New Therapeutic Approach For Difficult-To-Treat Subtype Of Ovarian Cancer Identified

New Therapeutic Approach For Difficult-To-Treat Subtype Of Ovarian Cancer IdentifiedA potential new therapeutic strategy for a difficult-to-treat form of ovarian cancer has been discovered by Wistar scientists. The findings were published online in Nature Cell Biology.

Ovarian clear cell carcinoma accounts for approximately 5 to 10 percent of American ovarian cancer cases and about 20 percent of cases in Asia, ranking second as the cause of death from ovarian cancer. People with the clear cell subtype typically do not respond well to platinum-based chemotherapy, leaving limited therapeutic options for these patients.

Previous studies, including those conducted at The Wistar Institute, have revealed the role of ARID1A, a chromatin remodeling protein, in this ovarian cancer subtype. When functioning normally, ARID1A regulates expression of certain genes by altering the structure of chromatin—the complex of DNA and proteins in which DNA is packaged in our cells. This process dictates some of our cells’ behaviors and prevents them from becoming cancerous.

“Conventional chemotherapy treatments have proven an ineffective means of treating this group of ovarian cancer patients, meaning that alternative strategies based on a person’s genetic makeup must be explored,” said Rugang Zhang, Ph.D., professor and co-program leader in Wistar’s Gene Expression and Regulation Program and corresponding author of the study. “Therapeutic approaches based on the ARID1A mutation have the potential to revolutionize the way we treat these patients.”

Recent studies have shown that ARID1A is mutated in more than 50 percent of cases of ovarian clear cell carcinoma. Mutations of ARID1A and the tumor suppressor gene TP53 are mutually exclusive, meaning that patients with a mutation of ARID1A do not also carry a mutation of TP53. Despite this, the function of TP53, which protects the integrity of our genome and promotes programmed cell death, is clearly impaired as patients with the disease still have a poor prognosis.

In this study, Zhang and colleagues studied the connection between ARID1A and histone deacetylases (HDACs), a group of enzymes involved in key biological functions. They found that HDAC6 activity is essential in ARID1A-mutated ovarian cancers. They were able to show that HDAC6 is typically inhibited by ARID1A, whereas in the presence of mutated ARID1A, HDAC6 levels increase. Because HDAC6 suppresses the activity of TP53, therefore inhibiting its tumor suppressive functions, higher level of HDAC6 allow the tumor to grow and spread.

Using a small molecule drug called rocilinostat that selectively inhibits HDAC6, the Zhang lab found that by blocking the activity of the enzyme in ARID1A-mutated cancers, they were able to increase apoptosis, or programmed cell death, in only those tumor cells containing the ARID1A mutation. This correlated with a significant reduction in tumor growth, suppression of peritoneal dissemination and extension of survival of animal models carrying ARID1A-mutated ovarian tumors.

“We demonstrated that targeting HDAC6 activity using a selective inhibitor like rocilinostat represents a possible therapeutic strategy for treating ovarian clear cell carcinoma and other tumors impacted by mutated ARID1A,” said Shuai Wu, Ph.D., a postdoctoral fellow in the Zhang lab and co-first author of the study. “Inhibitors like the one we used in this study have been well-tolerated in clinical trials, so our findings may have far-reaching applications.”

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Combinations May Be the Future for Ovarian Cancer

Combinations May Be the Future for Ovarian CancerImmunotherapy and PARP inhibitor combinations may be the future of ovarian cancer treatment, says Samir N. Khleif, M.D.

Clinicians are seeking alternatives to chemotherapy because, despite an 80 percent response, recurrence is universal with few options available following recurrence. Ovarian cancer is an immune-dependent cancer; ovarian cancers with T-cell infiltration within the tumor microenvironment are associated with superior progression-free survival and overall survival.

Researchers have defined multiple tumor-associated antigens, and in turn, tested and developed an array of vaccines. Unfortunately, vaccines have demonstrated limited efficacy in this setting.

“Most have approached the vaccine as a single agent rather than as a combination agent, either in a specific antigen, either synthetic, naked DNA, RNA, bacterial, or viral; whole-cell lysate, or anti-idiotype vaccine and it is either given by itself or given in the context of a dendritic cell,” said Khleif, director of the Georgia Health Sciences Cancer Center in Augusta.

Ovarian cancer is an immune-driven tumor. But the tumor itself is immune-suppressive environment. As a result, T cells are activated and captured by various mechanisms, but unable to generate a proper immune response. These mechanisms include accumulation of intratumoral T regulatory cells (Tregs) that block an immune response, production of the enzyme IDO (leading to activation of suppressive populations of Tregs) by tumor cells, and suppression of effector T cells by engagement of PD-1 with PD-L1.

“When we think of our approach to vaccines, it’s pretty naïve to think that a vaccine is going to generate T cells, and the T cells are going to be taking care of a tumor that is that immune suppressive,” said Khleif.

In response, physicians and researchers have proposed using PD-1 inhibitors and other checkpoint inhibitors in ovarian cancer, but so far, the data are scant. The expression of PD-1 in ovarian tumors is dependent on the grade of the tumor, with high-grade tumors having higher expression.

In Hamanishi et al, researchers observed two complete responses and one partial response after treatment with Opdivo (nivolumab) at 1 mg/k or 3 mg/kg every two weeks in 20 patients with platinum-resistant ovarian cancer. Levels of PD-L1 expression did not seem to influence response, “which might be a little bit different than other diseases like lung cancer,” he said.

In a phase 1b study of Bavencio (avelumab) conducted by Disis et al, 10 mg/kg, in 124 patients demonstrated an objective response rate of 9.7 percent and stable disease in 44 percent. Another study of Opdivo in 17 patients with recurrent/refractory epithelial ovarian cancer, showed one partial response and two patients with stable disease after treatment.

“As a single agent, so far, we have some responses but we did not break that tolerance yet,” Khleif said, and noted that the responses rarely lasted very long.

He added that addressing the immune suppressive state of the tumor microenvironment in ovarian cancer will likely require a multiplication of effort. “That is why combination immune therapy is going to be, and is, the name of the game.”

Chemotherapy is known to induce PD-L1 expression and lead to enhanced infiltration of CD8-positive cells in the tumor, possibly enhancing the efficacy of checkpoint inhibitors.

Khleif’s team has discovered that PI3K isoforms differentially regulate Tregs and T conventional cells (Tconvs). Tregs are primarily dependent on the PI3K-delta isoform, whereas in Tconvs, PI3K-alpha and -beta provide a redundant pathway to PI3K-delta. This dichotomy can be exploited to target Tregs by inhibiting the PI3K-delta isoform while leaving Tconvs intact.

Co-administration of an inhibitor of PI3K-delta with a tumor-specific vaccine decreased the number of suppressive Tregs and increased the number of vaccine-induced CD8 T cells within the tumor microenvironment in a mouse model of lung cancer, resulting in a large reduction in tumor volume. The authors concluded that these findings “offer a mechanistic rationale to employ PI3K-delta inhibitors to selectively target Tregs and improve cancer immunotherapy.”

PARP has emerged as an important target in ovarian cancer. PARP inhibitors have been shown to have clear beneficial effects on clinical outcomes in the treatment of ovarian cancer in several clinical trials. The combination of a PARP inhibitor with CTLA-4 blockade improved overall survival in a BRCA1-deficient murine ovarian cancer model compared with treatment with CTLA-4 or PD-1/PD-L1 monoclonal antibodies alone.

In results published by Clinical Cancer Research earlier this year, PARP inhibitor enhanced apoptosis and tumor volume shrinkage within the tumor microenvironment when given in addition to a PD-1/PD-L1 blocker. PARP inhibition attenuated anticancer immunity via upregulation of PD-L1, and blockade of PD-L1 re-sensitized the PARP inhibitor-treated cancer cells to T-cell killing, the authors found.

Khleif added that multiple trials combining PARP inhibitors and checkpoint inhibitors are ongoing.

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‘No’ Yet Again to Routine Ovarian Cancer Screening

'No' Yet Again to Routine Ovarian Cancer ScreeningNew draft guidelines from the US Preventive Services Task Force (Task Force) recommend against screening for ovarian cancer in women who have no signs or symptoms.

“The Task Force found that screening women without signs or symptoms for ovarian cancer does not decrease the number of deaths from the disease and may lead to unnecessary surgeries,” said Task Force member Maureen Phipps, MD, MPH, in a statement.

“Therefore, the Task Force recommends against screening for ovarian cancer in women who have no signs or symptoms and who are not at high risk for ovarian cancer,” she said.

This recommendation applies only to asymptomatic women who are not deemed to be at a higher risk of developing ovarian cancer. It does not pertain to woman who are known to be at higher risk, such as those who harbor BRCA mutations.

Overall, the Task Force found adequate evidence that routine screening in asymptomatic women or in those not deemed to be at high risk did not decrease ovarian cancer mortality.

There was also evidence that the harms associated with screening were at least moderate and in some cases could be substantial and that there was “at least moderate certainty” that the potential harms outweighed the potential benefits. These harms include false positive results, which could lead to diagnostic surgery and potential removal of the ovaries and fallopian tubes.

The recommendations in the new draft paper are consistent with the previous recommendation for ovarian cancer, which was issued in 2012 and gave routine screening a grade D recommendation (ie, not recommended).

The 2012 report, in turn, echoed a 2004 recommendation made by the Task Force, which found that “the potential harms outweighed the potential benefits of screening.”

No Mortality Benefit

In their review of available data, the Task Force identified three good-quality studies that evaluated the effect of annual screening in asymptomatic women who were not deemed to be at a high risk of developing ovarian cancer. None of the findings demonstrated that screening significantly reduced ovarian cancer mortality.

The United Kingdom Collaborative Trial of Ovarian Cancer Screening, which is the largest and most recent trial, was conducted after the initial 2012 recommendations were issued. It confirmed the findings from the earlier Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial that screening does not decrease mortality in this population.

Data from the three studies, along with a fourth fair-quality study that examined quality of life and the psychological harms of screening (Quality of life, Education, and Screening Trial) were analyzed to determine the risks associated with screening.

Calculated false positive rates of the various screening methods ranged from 4.2% to 44.2%; from 0.2% to 3.2% of patients eventually underwent surgery. Among this group, major surgical complications were observed in 0% to 15%.

In Sync With Other Groups

Ovarian cancer screening for the general population is not recommended by any of the major medical and public health organizations. The American College of Obstetricians and Gynecologists, the American Cancer Society, and the American College of Radiology do not recommend screening for women at average risk. The American Academy of Family Physicians (AAFP) also recommended against screening in 2012; the AAFP is currently reviewing this recommendation.

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UC San Diego Awarded $5.8M For Cancer Therapy Research

UC San Diego Awarded $5.8M For Cancer Therapy ResearchResearchers at the UC San Diego School of Medicine were awarded $5.8 million Thursday to develop an immunotherapy that would target certain cancer stem cells.

The grant from the California Institute for Regenerative Medicine’s Independent Citizens Oversight Committee addresses cancers that defy standard treatment. According to UCSD Health, cancer stem cells present survival abilities that often render regular therapies ineffective or short-term.

The money will be used to test the concept of the therapy and generate safety data prior to human trials, according to Dr. Ezra Cohen, professor of medicine and associate director for translational science at UC San Diego Moores Cancer Center.

“Our overall goal by the end of this 30-month process is to have a full-fledged, pre-clinical plan in place, with input and support from the (U.S. Food and Drug Administration), so that we develop a new drug and test it in clinical trials,” Cohen said.

The idea is to extract immune system T cells from a patient, add a gene that would activate the cell when confronted with a receptor called ROR1, grow large numbers of the altered T cells and infuse them back into the patient.

The T cells would then seek out and attack cancer stem cells expressing ROR1. The receptor is expressed in both solid and blood cancers but not in normal tissues.

Previous culture dish studies have shown that the T cells are effective against ROR1 in head and neck squamous cell carcinoma, triple-negative breast cancer, pancreatic cancer, ovarian cancer and chronic lymphocytic leukemia. All five cancers are among the most deadly, difficult to treat or most likely to recur.

Philanthropists Ralph and Fernanda Whitworth and their Solana Beach-based Immunotherapy Foundation provided initial funding for Cohen’s pilot research related to the CIRM grant.

Ralph Whitworth was a San Diego activist investor who died in 2016 of complications from cancer.

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

Cancer Protein CA125 Blocks Investigational Therapy Farletuzumab’s Anti-Tumor Effectiveness, Study Finds

Cancer Protein CA125 Blocks Investigational Therapy Farletuzumab’s Anti-Tumor Effectiveness, Study FindsThe protein CA125, which is commonly expressed on the surface of ovarian cancer cells and is secreted into the bloodstream, was found to block the activity of investigational drug farletuzumab. Farletuzumab is currently in clinical development for the treatment of ovarian cancer.

This process was described in the preclinical study, “Tumor antigen CA125 suppresses antibody-dependent cellular cytotoxicity (ADCC) via direct antibody binding and suppressed Fc receptor engagement,” published in the journal Oncotarget, according to a statement from the therapy’s developer.

Farletuzumab, also known as MORAb-003, is an antibody developed by Eisai subsidiary Morphotek to specifically target the folate receptor alpha (FRA), which is almost entirely absent in normal cells but highly expressed in several cancers, including ovarian, endometrial, and breast cancers. After binding to the target cells by their FRA receptor, farletuzumab then activates immune cells to recognize and kill cancer cells.

In a Phase 3 clinical trial (NCT00849667), researchers tested the safety and effectiveness of weekly farletuzumab infusions combined with standard platinum-based chemotherapy — Paraplatin (carboplatin) plus a taxane — to treat relapsed platinum-sensitive ovarian cancer patients.

A total of 1,100 patients were included in the trial and received standard chemotherapy with 1.25 mg/kg or 2.5 mg/kg of farletuzumab, or a placebo. However, none of the farletuzumab dosages achieved the primary intended outcome of progression-free survival (PFS) when compared to the placebo, and no differences were observed in survival between groups.

Despite the discouraging results, researchers found that 290 patients with low baseline levels of CA125 had better PFS and overall survival when treated with farletuzumab 2.5 mg/kg, as compared to a placebo. The results of this subgroup analysis suggested that CA125 protein could negatively affect farletuzumab’s therapeutic potential.

A new preclinical study showed that CA125 can bind directly to the investigational drug. While this did not affect the ability of farletuzumab to target cancer cells, it blocked its ability to activate the immune system, a development that could explain the clinical outcomes observed in the Phase 3 trial.

Based on the subgroup analyses and current understanding of the interaction between CA125 and farletuzumab, a Phase 2 trial (NCT02289950) will further explore farletuzumab’s therapeutic potential and safety profile in combination with chemotherapy in first-relapsed, platinum-sensitive ovarian cancer patients with low CA125 blood levels.

Morphotek expects to enroll up to 210 patients across several centers in the United States, Japan, and Europe for this clinical trial.

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Risk-Reducing Mastectomy Questioned For BRCA Mutation Carriers With Prior Ovarian Cancer

Risk-Reducing Mastectomy Questioned For BRCA Mutation Carriers With Prior Ovarian CancerMutations in the BRCA gene correspond to a higher lifetime risk of developing breast and ovarian cancers, and many women who carry these mutations consider undergoing mastectomy or removal of the ovaries and fallopian tubes as preventive measures.

But for the subset of women with BRCA mutations who have already had ovarian cancer, risk-reducing mastectomy might not be worth the price tag. New research from the Duke Cancer Institute finds that for many women in this unique group, prophylactic mastectomy does not produce a substantial survival gain and is not cost-effective.

The finding is especially noteworthy because of updated National Comprehensive Cancer Network guidelines recommending that many women with ovarian cancer be considered for genetic testing regardless of family history. Now, more than ever before, some women with ovarian cancer are also learning that they carry a BRCA mutation.

“Risk-reducing mastectomy is costly and can require many months of follow-up and recovery,” said Charlotte Gamble, M.D., the study’s lead author and a resident physician at Duke University School of Medicine. “Our results emphasize that prophylactic mastectomy should be used selectively in women with both a BRCA mutation and a history of ovarian cancer.”

In the study, published online July 11 in the journal Annals of Surgical Oncology, Gamble and co-researchers constructed a statistical model comparing risk-reducing mastectomy to breast cancer screening, including mammogram and MRI. The model incorporated clinical factors such as the age at ovarian cancer diagnosis, time between ovarian cancer diagnosis and risk-reducing mastectomy, BRCA mutation status, cancer survival rates and treatment costs. Risk-reducing mastectomy was compared to breast cancer screening performed every six months following ovarian cancer diagnosis.

The study’s authors also considered a cost-effectiveness measurement called the incremental cost effectiveness ratio. Healthcare interventions where this ratio is less than $100,000 per year of life saved are commonly considered cost-effective in medical literature. The authors used the same threshold in this study.

According to the authors’ analysis, the benefit of risk-reducing mastectomy over screening alone largely depended on the patient’s age at the time of her ovarian cancer diagnosis and time to mastectomy:

For women diagnosed at any age with BRCA 1 and 2 gene mutations and within the first four years after ovarian cancer diagnosis, prophylactic mastectomy was associated with a negligible gain in survival and was therefore not found to be cost-effective;

For women diagnosed at age 60 or older, regardless of time since ovarian cancer diagnosis, the gain in survival months was also negligible and the procedure was not cost-effective;

For women diagnosed at age 40 to 50 with BRCA 1 and 2 mutations and at least five years after an ovarian cancer diagnosis, the procedure was associated with a survival benefit of two to five months compared to screening and found to be cost-effective.

“Our study provides clarity on how a woman’s age and timing of a risk-reducing mastectomy after an ovarian cancer diagnosis impact the benefit of this procedure,” Gamble said. “Within the first five years, nobody benefitted from risk-reducing mastectomy and after that threshold, survival gains were seen mostly in the youngest, healthiest ovarian cancer patients.”

“There is no right or wrong answer on how to manage breast cancer risk in this unique population,” added senior author Rachel Greenup, M.D., assistant professor of surgery at Duke. “However, we hope that our findings provide guidance to women and their doctors deciding if and when prophylactic mastectomy is beneficial following ovarian cancer treatment.”

In addition to Gamble and Greenup, Duke co-authors include Laura Havrilesky, Evan R. Myers, Junzo Chino, Scott Hollenbeck, Jennifer Plichta, P. Kelly Marcom, E. Shelley Hwang, and Noah D. Kauff.

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Is Junk Science About To Enter An L.A. Courtroom In A Lawsuit Over Ovarian Cancer?

Is Junk Science About To Enter An L.A. Courtroom In A Lawsuit Over Ovarian Cancer?Toward the end of the great adventure movie “A High Wind in Jamaica,” a gang of pirates is sentenced to hang for a murder they didn’t commit.

“I don’t want to die innocent!” a crewman cries out to his captaI in.

“Zac,” replies the captain, “you must be guilty of something.”

One could cite that line to explain the lawsuits lodged against the giant consumer company Johnson & Johnson by more than a thousand women suffering from ovarian cancer, and their families. They claim their disease was caused by dusting themselves over a lifetime with talc that the company marketed to women under brand names such as Johnson’s Baby Powder and Shower to Shower and the jingle, “A sprinkle a day helps keep odor away.”

State court juries in St. Louis have hit J&J with awards totaling more than $300 million in actual and punitive damages so far. (The company has said it will appeal.)

Another 2,400 lawsuits are pending around the country. Jury selection in the trial of one brought by Eva Echeverria, a 63-year-old Los Angeles resident, is scheduled to start July 17 in L.A. County Superior Court. Related lawsuits have been filed by six other Southern California women, and those trials presumably will follow.

The plaintiffs say they trusted that Johnson & Johnson wouldn’t market an unsafe product, only to learn after they fell ill that research had established a link between talc and ovarian cancer years earlier, and the company had refused to place a warning label on its packaging.

Yet these cases should raise the same doubts as the other lawsuits, which we aired last year. Put simply, is the science strong enough to support judgments of this magnitude? The answer seems to be no.

Some studies have reported a link between talc and ovarian cancer. But they’re generally retrospective case control studies. These rely on their subjects to report their past experiences, which could be marred by poor recollection or biased by the desire to pinpoint a cause of disease.

On the other side of the ledger are prospective studies, which select their subjects first and then follow them over a period of years. One such study reported in 2000 by researchers at Harvard was part of the National Nurses Health Study of more than 121,000 women, including 78,630 who said they had used talc. Ovarian cancer eventually struck 307 of them. The study revealed “no overall association” between talc use and “epithelial ovarian cancer,” though there was a “modest elevation in risk” for one variety of the disease. That variety, invasive serous ovarian cancer, is what Echeverria is suffering from, according to court papers.

“Our results provide little support for any substantial association between perineal talc use and ovarian cancer risk overall,” the researchers reported.

Another prospective study performed by the University of Massachusetts followed 61,576 post-menopausal women without a history of cancer for more than 12 years. It found “no association” with risk of ovarian cancer.

As I observed in relation to the St. Louis jury awards last year, cases like these present an extraordinary challenge for the American jury system.

The scientific evidence is equivocal. Talc’s role may well be incremental or marginal, swamped by other potential contributing factors such as obesity, genetics and other aspects of the patients’ medical histories.

Ovarian cancer accounts for only 1.3% of all new cancer cases in the U.S., according to the National Cancer Institute. But it’s the eighth most common cancer and the fifth leading cause of cancer-related death among women. Fewer than half of all patients survive five years after diagnosis. Still, pinpointing one factor as a “cause” of an individual patient’s disease is no simple matter.

Perhaps most important, the verdicts may reflect the decline of science’s reputation for objectivity. Some studies on the link between talc and ovarian cancer, pro and con, have financial ties to one side or another. The author of an influential paper asserting the connection has been a paid consultant for plaintiffs; but one of the more comprehensive papers debunking the link was paid for partially by a law firm representing a talc manufacturer. It’s unsurprising that the public, and jurors, can’t decide who to believe.

So what really underlies these lawsuits? It’s quite possible that it’s the David-and-Goliath factor: On one side of the courtroom is a plaintiff who is undeniably sick with a terrible disease, or if she has passed away, her survivors. On the other side, Johnson & Johnson, which earned a profit of $16.5 billion last year and doesn’t have an entirely spotless record of corporate integrity.

Getting across to a jury the message that Johnson & Johnson may have deliberately suppressed evidence of health risks to sell baby powder shouldn’t be beyond the capability of a reasonably experienced trial lawyer. The discovery process in such litigation almost inevitably yields all sorts of seemingly incriminating paperwork: Letters, say, from Alfred Wehner, an epidemiologist working for the talc industry, acknowledging that research exists pointing to a talc-cancer connection.

In 1997, Wehner upbraided a J&J executive for dismissing the research in PR statements. “Anybody who denies this,” Wehner wrote, “risks that the talc industry will be perceived by the public like it perceives the cigarette industry: denying the obvious in the face of all evidence to the contrary.”

But Wehner wasn’t arguing that there’s anything to the connection. He was saying the industry had gone too far in addressing the research. “The industry does have powerful, valid arguments to support its position,” he wrote, but those would be undermined if it acted as though the evidence cited by its critics didn’t exist at all.

Further muddying the water is the fact that some research has associated talc with cancer and other diseases— but diseases of the lung, in cases where victims inhaled the mineral, especially when the talc was contaminated with asbestos. Talc marketed to the public has had to be asbestos-free since the 1970s.

There’s been very little judicial pushback against the plaintiffs’ claims. Last September, a New Jersey state judge, Nelson C. Johnson, threw out expert testimony promoting the ovarian cancer link from Daniel W. Cramer, a Harvard researcher who has produced the leading research indicating the link. Johnson’s ruling was provided to me by representatives of Johnson & Johnson.

Johnson cited the differences between the conclusions of Cramer’s retrospective research and those of the prospective studies. He noted that Cramer’s work and other studies pointing to a link don’t have conclusive descriptions why talc would cause ovarian cancer. He called the experts’ failure to “articulate a plausible hypothesis for the biological mechanism” a “huge hole” in the plaintiffs’ case. None of the plaintiffs’ witnesses, he said, “ventured to articulate just how it is that talc in the ovaries, or what it is about talc in the ovaries, that sets off a chain of events which purportedly causes ovarian cancer.”

To read this entire article on The Los Angeles Times, please click here.