New hope is on the horizon for recurrent ovarian cancer patients. A new gene therapy is showing promising results in possibly improving survival rates among patients with ovarian cancer that has recurred following chemotherapy.
Ovarian cancer, known as the ‘silent killer’, is the 5th leading cause of cancer-related deaths among women ages 35 to 74. As of this year, it is estimated that more than 22,000 new cases of ovarian cancer will be diagnosed.
According to the American Cancer Society, if the disease is diagnosed and treated in the earliest stages, the five-year survival rate is over 90%. However, due to its non-specific symptoms and lack of early detection tests, only around 20% of all ovarian cancer cases are diagnosed at stage I or II. Caught in stage III or higher, the survival rate can be as low as 28%.
New hope on the horizon
Being diagnosed with ovarian cancer can be shocking, frightening, and overwhelming. However, finding out that the cancer has recurred can be devastating. Ovarian cancer recurs when malignant cells resurface after cancer treatments, like chemotherapy or surgery, were completed a period of time ago. The cancer may recur at its original location or it may be found in other areas within the body.
Many women are diagnosed with recurrent ovarian cancer months or years following treatment, while others remain cancer-free. There are also those who go in and out of remission for months or even years. Sadly, recurrence occurs nearly 70% of the time.
But now, new hope is on the horizon for recurrent ovarian cancer patients. A new gene therapy has been found to deliver a protein that suppresses the development of female reproductive organs. It is showing promising results in possibly improving survival rates of women whose ovarian cancer has recurred following chemotherapy.
A Harvard-affiliated Massachusetts General Hospital research team reported how a just one injection of an altered form of Mullerian inhibiting substance (MIS) can suppress the growth of chemo-resistant ovarian tumors in a test mouse. MIS is a type of protein that is vital to sexual development. During embryonic development, the protein is released in male embryo tissue for the purpose of preventing the Mullerian duct from maturing. Following maturation, the Mullerian persists to develop female reproductive organs, including the fallopian tubes, the uterus, and part of the vagina. “We hypothesized that since ovarian cancer cells still express the receptors to MIS, why not use the hormone that causes regression in the fetus to target these cells? Cancer cells often behave a lot like cells in early development” said David Pepin, Harvard Medical School instructor in surgery and lead author of the study.
The tumors that were tested were grown from cells grafted from patient tumors. Although not all of them were responsive to the treatment, the researchers did find a non-invasive approach to screening cancer cells in vitro for proper responsiveness. “Our findings are important because there are currently no therapeutic options for recurrent, chemo-resistant ovarian cancer. This is also a proof of concept that gene therapies with the AAV9 vector can be used to deliver biologics for the treatment of ovarian cancer, and represents the first time this approach has been tested in this type of ovarian cancer model” said Pepin.
Ovarian cancer treatment potential
For several years now, the potential of MIS in suppressing the growth of chemo-resistant ovarian tumors was studied by targeting cancer stem cells that survived after chemotherapy. Studies were conducted in animal and human cell lines, although the results were insufficient for preclinical testing.
However, a few years ago, a study was published by Pepin and Patricia Donahoe and Marshall K. Bartlett, Distinguished Professor of Surgery at HMS, in which they revealed an altered form of MIS that produced a purer and effectiveness version of the protein. MIS was combined with the viral vector AAV9 and then tested against tumor cells taken from ascites that had built up in the abdomens of quite a few patients with recurrent ovarian cancer. Ascites refers to the abnormal fluid that accumulates in the abdominal cavity, which is a common site for ovarian cancer recurrence.
The current study confirmed that the tumor cells expressed the MIS protein and carried markers to indicate their identity as cancer stem cells. MIS also inhibited their growth in vitro. Furthermore, it was discovered that just one injection of the MIS/AAV9 combination into the abdominal cavity of mice brought about elevated levels of MIS.
From there, effectiveness of the MIS/AAV9 combination was tested in mice that were implanted with ovarian cancer cells. The results revealed that one injection, three weeks before tumor implantation, significantly suppressed tumor growth. “The AAV9 does not hit the tumor directly. It gets expressed in muscle and other organs, and so the patients themselves become a bioreactor for the production of MIS, which then acts on the tumor” explained Dr. Donahoe. The treatment was also applied to mice with induced tumors by implanting cancer cells from 5 different patients. It was found that the MIS/AAV9 combination significantly suppressed the tumor growth generated from the cells of 3 out of 5 patients.
With further analysis of tumor samples from over 200 patients, it was found that 88% prompted some level of the MIS receptor, with 65% displaying moderate to high protein expression. “Since the response to MIS gene therapy is not the same for all patients, it will be important to first screen each patient’s tumors to ensure they will respond” said Pepin. “While we have not yet identified biomarkers of treatment response — something we are currently searching for — we have described a way to rapidly grow tumor cells from ascites to be evaluated for drug sensitivity. If further study confirms the susceptibility of chemo-resistant tumors to this MIS gene therapy, the ability to inhibit tumor recurrence could significantly extend patient survival” he added.
All of the implanted tumor cells were taken from patients who had failed to respond to previous treatments. That being said, a 65% response rate with MIS/AAV9 was found to be quite impressive for a mere agent. “The ability to administer this MIS/AAV9 construct as a single, long-acting injection makes the use of this effective but complex protein both clinically feasible and patient-friendly. Our results provide proof of concept and predict a translation into patient care that was not previously possible” said Donahoe.
Seeing as how MIS/AAV9 is much safer for use than previous gene therapy viruses, Donahoe and Pepin are currently in search of commercial partners to produce the AAV9 gene therapy and to test it out in a clinical trial.
Focusing on effective management
According to the Ovarian Cancer National Alliance, a majority of women diagnosed with ovarian cancer experience recurrence. The rate of recurrence varies from patient to patient, but the risk increases with the cancer’s stage at diagnosis. For instance, women initially diagnosed with stage I ovarian cancer have a 10% chance of recurrence. The more advanced the stage, the higher the risk. Having said that, follow-up appointments with an oncologist are crucial to detecting ovarian cancer recurrence early on. In addition, routine gynecologic care and yearly pelvic examinations are recommended to screen for non-specific ovarian cancer recurrence symptoms, including persistent abdominal bloating and changes in appetite, to name a few.