PARP Inhibitors Advance in Ovarian Cancer

With olaparib approved and niraparib and rucaparib advancing through clinical development, PARP inhibition is becoming a valuable option in the ovarian cancer armamentarium.

In a discussion at the 2016 CFS,^™ Michael Birrer, MD, PhD, director of Medical Gynecologic Oncology at Massachusetts General Hospital, said he anticipates that the FDA will approve niraparib and rucaparib in ovarian cancer in the next 6 months to a year.

The focus now, according to Birrer, is on optimizing the use of these treatments. “We need to find the best patient population to treat and we need to define whether we use these drugs in maintenance treatment, or early or late [in sequencing].”

Olaparib was approved in 2014 for women with BRCA-positive advanced ovarian cancer following treatment with ≥3 prior lines of chemotherapy. The approval was based on a phase II study in which olaparib had an objective response rate (ORR) of 34% in 137 heavily pretreated patients with BRCA-positive ovarian cancer. The ongoing phase III SOLO trials are examining olaparib as maintenance therapy or an alternative to chemotherapy in patients with recurrent disease.

In August 2016, the FDA granted a priority review to rucaparib for patients with BRCA-positive advanced ovarian cancer who have received ≥2 prior lines of chemotherapy, based on data from 106 patients across 2 trials, including the ARIEL2 study. In a pooled analysis of data from the studies, the ORR was 54% with rucaparib. A final decision is scheduled by February 23, 2017.

An application was recently submitted to the FDA for niraparib as a maintenance treatment for women with recurrent platinum-sensitive ovarian, fallopian tube, or primary peritoneal cancer. The application is based on the phase III NOVA trial, in which niraparib reduced the risk of progression or death by 73% compared with placebo for patients with germline BRCA-positive, platinum-sensitive, recurrent ovarian cancer. The phase III PRIMA trial is examining niraparib as a frontline maintenance treatment in patients with advanced ovarian cancer and homologous recombination deficiency (HRD).

Expanding on HRD, a target for PARP inhibitors, Birrer said that HRD testing may increase the therapeutic opportunities for these agents. Researchers are evaluating HRD assays in many ongoing trials. “The optimal [HRD] assay is not yet defined. It’s evolving fast. We hope that it will be predictive of a PARP inhibitor clinical benefit,” said Birrer.

Summarizing the available data for olaparib, niraparib, and rucaparib, Birrer said, “They all inhibit PARP 1 and PARP 2. There are some slight differences in potency, but I’m not so sure that is clinically relevant. The most extensively studied has been olaparib, but there are no direct comparisons yet [among the agents].”

Birrer said combinations have become the focus for further enhancing the benefit of PARP inhibitors in ovarian cancer. A phase II trial examined olaparib in combination with the VEGF inhibitor cediranib in patients with platinum-sensitive recurrent ovarian, peritoneal, or fallopian tube cancer who have received at least 1 prior platinum based-regimen.

The median progression-free survival with the combination was 17.7 months compared with 9.0 months with olaparib alone (HR, 0.42; 95% CI, 0.23-0.76; P = .005). Birrer noted that there were some significant grade 2-4 toxicities in the combination arm, including hypertension (75%), diarrhea (69%), and fatigue (54%). Two ongoing phase III trials, NRG GY004 and NRG GY005, are further examining the combination in ovarian cancer.

Another PARP/VEGF combination being explored is niraparib and bevacizumab, which is being compared to monotherapy with either agent in the phase III AVANOVA trial. Birrer said the study is now open in Europe and will open in the United States soon.

To read this full article on Targeted Oncology, please click here.

New Possibility In Treating Aggressive Ovarian Cancer, Study Shows

A recent discovery by researchers from the Cancer Science Institute of Singapore (CSI Singapore) at the National University of Singapore (NUS) may lead to a new treatment strategy for an aggressive ovarian cancer subtype.

Ovarian cancer is the most deadly gynecological cancer and it is the seventh most common cancer in women worldwide. Most women with ovarian cancer are diagnosed at the advanced stage, which is more difficult to treat.

In a study led by Dr Ruby Huang, Principal Investigator at CSI Singapore, researchers identified a molecule called AXL which is found to trigger the spread of an aggressive form of ovarian cancer called the Mes subtype. This is one of two aggressive subtypes of ovarian cancer — the other subtype is called Stem-A — that was identified by Dr Huang’s group in an earlier study. These two subtypes of ovarian cancers have a higher ability to undergo Epithelial-Mesenchymal Transition (EMT). EMT is the process by which epithelial cells transform into mesenchymal cells, which have been associated with aggressive metastatic cancer.

By carrying out experiments on Mes subtype ovarian cancer cells, Dr Huang and her team found that AXL, when activated, was able to interact with other proteins in the cell to form a cellular pathway that contributes to the aggressive spread of ovarian cancer cells. Results from this study were published in the October issue of the journal Science Signaling.

New Hope For Treating Advanced Ovarian Cancer

Currently, there is no specific treatment for the Mes ovarian cancer subtype, and the findings from this study suggest that blocking AXL could be an effective treatment option for these patients.

“Though earlier studies have suggested the role of AXL in contributing to the spreading of ovarian cancer cells, no study has investigated the AXL function in ovarian cancer with different molecular backgrounds. This study builds upon our previous efforts in understanding the biology among different ovarian cancer subtypes, and the current finding represents an advancement into novel roles of AXL in ovarian cancer and brings another layer of sophistication in ovarian cancer treatment,” said Dr Huang.

The research team from CSI Singapore is collaborating with several pharmaceutical companies to develop anti-AXL drugs, in order to bring the discovery from bench to bedside for ovarian cancer treatment. Dr David Tan, who holds dual appointments with CSI Singapore and National University Cancer Institute, will be leading the clinical development of the anti-AXL treatment.

This study was carried out in collaboration with clinicians from the National University Hospital as well as scientists from Imperial College London, and supported by the National Research Foundation Singapore, Singapore Ministry of Education, and National Medical Research Council. The first author of the paper, Dr Jane Antony, had recently graduated from the joint PhD programme between NUS Graduate School for Integrative Sciences and Engineering as well as Imperial College London.

To read this article on ScienceDaily.com, please click here.

Researchers Develop New Compound To Reduce Tumor Growth

A baseball glove is typically made from leather. If a new design made gloves more attractive to baseballs—catching them at higher rates than the typical glove—would it be a game changer?

Researchers at Stanford University School of Medicine created such a glove at a microscopic scale. They developed a receptor—with a half-circle shape like that of a baseball glove—that attracted a key cancer-causing molecule called Gas6 and took it out of play, slowing the progression of pancreatic and ovarian cancer in mice.

The study will be published online Nov. 28 in The Journal of Clinical Investigation.

When used alone or in combination with chemotherapy in mice, their “decoy receptor” showed a higher ability to reduce or stop cancer growth than other treatments did.

They also elucidated a previously unknown mechanism in the body. In mice, when the researchers inhibited Gas6 from binding to its native receptor, Axl, the cancer cells began to release DNA-damaging molecules, causing the cells to die. This suggests a potential method to improve current therapeutic approaches.

“We were even able to get some animals cured, even those that started out with widespread and aggressive metastatic disease,” said Amato Giaccia, PhD, professor of radiation oncology and lead author of the study.

The Problem With Current Treatment

The researchers wanted to test their molecule in animal models of ovarian and pancreatic cancer, which are hard to detect in early stages. Current treatment options for ovarian and pancreatic cancer patients are limited and usually require a combination of surgery, radiation and chemotherapy. The therapies can have toxic side effects and rarely lead to a complete cure. So researchers have been increasingly turning to other medications, such as antibiotics or small compounds called tyrosine kinase inhibitors, to use with them. But those medications also have drawbacks: They’re toxic, so they can’t be delivered in large quantities, and they are unable to beat the strong attraction between Gas6 and Axl. Although they can sometimes stop tumor growth, they rarely result in complete eradication of cancer.

“A lot of treatments out there are very toxic because they are not specifically targeting the cancer cells, and they have a huge burden on the liver and kidney,” said Rebecca Miao, PhD, a Stanford research associate who shares lead authorship of the study. “Our decoy receptor seems in mice to not only to be very efficacious but also safe.”

Giaccia said, “We basically came up with a better glove, with a much stronger ability to catch the baseball—in this case, Gas6.”

Activation of Axl: A Key Player In Different Forms Of Cancer

Gas6 is a molecule that binds and activates Axl, the surface receptor that plays a key role in cell survival, growth and migration. In many forms of cancer, Axl is over-expressed and binds Gas6 very strongly, which makes it difficult for the development of therapeutics to target this complex.

However, Giaccia and his team developed a decoy receptor that binds to Gas6 around 350 times better than Axl does. When given to mice, the decoy took out the Gas6 molecules from the system and blocked them from activating Axl, suppressing cell growth and migration and stopping cancer growth.

“Our molecule has a higher affinity for Gas6, so it is more effective in taking it out,” said Giaccia.

To create the decoy receptor, called MYD1-72, they used yeast as a vessel to express different mutations of the Axl protein. They then labeled Gas6 with a fluorescent molecule so that they could detect which mutated Axl protein it best bound with.

Once they found the most effective mutation, they tested it against other promising therapies that target the Axl pathway and that are currently in clinical trials: BGB324 and foretinib. MYD1-72 and foretinib were both able to reduce tumor size and metastasis, but foretinib showed toxicity in the mice. BGB324 showed little in the way of harmful effects on the mice, but did not reduce tumor burden.

The researchers further tested their new decoy receptor on pancreatic and ovarian cancer in mice.

In ovarian cancer models, they tested the efficacy of MYD1-72 both alone and in conjunction with a DNA-damaging agent called doxorubicin that is commonly used for treatment. They found that alone, MYD1-72 reduced tumor burden by 95 percent. In combination with doxorubicin, most mice ended up with almost complete tumor reduction. In mice with more aggressive forms of ovarian cancer, MYD1-72 alone decreased tumor weight by 51 percent, whereas doxorubicin decreased tumor weight by 91 percent. When used together, the researchers measured a 99 percent reduction of tumor weight.

In pancreatic cancer, they also found that MYD1-72 in combination with a DNA-damaging agent called gemcitabine showed greater tumor reduction. Alone, MYD1-72 did not make any impact on the mice’s tumor burden. Mice treated with MYD1-72 and gemcitabine together had a three times higher survival rate than mice not on any treatment.

These results suggested that a combination therapy of their decoy receptor and DNA-damaging agents could result in significantly lower levels of tumor burden.

Hoping To Bring Therapy To Clinic

“We are actively working to push this into clinical trials,” said Miao. “But we are also interested in looking at how our molecule affects other types of cancers.” They hope to continue studies on how this decoy receptor could enhance treatments for other types of cancer, such as leukemia.

“These pre-clinical models in mice are pretty robust as we’ve shown in a number of different tumor settings and now in ovarian cancer and pancreatic cancer,” said Giaccia. “But we need to ultimately test this in human cancers.”

To read this full article on MedicalXpress.com, please click here.

PARP Inhibitor Shows Benefit in Ovarian Cancer

Lynparza (olaparib) demonstrated improved progression-free survival (PFS) compared to the placebo arm for patients with ovarian cancer, according to findings from the phase 3 SOLO-2 trial. The single-agent PARP inhibitor was tested in the maintenance setting for patients with advanced BRCA-positive ovarian cancer.

Although specific data from the trial are not yet available, AstraZeneca, the manufacturer of Lynparza, reported that the median PFS with Lynparza was significantly higher than in the Lynparza arm of the phase 2 Study 19 in a similar population. The safety profile for the PARP inhibitor was consistent with results reported from previous trials.

“We are pleased with the robust improvement in progression-free survival demonstrated by Lynparza in the SOLO-2 trial. We will work with regulatory authorities to make Lynparza tablets available as quickly as possible to patients with ovarian cancer. We remain committed to investigating the full potential of Lynparza, both as monotherapy and in combinations, and to identifying all patients who may benefit from this important medicine,” Sean Bohen, M.D., Ph.D., executive vice president, Global Medicines Development, and Chief Medical Officer at AstraZeneca, said in a statement.

The multicenter phase 3 SOLO-2 trial included 295 patients with platinum-sensitive, relapsed/recurrent, BRCA-positive ovarian cancer who had received two or more prior lines of platinum-based chemotherapy. Patients were randomized to receive either Lynparza at 300 mg twice daily or placebo until disease progression.

The latest data from the phase 2 Study 19, which were presented at the 2016 American Society of Clinical Oncology (ASCO) Annual Meeting, showed that in patients with platinum-sensitive relapsed serous ovarian cancer, Lynparza increased overall survival (OS) when given as maintenance therapy.

Results of the study’s extension showed that the PARP inhibitor demonstrated the greatest OS advantage in women who had a BRCA mutation, according to lead author Jonathan Ledermann, M.D., professor of Medical Oncology at the University College London Cancer Institute and director of the Cancer Research UK & UCL Cancer Trials Centre, who presented the results at ASCO.

Additional key findings were that both time to first subsequent therapy or death (TFST) and time to second subsequent therapy or death (TSST) were substantially prolonged in patients taking Lynparza; again, the greatest benefit was seen in those with a BRCA mutation. Additionally, the unprecedented long-term exposure meant that 13 percent of all trial patients (15 percent of BRCA-mutated patients) received maintenance Lynparza for at least five years. In three years of follow-up since the 2012 analysis, there were no new safety findings.

Study 19 assessed patients with platinum-sensitive, recurrent high-grade serous ovarian cancer (265 patients). They had received two or more prior regimens of platinum-based chemotherapy and experienced complete response or partial response to their most recent regimen. In a double-blind, one-to-one randomization, half the patients received Lynparza 400 mg capsules twice daily as maintenance therapy (136 patients) and half received placebo capsules twice daily (129 patients).

BRCA testing occurred for all patients in the form of case reports that contained the results of previous local germline BRCA testing or retrospective germline BRCA testing or tumor BRCA testing. The division between patients was nearly even between those BRCA mutations (136 patients) and those with wild-type BRCA findings (118 patients), meaning that they either did not have a detected BRCA mutation or they had a BRCA mutation of unknown significance.

In Study 19, the median PFS for patients taking maintenance Lynparza was 8.4 months, compared to 4.8 months for the control group. The difference in the BRCA mutation subgroup was even more pronounced: 11.2 months with Lynparza and 4.3 months with placebo.

The third data analysis of Study 19, with data cutoff at Sept. 30, 2015, was performed with data at 77 percent maturity, OS in the overall study population (265 patients) was a median 29.8 months in the Lynparza group and 27.8 months in the placebo. In the BRCA mutation group (136 patients), where the data were at 70 percent maturity, median OS was 34.9 months for the Lynparza group and 30.2 months for placebo.

With a median follow-up interval of 5.9 years, 15 patients (11 percent) were still receiving Lynparza (eight with BRCA mutations). One BRCA-mutated patient was still receiving placebo. Twelve percent of BRCA wild-type patients on Lynparza achieved median follow-up of between five and six years.

In the overall study population, 59 patients (43 percent) experienced an adverse event (AE) of grade 3 or above, while only 28 (22 percent) of those on placebo did. Those percentages remained fairly consistent among patients who remained on trial for two years or more: 15 (47 percent) in the Lynparza arm and one (20 percent) in the control arm.

Likewise, the percentages of dose reductions due to AEs were consistent over time, and there were few treatment discontinuations due to AEs: eight active and two control patients overall and three Lynparza patients from the long-term treatment group. No patients from the long-term placebo group discontinued treatment due to AEs.

In June 2014, the FDA’s Oncologic Drugs Advisory Committee voted 11-2 against the accelerated approval of Lynparza as a maintenance therapy for women with platinum-sensitive relapsed ovarian cancer with germline BRCA mutations. By voting no, the committee recommended waiting for results from the SOLO-2 trial before approving Lynparza in this setting.

Following this vote, AstraZeneca submitted an amendment to Lynparza’s new drug application upon the FDA’s request, which led to the drug’s eventual approval in December 2014 for the treatment of women with BRCA-positive advanced ovarian cancer following treatment with three or more prior lines of chemotherapy.

To read this entire article on CureToday.com, please click here.

GPs Miss Nearly Half Of Ovarian Cancer Cases

Almost half of women with ovarian cancer were initially misdiagnosed, a charity has found.

And four in ten patients with the cancer said their symptoms were not taken seriously by dismissive GPs.

Research found that women were ‘dying needlessly’ because they were fobbed off by doctors who attributed symptoms to other issues such as digestion problems, the menopause or stress.

About 46 per cent of patients were initially referred for tests for something other than ovarian cancer, delaying their diagnosis and treatment.

Annwen Jones, from the charity Target Ovarian Cancer, which carried out the study, said: ‘Women with ovarian cancer are being failed at diagnosis, in access to trials and effective drugs, and they lack support. They deserve better than this.’

A fifth of sufferers aged 50 or above were first told they had irritable bowel syndrome (IBS) despite official guidelines stating older women with symptoms of IBS should be screened for ovarian cancer.

And 40 per cent of patients said their GP had not considered their symptoms to be serious, with nearly one in ten told they may have a mental health problem instead. A further 41 per cent of women had to visit their doctor at least three times before being referred for cancer tests, according to the research.

Even when women were referred for tests, three quarters were not told they might have ovarian cancer.

The cancer is often misdiagnosed or diagnosed late because of a lack of awareness about the symptoms among both the public and doctors. Signs include persistent stomach swelling, appetite loss and pelvic or abdominal pain.

Every year 7,300 women are diagnosed with the disease and 4,100 die. Only a third of women survive for ten years after diagnosis and 15 per cent die within two months.

Target Ovarian Cancer interviewed 396 ovarian cancer patients, as well as 504 GPs and 41 nurses for its annual Pathfinder survey.

It found nearly half of cancer nurses did not think their unit had enough staff to care properly for patients, while two thirds of the nurses surveyed did not have time to explain the symptoms of recurrent ovarian cancer.

Only one in four patients were involved in a clinical trial, despite more than half saying that they would like to be involved in one.

The report authors wrote: ‘Too many women continue to think cervical screening protects them against ovarian cancer and many have a false confidence in their ability to spot the symptoms of ovarian cancer.

‘Women continue to face repeat visits to their GP before being referred for diagnostic tests and many GPs still falsely believe symptoms only present themselves in the later stages of the disease and continue to be unaware of the importance of family history on both sides of the family.’

Professor Michael Peake, from the National Cancer Registration and Analysis Service, who oversaw the research, said the results showed ‘where women’s lives could be saved if the quality of services were to be improved and, where necessary, investment made’.

To read this article on DailyMail.com, please click here.

PARP Inhibition at the Forefront of Ovarian Cancer Treatment Paradigm

PARP inhibition is quickly becoming a major element of the overall ovarian cancer treatment landscape, as several of these agents are continuing to advance through clinical development.

During a discussion at the 34th Annual Chemotherapy Foundation Symposium™, Michael Birrer, MD, PhD, director of Medical Gynecologic Oncology at Massachusetts General Hospital, said that he expects that the FDA will soon approve both niraparib and rucaparib, joining the recent approval of olaparib (Lynparza) in ovarian cancer. The primary focus now, says Birrer, is to optimize the clinical use of these treatments.

“We need to find the best patient population to treat, and we need to define whether we use these drugs in maintenance treatment, or early or late [in sequencing],” he said.

Olaparib was approved in 2014 for women with BRCA-positive advanced ovarian cancer following treatment with ≥3 prior lines of chemotherapy. The approval was based on a phase II study in which olaparib had an objective response rate (ORR) of 34% in 137 heavily pretreated patients with BRCA-positive ovarian cancer. The ongoing phase III SOLO trials are examining olaparib as maintenance therapy or an alternative to chemotherapy in patients with recurrent disease.

In August 2016, the FDA granted a priority review to rucaparib for patients with BRCA-positive advanced ovarian cancer who have received ≥2 prior lines of chemotherapy, based on data from 106 patients across 2 trials, including the ARIEL2 study. In a pooled analysis of data from the studies, the ORR was 54% with rucaparib. A final decision is scheduled by February 23, 2017.

An application was recently submitted to the FDA for niraparib as a maintenance treatment for women with recurrent platinum-sensitive ovarian, fallopian tube, or primary peritoneal cancer. The application is based on the phase III NOVA trial, in which niraparib reduced the risk of progression or death by 73% compared with placebo for patients with germline BRCA-positive, platinum-sensitive, recurrent ovarian cancer. The phase III PRIMA trial is examining niraparib as a frontline maintenance treatment in patients with advanced ovarian cancer and homologous recombination deficiency (HRD).

Expanding on HRD, a target for PARP inhibitors, Birrer said that HRD testing may increase the therapeutic opportunities for these agents. Researchers are evaluating HRD assays in many ongoing trials. “The optimal [HRD] assay is not yet defined. It’s evolving fast. We hope that it will be predictive of a PARP inhibitor clinical benefit,” said Birrer.

Summarizing the available data for olaparib, niraparib, and rucaparib, Birrer said, “They all inhibit PARP 1 and PARP 2. There are some slight differences in potency, but I’m not so sure that is clinically relevant. The most extensively studied has been olaparib, but there are no direct comparisons yet [among the agents].”

Birrer said combinations have become the focus for further enhancing the benefit of PARP inhibitors in ovarian cancer. A phase II trial examined olaparib in combination with the VEGF inhibitor cediranib in patients with platinum-sensitive recurrent ovarian, peritoneal, or fallopian tube cancer who have received at least 1 prior platinum based-regimen.

The median progression-free survival with the combination was 17.7 months compared with 9.0 months with olaparib alone (HR, 0.42; 95% CI, 0.23-0.76; P = .005). Birrer noted that there were some significant grade 2-4 toxicities in the combination arm, including hypertension (75%), diarrhea (69%), and fatigue (54%). Two ongoing phase III trials, NRG GY004 and NRG GY005, are further examining the combination in ovarian cancer.

Another PARP/VEGF combination being explored is niraparib and bevacizumab, which is being compared to monotherapy with either agent in the phase III AVANOVA trial. Birrer said the study is now open in Europe and will open in the United States soon.

To view this full article on OncLive, please click here.

Newly Discovered Biomarker Could Help Guide Cancer Therapy, Avoid Drug Resistance

MIT biologists have identified a new biomarker that can reveal whether patients with a particularly aggressive type of breast cancer will be helped by paclitaxel (commercially known as Taxol), one of the drugs most commonly used to treat this cancer.

The findings could offer doctors a new way to choose drugs for this type of breast cancer, known as triple-negative because it lacks the three most common breast cancer markers: oestrogen receptor, progesterone receptor, and Her2 protein. The biomarker, a protein called Mena, has previously been shown to help cancer cells spread through the body.

The researchers also showed that combining paclitaxel with another drug that interferes with Mena’s effects can kill the cells much more effectively than paclitaxel alone.

“Drugs that target that pathway restore paclitaxel sensitivity to cells expressing Mena,” says Frank Gertler, an MIT professor of biology and a member of the Koch Institute for Integrative Cancer Research. “The study also suggests that during the course of treatment it might be worth monitoring the level of Mena. If the levels begin to increase, it might suggest that switching to another type of therapy could be useful.”

Gertler is the senior author of the study, which appears in the journal Molecular Cancer Therapeutics. Madeleine Oudin, a Koch Institute postdoc, is the paper’s lead author.

How Cells Survive

The Mena protein is known to interact with a cell’s cytoskeleton in ways that help the cell to become mobile. Many cancer patients have an alternative form of the protein known as Mena invasive or MenaINV, which helps cancer cells to spread from their original location through a process known as metastasis. Gertler’s research group has previously found that breast cancer patients who have high levels of the protein’s invasive form tend to have more metastasis and lower survival rates.

The researchers wondered if Mena might also play a role in cancer cell resistance to chemotherapy. Between 30 to 70 percent of triple-negative breast cancer patients respond well to chemotherapy, but the disease reappears within six to 10 months, on average.

“We know we have good drugs that can kill a lot of cancers, but some people don’t respond to them, and some people do respond but only for a short amount of time,” Oudin says.

They tested several different chemotherapy drugs on triple-negative breast cancer cells with varying levels of Mena, and found that those cells with the highest Mena levels were resistant to paclitaxel. However, Mena levels did not affect sensitivity to two other commonly used chemotherapy drugs, doxorubicin and cisplatin.

Paclitaxel, which is also used to treat ovarian cancer, works by interfering with microtubules — small tubular proteins that make up the cell’s cytoskeleton and help with cell division. Microtubules can be either dynamic or stable, and the dynamic version is necessary for cell division. Paclitaxel stabilizes the microtubules, interfering with cell division and killing the cells.

After giving paclitaxel to mice with metastatic triple-negative tumours, the researchers found that tumours with the highest levels of Mena showed the worst response: The drug did not slow growth of either the original tumours or metastases. This effect was the same whether the tumours expressed the invasive form of Mena or the original version.

The researchers also showed that cancer cells with high Mena levels had more dynamic microtubules than cells with low Mena levels. This increase in dynamic microtubules makes it easier for the cells to divide and allows them to resist the effects of paclitaxel.

Countering Resistance

Previous studies have shown that paclitaxel treatment also affects a cellular pathway known as ERK signalling, which is often overactive in cancer cells and drives cell proliferation. Paclitaxel treatment turns on this pathway, which helps cancer cells to survive the treatment, but if an inhibitor of ERK signalling is given at the same time, the treatment is more successful.

In the Molecular Cancer Therapeutics study, the MIT team tried the paclitaxel-ERK pathway inhibitor combination in breast cancer cells with high levels of Mena and found that it killed cells much more effectively than paclitaxel alone. Clinical trials are already underway to test this combination of drugs in breast cancer.

“Our work would suggest that for a certain subset of patients that have high levels of Mena, that could be an efficient combination to try,” Oudin says.

The findings could also help doctors choose treatments for patients based on the levels of Mena in their tumours. To pursue that possibility, the researchers now hope to do studies with human tumour samples to see if they show the same relationship between Mena levels, paclitaxel sensitivity, and patient outcome. This work may be done in collaboration with MetaStat, a company that Gertler and others founded to develop diagnostic tests based on Mena and other biomarkers.

“The hope is it may also provide more information on therapeutic choice and potentially spare some patients treatment with a chemotherapy that is likely to be less effective,” Gertler says.

“Triple-negative breast cancer patients don’t have many treatment options,” says Bruce Zetter, a professor of cancer biology and surgery at Harvard Medical School. “If this work can help identify patients most likely to respond to Taxol and encourage greater use of the combination of MEK inhibitors and Taxol, that could potentially lead to greater survival of patients with that disease.”

The researchers also hope to uncover more of the mechanism of how Mena affects microtubules, and to see if the same interaction plays a role in drug resistance in other types of cancer, such as ovarian cancer.

To read this full article on Scicasts.com, please click here.

What You Need to Know About Ovarian Cancer

Ovarian cancer is among the 3 most common gynecologic cancers, along with cervical and endometrial cancers. According to the American Cancer Society, 1 in 75 women will have ovarian cancer in their lifetime, about 22,280 women will be diagnosed with ovarian cancer, and about 14,240 will die from it in 2016. Ovarian cancer ranks fifth in cancer-related deaths in women, accounting for more deaths than any other cancer of the female reproductive system.

Ovarian cancer is more common in older women; about 50% of women diagnosed are aged 63 years or older. It is also more common in white women than in African-American women. Overall, over the past 20 years, the rate of new cases has been slowly decreasing.

How Ovarian Cancer Grows

In ovarian cancer, cancerous cells develop in the tissues of the ovaries. The ovaries are the glands that produce eggs needed for reproduction; they are also the main source of the female reproductive hormones, estrogen and progesterone, which control sexual development.

More than 30 types of ovarian cancer are known, and they are classified by the type of cells from which they originate. The 3 most common types of ovarian cancer are:

Epithelial tumors, which originate in the epithelium, the tissue that covers the outside surface of the ovary. This type accounts for about 90% of ovarian cancers, and it occurs mainly in women older than 60. This cancer is often diagnosed at an advanced stage.

Germ-cell tumors originate in the germ cells, which are responsible for producing reproductive eggs. It is a rare type, affecting mostly teenagers and women in their 20s.

Stromal tumors start in the supporting tissues of the ovary, where estrogen and progesterone are produced. This is a relatively rare type, occurring mainly in women aged 40 to 60.

Risk Factors

Several factors increase the likelihood of getting epithelial ovarian cancer; these don’t apply to the less common types of ovarian cancer.

Age. The risk for ovarian cancer increases with age, and most cases occur after menopause, with half of all cases occurring at age 63 or later.

Obesity. Being obese (body mass index of at least 30 kg/m²) increases the risk for ovarian cancer.

Reproductive history. Being pregnant and delivering a child before age 26 reduces the risk for ovarian cancer. Women who first deliver a baby after age 35 or who have never had a baby are at increased risk.

Fertility drugs. Using the fertility drug Clomid (clomiphene citrate) for more than 1 year may increase the risk for this cancer.

Androgens. Danazol, a drug that increases androgen levels, also increases the risk for ovarian cancer.

Estrogen and hormone therapy. Using estrogens after menopause increases the risk for ovarian cancer; the risk is higher in women taking estrogen alone (without progesterone) for at least 5 to 10 years. This risk is less certain when taking estrogen with progesterone.

Family history. The risk increases if a first-generation relative (mother, sister, or daughter) has the disease. A family history of other cancers, such as colorectal or breast cancers, can also increase the risk. Some ovarian cancers are associated with a family cancer syndrome caused by inherited mutations (alterations) in certain genes, such as BRCA1 and BRCA2. Having the BRCA2 mutation increases the risk for ovarian cancer by age 70. Other family-inherited cancer syndromes, such as Cowden disease, Lynch syndrome, Peutz-Jeghers syndrome, and MUTYH-associated polyposis, are linked to ovarian cancer risk.

Personal history of breast cancer. The risk for ovarian cancer after breast cancer is highest in women with a family history of breast cancer and a BRCA1 or BRCA2 mutation.

Talcum powder. It has been suggested that talcum powder applied directly to the genital area or on sanitary napkins may cause ovarian cancer.

Common Symptoms

The symptoms of ovarian cancer resemble other conditions, so the disease is often diagnosed late. Symptoms are more likely to manifest when the disease has spread beyond the ovaries, but even early-stage disease has symptoms. A woman who has these symptoms more than 12 times per month should see her gynecologist.

The most common symptoms include bloating; pelvic or abdominal pain; trouble eating or feeling full quickly; urinary symptoms, such as urgency or frequency; fatigue; upset stomach; back pain; pain during sex; constipation; menstrual changes; and abdominal swelling with weight loss.

Diagnosis

The methods used to diagnose ovarian cancer include physical exam; CA-125 blood test; blood tests (human chorionic gonadotropin HCG, alpha-fetoprotein AFP, lactate dehydrogenase LDH tumor markers); radiology imaging, including CT scans, MRI, pelvic/transvaginal ultrasound, PET scan; colonoscopy; and surgical laparoscopy with biopsy.

Prevention Strategies

Oral contraceptives. Using oral contraceptives (birth control pills) is associated with a lower risk for ovarian cancer.

Gynecologic surgery. Tubal ligation and/or hysterectomy may reduce the risk for ovarian cancer.

Diet. Women who follow a diet low in fat and high in vegetables and healthful foods have lower risk for ovarian cancer.

Treatment of Ovarian Cancer

Surgery is the main treatment for most ovarian cancers, with the goal of removing the cancer. This typically involves removing the uterus (hysterectomy) and the ovaries, and removing as much of the tumor as possible (debulking).

Radiation is rarely used as the main treatment for ovarian cancer.

Chemotherapy drugs. The standard chemotherapy for ovarian cancer is to combine a platinum-based drug, such as cisplatin or carboplatin, with a taxane, such as paclitaxel or docetaxel. The typical course of chemotherapy for epithelial ovarian cancer involves 3 to 6 chemotherapy cycles. Chemotherapy drugs used include Abraxane (paclitaxel), Hexalen (altretamine), Xeloda (capecitabine), Cytoxan (cyclophosphamide), VP-16 (etoposide), Gemzar (gemcitabine), Ifex (ifosfamide), Camptosar (irinotecan), Doxil (liposomal doxorubicin), melphalan, Alimta (pemetrexed), Hycamtin (topotecan), and Navelbine (vinorelbine tartrate).

Targeted therapy is a newer type of cancer treatment that uses drugs or other substances to attack cancer cells while doing little damage to normal cells. Avastin (bevacizumab) is a targeted drug that stops or slows the growth of cancer. Avastin was approved in 2014 for use in combination with chemotherapy for recurrent ovarian cancer. Lynparza (olaparib) was approved in late 2014 for advanced ovarian cancer and the BRCA mutation. Lynparza is a PARP inhibitor; by blocking the PARP pathway, Lynparza makes it difficult for tumor cells with a BRCA mutation to repair damaged DNA.

Hormone therapy involves the use of hormones or hormone-blocking drugs to treat the less common ovarian cancer. Drugs that stop estrogen production by the ovaries are called LHRH agonists and include Zoladex (goserelin acetate) and Lupron(leuprolide acetate). Tamoxifen is an anti-estrogen that keeps estrogens from stimulating cancer-cell growth. Aromatase inhibitors are drugs that block the aromatase enzyme from turning other hormones into estrogen in postmenopausal women; these include Femara (letrozole), Arimidex (anastrozole), and Aromasin (exemestane), and they are mainly used in breast cancer but sometimes also for ovarian cancer off-label.

New Drugs on the Horizon

Several drugs are being tested in clinical trials for ovarian cancer. Yondelis (trabectedin) and belotecan have shown promise in some studies; other studies are investigating carboplatin for intraperitoneal chemotherapy. Votrient (pazopanib) is a promising targeted therapy that stops new blood vessels from supplying nutrients for cancer cells. Vintafolide (EC145) is a new drug that targets the folic acid receptor; in one study, vintafolide stopped the growth of ovarian cancer cells that had the folic acid receptor.

A new approach being studied is tumor vaccines that program the immune system to identify and destroy cancer cells. Monoclonal antibodies that attack ovarian cancer cells include farletuzumab, which is directed against the folic acid receptor that is on the surface of some ovarian cancer cells. Catumaxomab is another monoclonal antibody being studied in ovarian cancer.

To read this full article on Conquer Magazine, please click here.

Expert Analyses How Stress Affects Outcomes in Ovarian Cancer

Stress and depression not only affect the quality of life of women with ovarian cancer, but it can also have a negative impact on their prognosis, according to Susan Lutgendorf, Ph.D., professor and Starch Faculty Fellow at the University of Iowa.

In an interview with CURE at the 2016 Society for Immunotherapy of Cancer (SITC) Annual Meeting, Lutgendorf discussed how stress affects the immune response in ovarian cancer cells, increasing inflammation and shortening survival outcomes.

“The bottom line is that we see that these behavior factors affect both the immune response as well as tumor progression,” Lutgendorf said.

When looking at patients who were matched for histology, age, cancer types and other clinical factors, Lutgendorf found that patients with high levels of distress, who may lack a strong social support system, have a poorer innate immune response and poorer T cell responses within their tumor-infiltrating lymphocytes. This has a negative impact on the effectiveness of immunotherapy. Patients with higher levels of depression also tended to have aggressive tumors that progressed more quickly because stress was increasing the ability of the tumor cells  to travel through the lymph system, giving them another mode of transport that is not only blood-born.

“Those with high levels of depression have a gene signature that is related to greater levels of aggressiveness and tumor activation – the kinds of things that would underlie tumor progression,” Lutgendorf said. “To add to that, one of the things we’ve seen is that ovarian cancer patients with low levels of social support have about a year shorter survival than patients with high levels of social support in models that are controlling for a variety of clinical factors.”

Stress factors that were considered included: stress levels, depression status and support system.

“The bottom line here is that stress factors seems to promote tumor progression, deplete tumor-related immunity, and when you look at that packaged together, it’s extremely nefarious in a way,” she said.

Lutgendorf said that she hopes more trials will be conducted to gain a firmer grasp on how stress affects outcomes in not only ovarian cancer, but in other tumor types as well. One interesting prospect she mentioned is the use of beta blockers, which are typically used in cardiovascular disease to treat hypertension, to block stress-related tumor progression.

“These trials are in the earlier stages,” Lutgendorf said. “But other promising trials are looking at mind-body interventions, like stress management interventions, mind-body interventions, mindfulness, yoga and tai chi.”

As these kinds of studies continue to publish results on the affects of stress in cancer tumors, Lutgendorf said that patients can employ strategies that may play a direct hand in the outcomes of their disease, such as diet and exercise, which play a key role in stress.

“I think many patients feel like they’re in a situation where they don’t have control over their life and it’s in the hands of molecules and things with long names, and a medical system that is working with them,” she said. “Starting to understand what exercise, what diet and what stress or anti-stress factors, can help empower people and start to get control over their lives. That’s an important direction that this kind of work can be used in.”

To read this full article on CureToday.com, please click here.

Optimizing Neadjuvant Chemotherapy in Ovarian Cancer Depends on Patient Selection

The use of neoadjuvant chemotherapy (NACT) for the treatment of advanced ovarian cancer has risen dramatically in recent years, improving quality of life for patients and reducing morbidity, but challenges remain for oncologists looking to deploy this treatment approach in clinical practice.

Chief among them is selecting which patients should receive NACT, explained Michael A Bookman, MD, during a presentation at the 34th Annual Chemotherapy Foundation Symposium.™

Bookman, medical director of US Oncology Research and chair of the NRG Oncology Ovarian Committee, reminded his audience that treatment advances, including NACT, have failed to reduce ovarian cancer mortality primarily because the disease is often diagnosed at a later stage.

“We’ve made progress, helped patients, and improved outcomes, but we’re really only seeing modest declines in incidence and mortality,” said Bookman, developments which he attributes mostly to an uptick in risk-reducing surgery and a reduction in the use of hormone replacement therapy by postmenopausal women.

What has changed in this setting over the last several years, Bookman remarked, has been the adoption of NACT, and when phase III studies of the approach are considered in aggregate, they do tend to favor its use in patients with advanced-stage, high-risk ovarian cancer.

A recent study coauthored by Bookman and based on data from 6 NCI-designated cancer centers examined the use of NACT versus primary cytoreductive surgery. The results show that use of NACT increased from 16% in 2003 to 34% in 2012 in women with stage IIIC ovarian cancer, and from 41% to 62% in those with stage IV disease—a trend Bookman said has contributed to improved quality of life, symptom management, and reduced perioperative morbidity.

Yet questions remain about how to identify which patients are most likely to benefit from NACT, and better strategies are needed to triage patients between primary surgery and NACT.  In addition, not all microscopic residual disease is the same, Bookman noted, and the role of aggressive upper abdominal surgery in patients with extensive disease remains uncertain.

To shed light on these treatment challenges, researchers are exploring tumor markers and molecular pathways associated with invasive metastatic behavior, as well as comorbidities and distribution of disease. Bookman expects that in the future, there will be better information to guide decision making, but currently, “The paradigms are predictive, but not predictive enough for us to be comfortable making a surgical decision based on a laboratory test.”

In the meantime, Bookman said, with some 40% of patients undergoing NACT, “we have a way of looking at pre- and posttreatment biopsies to explore incorporating new agents and to try and move the field forward.”

A phase I/II trial under the auspices of NRG Oncology, which is currently recruiting participants, will evaluate toxicity and cumulative tolerability of paclitaxel and carboplatin–based NACT with or without ruxolitinib in patients with stage III/IV epithelial, peritoneal, or fallopian carcinoma (NCT02713386). Two other trials Bookman cited that are pending review will look at the addition of either pembrolizumab or metformin to the neoadjuvant paclitaxel-carboplatin regimen.

Beyond the need to tailor patient selection for surgical interventions in the setting of advanced ovarian cancer, other surgical challenges and opportunities include validating early response endpoints during NACT and integrating molecular targeted agents with NACT, Bookman said.

“NACT with interval cytoreductive surgery is safer, more controlled, and at least as effective as primary surgery in high-risk advanced disease,” Bookman concluded, “while offering a platform to evaluate new treatment interventions.”

Nevertheless, while “current therapy for ovarian cancer is effective, it is not generally curative, and we really need to foster innovation.”

To read this full article on Targeted Oncology, please click here.