safely performed. And there are patients, generally elderly, who are considered too frail to operate on safely until they are treated with nutritional therapy or physical therapy in order to gain strength for a good surgical outcome and recovery.
“Most cancer surgery would be considered at least semi-urgent,” says Dr. Crispens. But she adds that during this pandemic “there may be situations in which surgery can be safely delayed a little bit.” Patients have to discuss their own condition with their doctors to determine which course of action would be wisest for them.
PARP inhibitors have shown significant promise in the treatment of ovarian cancer. Olaparib is a PARP inhibitor that has been approved for maintenance for BRCA-mutated ovarian cancer in the recurrent and front-line setting as well as for treatment of BRCA-mutated ovarian cancer in patients who have received multiple prior lines of chemotherapy. In this review, we focus on the use of olaparib in the maintenance setting including the evidence to date, ongoing research, and future directions.
Ovarian cancer is the seventh most common cancer in women worldwide and is the leading cause of death from gynecologic cancers in high-income countries. The five year survival rate in the United States is 48% and the proportion of women dying from their disease has not improved substantially over time as compared to other prevalent cancers. Standard treatment for newly diagnosed advanced ovarian cancer consists of cytoreductive surgery and platinum-based chemotherapy with or without concurrent and maintenance bevacizumab, a vascular endothelial growth factor (VEGF) A inhibitor. The majority of women with epithelial ovarian cancer respond well to first-line platinum-based chemotherapy however there is a high rate of recurrence with a chemotherapy-free interval before disease progression ranging from 10 to 26 months. Response to subsequent therapies is variable and often short-lived, underscoring the need for novel effective treatment options to improve long-term disease control for women with ovarian cancer.
Homologous recombination (HR) is a DNA repair process crucial for the accurate repair of DNA damage. BRCA1/2 mutations are known to lead to defective HR and ultimately results in risk for malignant transformation of cells. BRCA mutations, both germline and somatic, are thought to occur in up to 25% of patients with newly diagnosed serous ovarian cancer. While BRCA1/2 mutations were initially thought to be responsible for the majority of hereditary epithelial ovarian cancers, further investigation has shown that compromise of the HR pathway can occur by several other potential mechanisms. Thus, it is thought that approximately 50% of high-grade serous ovarian cancers have a deficiency in HR.
There have been several studies investigating the role of maintenance therapy in ovarian cancer which until recently have not been found to significantly prolong survival. However, poly (ADP-ribose) polymerase (PARP) inhibitors have shown significant promise with several clinical trials demonstrating a survival improvement in women with newly diagnosed and recurrent ovarian cancer without a substantial increase in adverse effects. The antitumor effects of PARP inhibitors rely on an exploitation of the defective DNA damage repair in cancer cells with dysfunctional HR. Olaparib is a PARP inhibitor that has several approved indications for use in ovarian cancer and has demonstrated a progression-free survival (PFS) advantage in several trials.
Here, we review the use of olaparib as maintenance treatment for ovarian cancer. We will summarize the evolution of its use, current approved indications, and evidence with respect to its clinical safety and efficacy. Finally, we will provide guidance on treatment decisions with olaparib for patients with ovarian cancer as well as commentary regarding ongoing research and future directions.
For the past few years, as part of the University of Chicago Pritzker medical school obstetrics-gynecology rotation, med students at an optional lunchtime seminar hear from ovarian cancer survivors who share stories about the shock of diagnosis, painful treatments and constant worries about whether their cancer will come back.
Last year, listening to the women’s experiences became a mandatory part of their medical education. The hope is that by humanizing the disease, this relatively rare cancer will be on the radar of a new generation of doctors and will change this common patient narrative: “My doctor didn’t take my symptoms seriously until it was too late.”
“We felt it was important that students shouldn’t just learn about the biology of ovarian cancer, but we wanted them to know that every patient is a whole person with a story behind them,” University of Chicago gynecologic oncologist Nita K. Lee says.
The medical school curriculum change is a sign that the subject of ovarian cancer is being taken more seriously. It’s part of a surge of hopeful recent advances, including new research on blood tests to detect the disease at an early stage, new genetic understandings of dozens of cancer subtypes and new treatments. This year, in an effort to raise public awareness, the Centers for Disease Control and Prevention beefed up its consumer website on ovarian cancer and has plans to launch broadcast ads.
Compared to other cancer success stories, ovarian cancer historically has had a shortage of good news. It is deadlier and underfunded. Until recently, the disease has not benefited from new treatments for more than 40 years. About 22,240 U.S. women were diagnosed with ovarian cancer in 2018, and 14,070 women died the same year, according to government surveillance data. The reason: More than three-fourths are diagnosed when the cancer has advanced, and survival rates are low: Just 47 percent of patients survive five or more years.
That means that unlike the 3.4 million pink-clad U.S. breast cancer survivors who make up an army of activists marching for research money and attention, there are starkly fewer women living with ovarian cancer — just 225,000 in the United States — who are around to represent their cause.
Even their signature color — teal — is understated.
“Sometimes it’s hard feeling like a stepchild in a teal dress,” says activist Ellen Engle, a project manager from Potomac, Md., who was diagnosed with Stage 4 ovarian cancer four years ago at age 47. She’s an administrator of the Ovarian Cancer Support Group on Facebook. “We hear so many stories of women having their symptoms dismissed,” she says. “They’re told they’re going through menopause or have irritable bowel syndrome.”
Engle leaves educational cards warning women about the often-overlooked symptoms of ovarian cancer — abdominal bloating, changes in appetite, pelvic pressure, lower back pain or frequent urination — in women’s bathroom stalls at airports, fast-food restaurants, even a recent Elton John concert.
Another common story is that women chalk up persistent stomach bloating symptoms to gluten or lactose sensitivities that they try to treat with probiotics or elimination diets, says Bobbie Rimel, a gynecologic oncologist at Cedars-Sinai Medical Center in Los Angeles. “I see so many people in my practice who let this ride out for five or six months because they thought they could figure it out,” she says. “But I end up figuring out it’s cancer, and it’s really sad.”
Yet the onus isn’t only on patients and doctors to be more vigilant. The field has lacked good diagnostic tools. The most commonly used test, developed in the early 1980s to measure a protein called CA 125, finds only 80 percent of cases and is subject to false-positives since the protein can also rise during menstruation and pregnancy.
Yet the onus isn’t only on patients and doctors to be more vigilant. The field has lacked good diagnostic tools. The most commonly used test, developed in the early 1980s to measure a protein called CA 125, finds only 80 percent of cases and is subject to false-positives since the protein can also rise during menstruation and pregnancy.
It’s more effective when paired with a transvaginal ultrasound, which can detect an ovarian mass. But since the current imaging technology can’t reveal whether that mass is cancerous, women usually are diagnosed after undergoing surgery to remove part of or the whole ovary.
“I do anywhere from three to six surgeries for every cancer I find,” Rimel says. “And I often don’t find them early enough to make a difference in the survival of patients.”
In search of the screening breakthrough that would dramatically improve mortality rates, scientists are looking for clues in women’s blood to see if they detect the cancer before it becomes lethal. In February, University of Kansas researchers announced they had developed a low-cost method of finding cancer markers in cell byproducts called exosomes in a drop of blood.
At the University of Texas MD Anderson Cancer Center in Houston, ovarian cancer researcher Robert Bast, who co-discovered the CA 125 test, is working on developing a different blood test that could measure multiple markers simultaneously and shave off at least a year from the time when patients traditionally have been diagnosed.
“We want to be able to detect a smaller amount of cancer earlier rather than wait for the tumor to shed enough cells into the abdominal cavity,” Bast says.
Other researchers are exploring new genetic sequencing techniques to understand how micro RNA, short molecular segments that turn off part of a person’s genome, is expressed differently in women with ovarian cancer. The team of Kevin Elias, a gynecologic oncologist who runs a lab at Brigham and Women’s Hospital in Boston, is designing a clinical trial to study blood samples of women that were collected before they noticed symptoms and were diagnosed with cancer. The goal is to see whether micro RNA patterns could have predicted who would get the disease later and estimate the magic moment when to intervene surgically to remove tumors.
“We’re trying to figure out the lead time to catch women when they’re high risk and curable,” Elias says. He says a resulting test will first be offered to the 20 percent of women who have a hereditary risk for ovarian cancer and then to the general population.
There’s also hope that new biological understandings of ovarian cancer will lead to more effective personalized treatments and prolong survival.
“We’re learning that ovarian cancer isn’t just one disease. It’s made up of many subtypes with distinct pathways and risk factors,” says Beth Karlan, a gynecologic oncologist at the David Geffen School of Medicine at the University of California at Los Angeles. For example, one kind of ovarian cancer tumor might be the size of a grapefruit that doesn’t spread, while another pea-sized subtype will quickly metastasize.
“We can’t continue to treat women as ‘one-size fits all,’ ” she says.
Recently, the Food and Drug Administration has approved targeted oral therapies, called PARP inhibitors, which kill off cancer cells. Although their intended use is for ovarian cancer patients with BRCA genetic mutations, which account for 15 percent of cases, researchers are exploring whether they can help women with other subtypes of ovarian cancer.
And another drug called bevacizumab — sold under the name Avastin — that stops the growth of blood vessels that nourish cancer cells has been successful when combined with chemotherapy for women with recurrent ovarian cancer. (Last summer, it was approved as a first-line treatment following surgery.)
Other targeted agents and immunotherapies that activate the immune system to fight cancer are in clinical trials. Still, the range and success rates of current treatment options are depressingly limited.
In the meantime, women should take advantage of new genetic sequencing tools to identity their cancer subtype and ask their doctor about getting into the right clinical trial instead of “going from chemotherapy to chemotherapy regimen hoping that something works,” says San Diego biotech executive Laura Shawver, who in 2008 founded the Clearity Foundation. The nonprofit group helps women with ovarian cancer get their tumors genetically profiled so they can be better matched to appropriate treatments.
“Women need to be aware that this technology exists and is usually covered by insurance,” she says.
What’s frustrating, Shawver says, is that by the time many women cycle through multiple chemotherapy regimens — the current standard of care for recurrent ovarian cancer — they might not be eligible for a clinical trial of new drugs. Also, their tumors might have changed over multiple treatments, so the drugs that might have worked initially for their subtypes are less effective.
“Your best chance for a cure is your first treatment and not when you’ve failed five other options,” Shawver says.
Before Liz Laats died of ovarian cancer three years ago at age 46, the mother of three from the San Diego area had suffered through 88 rounds of chemotherapy during 10 treatment regimens over six years that left her exhausted with chronic bone pain.
“At first, doctors gave her the treatments they said had done the most good for the most people, but they didn’t know how to treat her specifically,” says her husband, Andy Laats, who took her to more than two dozen doctors around the country.
“We kept thinking, ‘There must be a smarter doctor somewhere who knows.’ But you’re left trying to connect those dots,” he says, adding that Liz tried the “best of a lot of crappy options,” including drugs being tested in clinical trials that had worked in mice or patients with lung cancer.
“It felt like the game Chutes and Ladders. You get small steps of hope and then you fall down,” Laats says.
Despite the uneven progress, Lee at the University of Chicago wants the next generation of doctors to know that the story of ovarian cancer is changing for the better in small and meaningful ways.
“I don’t want to sugarcoat this terrible disease, but I also want students to see that women are living longer,” she says of the school’s collaboration with the Survivors Teaching Students program run by the Ovarian Cancer Research Alliance. “I want them to see the pictures of their families and the trips they’re taking. I want them to know that women are thriving. And I want them to know they might have the opportunity to identify the disease early enough to save a life.’
Scientists at Yale School of Medicine design a virus to treat ovarian cancer
Scientists at Yale School of Medicine design a virus to treat ovarian cancer
PARP inhibitors have shown significant promise in the treatment of ovarian cancer. Olaparib is a PARP inhibitor that has been approved for maintenance for BRCA-mutated ovarian cancer in the recurrent and front-line setting as well as for treatment of BRCA-mutated ovarian cancer in patients who have received multiple prior lines of chemotherapy. In this review, we focus on the use of olaparib in the maintenance setting including the evidence to date, ongoing research, and future directions.
“We felt it was important that students shouldn’t just learn about the biology of ovarian cancer, but we wanted them to know that every patient is a whole person with a story behind them,” University of Chicago gynecologic oncologist Nita K. Lee says.