Ovarian Cancer: Statins Might Be Effective With Diet Control

Ovarian Cancer: Statins Might Be Effective With Diet ControlLaboratory tests have shown that statins, which are drugs used to control cholesterol, can kill ovarian cancer cells. But tests on human patients have yielded mixed results. Could choosing the right statin at the right dose, and excluding dietary sources of a compound that blocks the statin, be effective?

So suggests a new study led by Keele University in the United Kingdom and recently published in the journal Scientific Reports.

Ovarian cancer is cancer that starts in the cells of the ovaries, the almond-sized female organs that produce eggs for reproduction and the hormones estrogen and progesterone. A woman’s body normally contains two ovaries, which are located in the pelvis, with one on each side of the uterus.

The ovaries are made up of three main types of cell: epithelial, germ, and stromal cells. Any of these cells can give rise to cancer, but most ovarian tumors start in the cells that cover the outer surface of the organ, or epithelial cells.

Ovarian cancer is the tenth most common cancer in women in the United States. Although it only accounts for around 3 percent of all cancers in women, it causes more deaths in women than any other reproductive system cancer.

The Centers for Disease Control and Prevention (CDC) estimate that in 2014, 21,161 women in the U.S. found out that they had ovarian cancer and 14,195 died of the disease.

Need better treatments for ovarian cancer

In their study paper, the researchers explain that there is a shortage of effective treatments for ovarian cancer.

Most patients start off by responding well to chemotherapy, but unfortunately, in the majority of cases, the cancer returns and eventually develops resistance to the treatment.

New drugs that target specific molecules are starting to have an effect. These include, for example, PARP inhibitors that stop cancer cells being able to use an enzyme called PARP to repair their DNA.

However, even with these new treatments, the survival rate for ovarian cancer patients is still poor compared with many other cancers. At present, only around 40 percent of patients survive for longer than 5 years.

The researchers say that there is still a need to find new treatments, and one way to do this is to investigate drugs used to treat other diseases.

Statins show promise against ovarian cancer

A group of drugs that shows potential against ovarian cancer is statins, which are typically prescribed to lower cholesterol and thereby reduce the risk of heart attack and stroke.

Statins work by blocking an enzyme called hydroxymethylglutarate coenzyme-A reductase (HMGCR), which helps to make a precursor of low-density lipoprotein, or “bad” cholesterol. They also stop cells producing a compound called geranylgeraniol, which is present in some foods including rice and sunflower oil.

Laboratory studies have already shown that statins can kill ovarian cancer cells. There is also evidence, note the researchers, that the same HMGCR enzyme that statins block to reduce cholesterol also plays various roles in promoting cancer.

However, despite these promising observations, when statins have been tested in human cancer patients, the results have been disappointing.

The researchers – led by Dr. Alan Richardson, a reader in pharmacology in the School of Pharmacy at Keele University – suggest that there could be a number of reasons for the failure of statins to treat cancer. One reason they suggest is that the problem might lie with the size and frequency of dosage to ensure the continual targeting of the HMGCR enzyme.

They also discuss other properties of statins that might be important. For example, they suggest that statins with a longer metabolic half-life are more potent at killing cancer cells, and they also note that differences in their molecular structure might also be important.

Pitavastatin works without geranylgeraniol

Through such arguments, the researchers make a case for investigating a statin called pitavastatin, which has a long metabolic half-life and whose structure suggests that it is a potent inhibitor of the HMGCR enzyme. They also note that there have been no reports of clinical trials of pitavastatin’s effects against cancer.

The team first tested the effect of pitavastatin against cancer cells in the laboratory. They found that the statins triggered cell death in ovarian cancer cells, but also that this could be blocked by the presence of geranylgeraniol.

Further tests on mouse models of ovarian cancer showed that the tumors shrank when the mice were treated with pitavastatin as well as fed a diet lacking in geranylgeraniol.

However, when the mice’s diet was supplemented with geranylgeraniol, the ovarian cancer tumors continued to grow even after treatment with pitavastatin.

“This suggests that patients’ diet must be controlled for statins to be maximally effective in the treatment of cancer,” note the authors. “More generally, clinical trials of drugs which affect metabolic processes may need to take into account patients’ diet.”

Dr. Richardson explains, “Statins work in cancer by preventing cancer cells making geranylgeraniol. However, geranylgeraniol is present in various foods including sunflower oil and some rice, so in future clinical trials, we need to carefully control diet to limit geranylgeraniol.”

To read this full article in Medical News Today, please click here.

The Road Ahead for Ovarian Cancer

The Road Ahead for Ovarian CancerOpening the 20th Annual Ovarian Cancer National Conference in Chicago, John Moroney, M.D., underscored the challenges that remain in the prevention, earlier detection, and treatment of ovarian cancer, but also the tremendous hope that resides in robust clinical trial research.

“There are numerous early-phase clinical trials with targeted therapies that are by and large more tolerable and do not compromise quality of life that I think are the way forward,” Moroney told a packed ballroom at the conference, held July 7-9. “That is why I am such a proponent of early clinical trials. I think these offer people the best personal option, and then, of course, they have the benefit of helping everyone around you and the people behind you who are getting this diagnosis.”

Moroney, an associate professor of obstetrics and gynecology specializing in gynecologic cancers at University of Chicago Medicine, delivered this year’s Mello Abrams Lecture, established by Jay Schwamm to honor both his wife Judy Mello, who lost her life to ovarian cancer, and ovarian cancer advocate Judith Abrams.

“As survivors and family members you are aware – perhaps too aware – of what it takes to get through this disease,” Moroney said. Nevertheless, he set an optimistic tone for better treatments ahead, but cautioned that such progress will depend on an expansion of clinical trial research focused on gynecologic cancers.

There are about 24,000 new ovarian cancer diagnoses annually, and while the numbers are small compared with other gynecologic cancers, the disease is much more virulent. Eighty percent of patients are diagnosed at stage 3 or 4, and most women diagnosed at advanced stages recur.

“If we could find more stage 1 or 2’s, that would make a huge difference, but the development of an effective strategy for early detection is very challenging,” Moroney said, in part because ovarian is relatively rare compared with breast and endometrial cancers, and unlike colon cancer, there is no predictable pathway from pre-cancer to cancer.

“Most survivors have told me, ‘There was no way to tell that there was something wrong, until it was advanced.’ This is heartbreaking, but a reality for most patients.”

Thus far, studies of early screening methods like annual CA 125 testing, ultrasounds or both have not proven helpful or yielded overall survival benefits, though he acknowledged that there were likely people in the audience whose individual experience defy these statistics on screening.

The Risk of Ovarian Cancer Algorithm (ROCA), he said, is “probably the way forward,” following on two very large screening trials involving average-risk patients, including one involving 202,000 patients in the United Kingdom. Moroney said that though it did not demonstrate an overall survival advantage, “it did – and this is very important – describe what’s referred to as a ‘stage shift,’” whereby a higher number of patients receiving multimodal screening were diagnosed with early-stage cancers. The proprietary ROCA algorithm yields a score, based annual CA 125 levels along with other demographic factors like age and family history; the score determines what and when additional screening is warranted.

Beyond aging, consensus is lacking on other risk factors for ovarian cancer, Moroney said; for example, obesity and endometriosis are likely contributory, whereas talc use remains controversial, hormone replacement therapy may increase risk, and oral contraceptive use decreases it.

The consensus is clear, however, that heritable gene mutations are a risk factor and responsible for 15 to 25 percent of ovarian cancers. Research is ongoing into other druggable targets beyond BRCA, hyperthermic intraperitoneal chemotherapy (HIPEC), immunotherapy, and drug combinations.

Although there are no FDA-approved maintenance therapies after primary treatment for ovarian cancer in the U.S., it continues to be an area of interest and investigation, Moroney noted, “with multiple clinical trials with drugs vying for this space.”

For recurrent disease, however, the PARP inhibitor Zejula (niraparib) was approved by the FDA in March, 2017, for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy. The indication for Avastin (bevacizumab) was expanded by the FDA in December, 2016, for treatment of platinum-sensitive patients in combination with chemotherapy, followed by Avastin maintenance.

Also in December, 2016, Rubraca (rucaparib) was granted an accelerated approval from the FDA to treat patients with BRCA-positive (either germline or the tumor itself) advanced ovarian cancer who have received at least two prior lines of chemotherapy. Olaparib, the first PARP inhibitor on the market, was approved in December, 2014, for BRCA-mutated patients with three or more prior therapies.

In the realm of immunotherapy, early studies on the use of CAR T-cell therapy in ovarian cancer have had disappointing results so far, Moroney said, but, “as the technology behind the therapy improves, we hope that the responses will be better.” Checkpoint inhibition is moving beyond PD-1 and CTLA-4 inhibitors to include a host of new targets, he added.

“There are numerous other targets; this is the hottest area of cancer medicine with respect to new targets…they are not prime time now, but the hope is that some of these inhibitory, inactivating drugs will make a difference.”

Recently reported trial findings showed that the PD-1 inhibitor Keytruda yielded a 10 to 15 percent response rate in biomarker-positive ovarian cancer. What’s notable, however, Moroney said, is that “those patients who did respond tend to have very durable responses. If we can pick the right patients, based on their tumor genomics, we can make a huge difference.”

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

Clinical Trials Are the Way Forward for Ovarian Cancer, but They Need Advocates at Every Level

Clinical Trials Are the Way Forward for Ovarian Cancer, but They Need Advocates at Every LevelFor women with ovarian cancer, the message is clear: participating in clinical trials, even early-phase ones, offers the best hope for better treatments, but efforts are urgently needed at every level to ensure that more of these research opportunities are available.

“Every single major advance in ovarian cancer has come through a clinical trial,” Carol L. Brown, M.D., FACS, said in her presentation July 8, 2017 at the 20th Annual Ovarian National Conference in Chicago.

The critical importance of expanding the universe of clinical trials in gynecologic cancers was a recurring theme at the meeting. Speaking earlier that day, John Moroney, M.D., of University of Chicago Medicine, stressed that continued progress depends on an expansion of clinical trials focused on gynecologic cancers.

“This is not ‘FAKE NEWS’,” said Moroney, during his presentation. He and Brown both described a crisis in available clinical trials for women with gynecologic cancers and pointed to statistics showing a 90% reduction in patient enrollment in gynecologic cancer clinical trials from 2011-2016.

Why Should I Participate in a Clinical Trial?

Brown, a gynecologic oncologist and associate cancer center director for diversity and outreach at Memorial Sloan Kettering Cancer Center, noted that researchers already have a pretty good idea that a drug being tested in a phase 1 trial will provide some benefit to patients. With the dramatic advances now in cancer science, “Rarely is there a phase 1 trial that’s not going to benefit you at all. That’s important for patients to understand.”

The goal of phase 1 studies, she explained, is to determine a drug’s safety, its maximum tolerated dose and how the treatment is processed in the body. Phase 1 studies are small, however, usually between 20 and 40 patients will be given the new treatment.

Onto phase 2 trials, where Brown told her audience a lot of advances are being made. “The whole field is changing. Phase 2 trials are larger, they are happening more rapidly, and we’re working very hard to make them more accessible.”

While phase 1 trials are still mostly conducted at a specialized center, the base for phase 2 trials – the next stage in proving the anticancer effects of the drug in a larger population – has broadened. “You used to have to go to a cancer center for a phase 2 trial; it was unheard for phase 2 trials to be done in the community. That’s no longer true.”

“Researchers have realized that if we want to get people to participate, we have to take the trials to them. We can’t expect everyone to travel to the big cancer centers.”

Often seen as the “gold standard” of clinical trials, phase 3 studies today typically compare two treatments that researchers already know work well, Brown explained. They are looking to see if they work equally well, as well as at associated quality-of-life side effects like neuropathy and hormonal changes, even cost. Phase 3 findings are what the Food and Drug Administration look to when deciding whether a drug should be approved.

“Participating in a clinical trial gives you access to new drugs and interventions before they are widely available; if the treatment is a success, you are among the first to benefit,” Brown said. Yes, you are also contributing to the larger good and helping other women diagnosed in the future, she continued, but even with a phase 1 trial, “there’s something in it for you.”

Trial participants also will get health care and closer observation by leading physicians in the field of gynecologic cancer research. “When you participate in a clinical trial, you are getting extra CT scans and calls from the doctor or nurse to see how you are doing.”

Advocating for More Gynecologic Cancer Clinical Trials

Brown cited an array of practice-changing advances in ovarian cancer that are the result of clinical trials, including discovery of less toxic drugs like paclitaxel and carboplatin and the availability of targeted therapies in ovarian cancer, such as the oral PARP inhibitors Rubraca and Lynparza.

She noted that in the last three years, four new drugs have been approved for ovarian cancer; that’s compared with four over the previously 15 years: “Things are looking up, things are accelerating, it’s going to happen.”

This optimism is tempered, however, by disturbing trends that show a reduction in gynecologic cancer–focused trials. Brown cited reductions in federal research funding, a move toward smaller biomarker-driven studies, and reorganization of oncology cooperative group research as contributing factors: “Gynecologic cancer is unique and need its own set of resources.”

She urged the audience to advocate aggressively for trial funding and increasing awareness of the importance of gynecologic cancer trials by contacting their elected representatives. The Society of Gynecologic Oncology’s Legislative/Congressional Ambassadors Program is making increased support for the National Cancer Institute a priority and working to expand and integrate its network to educate patients and advocates on how to communicate with Congress.

“We need you to partner with us in this very important effort,” Brown concluded. “Now is the time for action, awareness, and funding,” “Together we have a powerful voice.”

To read this full article on Cure Today, please click here.

PARP Inhibitors Changing the Landscape of Ovarian Cancer Treatment

PARP Inhibitors Changing the Landscape of Ovarian Cancer TreatmentWith the FDA approval of two new PARP inhibitor drugs since last year’s Ovarian Cancer National Conference, it’s no surprise the topic was of great interest at this year’s meeting in Chicago, and a standing-room-only crowd was on hand July 8 to hear the latest news on this practice-changing class of drugs.

“There is a dizzying amount of data with respect to how effective they are, how tolerable they are, and when it’s best to use them,” noted John Moroney, M.D., the expert on hand to lead the discussion.

Three of these oral agents have been FDA-approved for specific indications in ovarian cancer: Lynparza (olaparib) in December, 2014, Rubraca (rucaparib) in December, 2016, and Zejula (niraparib) in March, 2017. These drugs continue to be the topic of investigation for expanded use in ovarian cancer, and Moroney mentioned two other PARP inhibitors in development: veliparib and talazoparib.

As just one indication of the impact of these agents on the research landscape, Moroney said that when he went on clinicaltrials.gov that morning, there were 57 active trials involving PARPs. That’s a big number, but it includes some smaller trials. Moroney, who is an associate professor of obstetrics and gynecology specializing in gynecologic cancers at University of Chicago Medicine, added that the majority of the phase 3 trials in patients with ovarian cancer are for those who respond to platinum chemotherapy.

Inhibitors of the enzyme poly ADP ribose polymerase (PARP), work specifically in women with BRCA mutations. Encouragingly, PARP inhibitors are also proving valuable for some patients who don’t have BRCA gene mutations.

The first approved PARP inhibitor, Lynparza, is indicated for women with germline BRCA-mutated advanced ovarian cancer who have had three or more lines of chemotherapy. The trial that led to the drug’s approval reported an objective response rate of 34 percent, and 55 percent of patients were free of progression at six months.

Rubraca is approved for the treatment of BRCA-positive advanced ovarian cancer after at least two lines of chemotherapy. With this drug, BRCA-positive status can be due either to a germline mutation or a mutation in the tumor itself, known as a somatic mutation. The FDA also approved a companion diagnostic to detect deleterious BRCA mutations in tumor tissue. Rubraca’s approval was based on data from 106 patients across two trials; in a pooled analysis of the data, the objective response rate was 54 percent.

The latest approved addition to the PARP class of drugs is Zejula. This drug can be prescribed as maintenance treatment following a partial or complete response to the patient’s most recent platinum chemotherapy, and it can be used in women who do not harbor BRCA mutations.

With PARP inhibitors now established as an efficacious ovarian cancer treatment option for many women, Moroney discussed some of the questions patients may have about them, including what side effects to look out for and when is the best time to use them. There is also interest in whether they may be used in combination with other drugs.

What are the most common side effects?

Moroney said that when PARPs first came to market, it was assumed the oral agents would be nothing like chemotherapy in terms of adverse events: “With more experience, we’ve learned that by and large, they are significantly more tolerable than many of the first-line chemotherapies,” but he cautioned that there are still some side effects.

He highlighted three gastrointestinal side effects – nausea, constipation, and abdominal pain – observed with all three FDA-approved PARPs, but few are the serious grade 3 or 4 adverse events that can result in treatment disruption or hospitalization. He did say, however, that when grade 2 toxicities persist over time for any drug, they can be very distressing for patients and deserve more attention.

Similar to the way chemotherapy can affect hemoglobin and platelets, Moroney explained that all of the PARP inhibitors can have some hematologic toxicities, principally involving decreased hemoglobin. Fatigue is another frequently reported side effect, which, Moroney acknowledged, “is much underappreciated by most oncologists, including me.” All of the agents can cause some fatigue, he said, but less than 10 percent of patients have had to stop the medication as a result.

When is the best time to use them?

Moroney said the answer to this question is not yet clear. PARP inhibitors were initially studied in the platinum-sensitive and platinum-resistant setting, but studies are being conducted of the agents as primary treatment. There are no FDA approvals in the primary setting yet, but Moroney anticipates that findings from these studies will help to determine whether PARPs are an option as primary treatment, with some expected to report results in approximately 18 months.

What about combination therapy involving PARPs?

Researchers are now investigating the agents in combination, including trials testing Lynparza combined with cediranib maleate in platinum-sensitive and platinum-resistant ovarian cancer. He explained that cediranib is similar to Avastin in that it is an anti-angiogenesis drug that keeps new blood vessels that feed the tumor from forming.

In updated findings from a small phase 3 trial studying the combination that was reported at the annual meeting of the American Society of Clinical Oncology in June, 2017, adding cediranib to Lynparza showed a superior median progression-free survival of 23.7 months, compared with 5.7 months with single-agent Lynparza in 23 women with recurrent platinum-sensitive ovarian cancer, but without a known BRCA germline mutation. The 24 women in the study with a BRCA mutation did not derive the same benefit. “In this trial, patients who were non–BRCA-mutated, actually did better than those who were,” Moroney noted.

PARP-immunotherapy combinations are also being explored, including one phase 1/2 study that is currently recruiting patients that is examining Lynparza with the monoclonal antibody tremelimumab in BRCA 1 and BRCA 2 carriers with recurrent ovarian cancer (NCT02571725).

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

CT Technology Shows How Blood Flow Can Predict Effectiveness of Ovarian Cancer Treatment

CT Technology Shows How Blood Flow Can Predict Effectiveness of Ovarian Cancer TreatmentTechnology developed at Western University and Lawson Health Research Institute can provide a new window into whether or not patients are responding to treatment for advanced ovarian cancer. A multi-centre clinical trial has demonstrated that CT Perfusion, which measures blood flow and blood volume to tumours associated with ovarian cancer, can provide an accurate prediction of how well a treatment is working, allowing physicians the opportunity to better plan treatment. Funding for the trial was provided by the US National Cancer Institute through the National Clinical Trials Network including NRG Oncology and ECOG-ACRIN.

“CT perfusion is honing into the change in blood flow to the tumour before and after treatment,” said Ting-Yim Lee, professor at Western University’s Schulich School of Medicine & Dentistry, scientist at Lawson Health Research Institute, and a medical physicist at St. Joseph’s Health Care London. “In this particular case we can see that blood flow tends to decrease in those who will survive longer without symptoms, whereas for those whose symptoms will recur within six months, we saw blood flow to the tumour increase after their treatment.”

The study, was published in the journal, Clinical Cancer Research. Its authors point out that in 60 to 85 per cent of ovarian cancer patients, relapse will occur after initial treatment. Using CT perfusion to identify which patients are more likely to benefit from a specific therapy, enables better patient selection and treatment planning, and also provides a biomarker for future clinical trials assessing new treatment options. The authors also point out that although the trial is promising, further studies are required to corroborate the current findings.

“Using this method we are able to see a change in the blood flow as early as four weeks after treatment. This means we don’t have to wait months to determine whether symptoms will recur, we are able to tell whether the treatment is effective much sooner,” said Lee.

Reference:

  1. Chaan S. Ng, Zheng Zhang, Susanna I. Lee, Helga S. Marques, Kyle Burgers, Feng Su, Joseph Bauza, Robert S. Mannel, Joan L. Walker, Warner King Huh, Stephen C. Rubin, Paul DiSilvestro, Lainie P. Martin, John K. Chan, Michael A. Bookman, Robert L. Coleman, Ting-Yim Lee. CT Perfusion as an Early Biomarker of Treatment Efficacy in Advanced Ovarian Cancer: An ACRIN and GOG Study. Clinical Cancer Research, 2017; DOI: 10.1158/1078-0432.CCR-16-1859

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

British Biotech Close To Breakthrough Test For Ovarian Cancer

British Biotech Close To Breakthrough Test For Ovarian CancerBritish biotech company Angle has unveiled the trial results of a potential breakthrough blood test for diagnosing ovarian cancer.

The test could lead to quicker diagnosis and referrals for women with malignant tumours to specialist surgeons.

Angle, an AIM-listed liquid biopsy specialist, said its new test proved 95pc accurate at detecting cancerous cells in the bloodstream in a study of 400 patients in Europe and the US.

It was also nearly twice as effective as current tests at identifying false-positives.

The test could help doctors differentiate more easily between malignant ovarian tumours – around one in ten cases – and benign tumours, allowing more cost-effective referrals to a specialist or general surgeon as appropriate.

In the UK alone 7,400 women are diagnosed with ovarian cancer each year.

Angle founder and chief executive Andrew Newlands said liquid biopsy had the potential to “transform cancer care in the future”.

“Through a simple blood test, it will be possible to provide repeat testing of patients’ cancer,” he added.

Commenting on the trial results, Louise Bayne, an ovarian cancer survivor and chief executive of ovarian cancer support charity Ovacome, said she was encouraged the test had “the potential to make the significant leap forward in diagnosing this difficult to detect disease”.

She added: “Our members experience significant delays between presentation at their GP and a referral and a simple blood test performed earlier in the diagnostic pathway has the potential to make significant impacts on the outcomes for thousands of women.”

Angle’s trial also showed the potential to gather gene expression information that can assist with selecting the right treatment. This comes as the Government’s chief medical officer, Prof Dame Sally Davies, called for a gene testing revolution.

The test results will now be validated in another study designed to meet European CE Mark and US FDA regulatory requirements.

Shares in Angle, which has a market cap of just over £50m, closed down 1.5pc at 67p on Tuesday, after spiking earlier in the day.

To read this entire article on The Telegraph, please click here.

FDA Grants Orphan Drug Designation To ALM201 For Ovarian Cancer

FDA Grants Orphan Drug Designation To ALM201 For Ovarian CancerThe FDA granted orphan drug designation to ALM201 for the treatment of ovarian cancer, according to the agent’s manufacturer.

ALM201 (Almac Discovery) is a therapeutic peptide developed to imitate properties of the FKBPL protein, a naturally secreted protein that has effects on multiple tumor biology processes, including cancer stem cells and angiogenesis.

“The FDA’s orphan drug designation of ALM201 in the treatment of ovarian cancer will allow for valuable assistance from the FDA during clinical development for either ourselves or our partners for this difficult-to-treat patient population,” Stephen Barr, PHD, managing director and president of Almac Discovery, said in a company-issued press release.

The FDA Office of Orphan Products Development grants orphan drug designation to novel drugs and biologics that are intended for the safe and effective treatment, diagnosis or prevention of rare diseases or disorders that affect fewer than 200,000 people in the United States. The designation allows manufacturers to qualify for various incentives, including tax credits for qualified clinical trials and — upon regulatory approval — 7 years of market exclusivity.

To read this full article on Healio, please click here.