With around 7500 new cases reported in the U.K. alone every year, ovarian cancer may occur because of the inheritance of faulty genes like BRCA. Although the exact reason for cancer-causing genetic mutations is unknown – as with all other kinds of cancer – ovarian cancer research has shown that the risk increases with age, exposure to radiation – especially from radiotherapy for the treatment of a previous cancer – and fertility issues, among other factors.
One of the most recent U.S. Food and Drug Administration (FDA)-approved drugs for ovarian cancer is American pharmaceutical ImmunoGen’s Elahere, for the treatment of ovarian cancer that has not responded well to platinum-based chemotherapy.
Up until recently, a major concern in ovarian cancer research was that tumors were developing resistance against certain drugs, and as a result, standards of care like chemotherapy are not always the most reliable option. But with recent progress in cancer research, these issues are being prioritized. Let us take a look at five advancements in ovarian cancer research over the past year that aim to bolster treatment response in patients and change cancer care.
Genelux’s immunotherapy sees success in phase 2 trials, begins phase 3
Focused on immunotherapies for cancer treatment, U.S.-based pharmaceutical Genelux is developing a drug to treat ovarian cancer. The candidate Olvi-Vec is a modified strain of vaccinia virus which stands out from other immunotherapies because of its multi-modal mechanism of action that leads to a personalized immune response, specifically with regard to the presentation of antigens and neoantigens unique to a patient’s tumor.
“Olvi-Vec utilizes a multi-modal mechanism of action to overwhelm a tumor’s sophisticated defenses by creating a localized tumor microenvironment ‘hot spot’ correlating to a more favorable prognosis. The process is catalyzed through the infection and selective reproduction within tumors, direct tumor cell killing and immunogenic cell death, while leaving normal tissue untouched,” said Thomas Zindrick, president and CEO of Genelux.
The drug, which converts the tumor tissue from an immunosuppressive to an immunostimulatory state, is administered in combination with platinum-based chemotherapy. In phase 2 trials, Olvi-Vec was found to have had a response rate of 54% in all patients in the cohort, including among platinum-refractory patients.
Moreover, the median overall survival of all patients stood at 15.7 months, Zindrick explained. “When looking at Durable Benefit, our phase 2 showed 20% long-term survivors after a median follow-up time of 47.0 months. In this end-stage population with limited to no therapeutic options, we refer to Olvi-Vec as having re-set the life-clock of responding patients.”
The company hopes to replicate these results in the phase 3 study, which will include a wide range of patients with ovarian cancer – regardless of tumor biomarkers, platinum refractory disease status, gene mutational status, expression level of tumor cell surface protein receptors, or the number of prior treatment lines they have undergone.
One case that particularly draws attention to the phase 2 trials is of a patient, who had previously undergone 10 treatment regimens that did not work, but responded to the Olvi-Vec-chemotherapy combination, and achieved 15.5 months of progression-free survival.
“Such significant clinical benefit is just one among several examples, showcasing remarkable responses to our therapy when many other options had been exhausted. It’s precisely these stories that fuel our commitment to instilling hope in both ovarian cancer patients and the field at large,” said Zindrick.
Research uncovers link between immune cells and treatment response
High-grade serous ovarian cancer (HGSOC) is the most common type of ovarian cancer, accounting for nearly 75% of all cases. In some of the tumors found in HGSOC, a certain kind of lymphoid tissue called tertiary lymphoid structures (TLS) are present. A recent study has identified the genes that code for these tissues, which have been found to significantly improve treatment response in those who have been diagnosed with HGSOC.
The research, conducted by Imperial College London in England, examined tumors from 242 patients with high-grade serous ovarian cancer, where they compared them before and after treatment. The scientists found that patients with TLS saw a better treatment outcome than patients who did not have TLS present in their tumors, making it one of the first time researchers were able to concretely link TLS in patients with HGSOC, to better prognosis.
“People tend to think of all cancer cell activity as purely malignant – but the reality is less clear-cut. Tumors can hijack a number of normal body processes and here, they seem to be hijacking the formation of normal human lymph tissue within themselves. Some of these lymphoid structures are able to then mature and activate T cells, which could attack the cancer itself,” said Haonan Lu, lead researcher from the Department of Surgery and Cancer at Imperial College London.
Playing a key role in draining out fluids to keep their amounts in check, the lymphatic system produces antibodies to help fight infections. And TLS are able to mimic lymphatic tissues, explaining why patients with TLS in the tumors could have had an enhanced response to therapy.
What’s more is that the researchers were able to pinpoint the location of the various genetic mutations – in IL15, CXCL10 and DCAF15 among others – that inhibited the development of regular lymph tissue and caused TLS formation.
“There is great potential for targeting these genes for benefits in ovarian cancer treatment. It’s now becoming clear how the genetic background of the tumor type interacts with a TLS to have more or less TLS function, and that will help us identify potential targets for therapy,” said Lu.
The study was published in Cell Reports Medicine, and funded by the National Institute for Health and Care Research Imperial Biomedical Research Centre. It also found that with the help of artificial intelligence, these high levels of TLS can be detected via a CT scan, making known how different treatments could benefit patients more quickly.
Preclinical study confirms new drug target for treatment-resistant ovarian cancer
PARP inhibitors (PARPi), a relatively new class of cancer drugs, is a targeted therapy that has previously proved to have increased chances of survival in patients with ovarian cancer. But, like with chemotherapy, it eventually stops working for patients, leaving them with no treatment options left. However, a new drug target has now been verified for drug-resistant ovarian cancer.
A preclinical research by scientists at the Perelman School of Medicine at the University of Pennsylvania in the U.S., observed that the protein B7-H4 – found in most breast and ovarian cancer diagnoses – was highly expressed in 92% of the HGSOC tumors that were examined. This was despite patients undergoing courses of chemotherapy and PARPi treatments, during which B7-H4 was still expressed. Moreover, the target was found outside the cells, allowing it to be more conveniently bound to by a drug.
Upon confirming the protein’s target capabilities, the scientists went on to administer antibody drug conjugates – a targeted therapy currently making rounds for causing far less bone marrow toxicity-related issues compared to traditional chemotherapy – to 20 patient-derived cancer models. As a result, 61% of the models that hadn’t received treatment prior to this, saw tumor size shrink after just one dose. And after 28 days, the tumors were found to have been significantly reduced when B7-H4 was targeted.
“We saw excellent anti-tumor activity, sustained over a long period of time in models that are drug-resistant, which is uncommon,” said Sarah Gitto, an instructor of Pathology and Laboratory Medicine at the University of Pennsylvania. “We’ve been able to show that B7-H4 is a very robust and widespread target that can be used across multiple stages of patient care.”
New drug combination found to reduce tumor size in ovarian cancer
Avutometinib is a dual RAF and MEK inhibitor, which suppresses enzymes to regulate pathways that are often overactive in cancers. Although, overtime, due to tumors developing drug resistance, the treatment turns out to be ineffective. But, a combination therapy of avutometinib with defactinib – a drug that can hinder a protein that promotes drug resistance – has now been found to work effectively in patients.
The study conducted by researchers at The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research in the U.K., showed that nearly half of the patients with advanced low-grade serous ovarian cancer (LGSOC), saw a marked reduction in tumor size. Moreover, 60% of the patients with a mutation on the oncogene KRAS, experienced notable shrinkage of their tumors, while nearly a third of patients without the mutation also responded well to treatment.
This is particularly encouraging as current standards of care for LGSOC – currently limited to chemotherapy and surgery – are only able to evoke a response rate ranging from zero to 14%. LGSOC accounts for about 10% of ovarian cancer cases, and because of its chemo-resistance, it is often hard to treat.
Susana Banerjee, lead investigator of the study and Consultant Medical Oncologist for The Royal Marsden NHS Foundation Trust Gynaecology Unit said: “These initial results could be fantastic news for women with low grade serous ovarian cancer, indicating a far more effective option than current treatments may be on the horizon… Low grade serous ovarian cancer does not respond well to currently approved treatments, so these results could represent a significant breakthrough in treating the disease.”
“We are hopeful this drug combination will one day become a standard of care for women with low grade serous ovarian cancer.”
Newfound proteins could aid in ovarian cancer detection
Biomarkers are key to detecting ovarian cancer, a disease that is hard to detect at the early stages, although patients would really benefit from early-stage diagnosis where it can be more easily treated. New research by scientists at Nagoya University in Japan has found proteins that could be isolated to provide an exact diagnosis for ovarian cancer, to advance targeted treatments early on.
Proteins, namely, FRα, Claudin-3, and TACSTD2, present in small extracellular vesicles – crucial biomarkers in cancer detection – released by cancer cells were first identified and then extracted from blood samples. They were captured using a novel technology that utilizes polyketone chain-coated nanowires (pNWs).
“Our findings showed that each of the three identified proteins is useful as a biomarker for HGSCs,” said Akira Yokoi, lead researcher from the Nagoya University Graduate School of Medicine. “The results of this research suggest that these diagnostic biomarkers can be used as predictive markers for specific therapies. Our results allow doctors to optimize their therapeutic strategy for ovarian cancer, therefore, they may be useful for realizing personalized medicine.”
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