PARP Inhibitors Advance in Ovarian Cancer

birrerWith 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

dna-magnifying-glassA 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

56cd5fec14a8aA 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

is_161006_ovaries_cancer_800x600Lynparza (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

3aab76a300000578-3962932-image-a-79_1479861655455Almost 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 at the Forefront of Ovarian Cancer Treatment ParadigmPARP 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

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.