Sangamo Therapeutics and Pfizer Announce Collaboration for Hemophilia A Gene Therapy

Sangamo Therapeutics, Inc. and Pfizer Inc. announced this week, an exclusive, global collaboration and license agreement for the development and commercialization of gene therapy programs for Hemophilia A, including SB-525, one of Sangamo’s four lead product candidates, which Sangamo expects will enter the clinic this quarter.

“Sangamo brings deep scientific and technical expertise across multiple genomic platforms, and we look forward to working together to advance this potentially transformative treatment for patients living with Hemophilia A,” said Mikael Dolsten, MD, PhD, President of Worldwide Research and Development at Pfizer. “Pfizer has made significant investments in gene therapy over the last few years and we are building an industry-leading expertise in recombinant adeno-associated virus (rAAV) vector design and manufacturing. We believe SB-525 has the potential to be a best-in-class therapy that may provide patients with stable and durable levels of Factor VIII protein with a single administration treatment.”

“With a long-standing heritage in rare disease, including hemophilia, Pfizer is an ideal partner for our Hemophilia A program,” said Dr. Sandy Macrae, Sangamo’s Chief Executive Officer. “We believe Pfizer’s end-to-end gene therapy capabilities will enable comprehensive development and commercialization of SB-525, which could potentially benefit Hemophilia A patients around the world. This collaboration also marks an important milestone for Sangamo as we continue to make progress in the translation of our ground-breaking research into new genomic therapies to treat serious, genetically tractable diseases.”

Under the terms of the collaboration agreement, Sangamo will receive a $70 million upfront payment from Pfizer. Sangamo will be responsible for conducting the SB-525 Phase 1/2 clinical study and certain manufacturing activities. Pfizer will be operationally and financially responsible for subsequent research, development, manufacturing and commercialization activities for SB-525 and additional products, if any. Sangamo is eligible to receive potential milestone payments of up to $475 million, including up to $300 million for the development and commercialization of SB-525 and up to $175 million for additional Hemophilia A gene therapy product candidates that may be developed under the collaboration. Sangamo will also receive tiered double-digit royalties on net sales. Additionally, Sangamo will be collaborating with Pfizer on manufacturing and technical operations utilizing viral delivery vectors.

Gene therapy is a potentially transformational technology for patients, focused on highly specialized, one-time, treatments that address the root cause of diseases caused by genetic mutation. The technology involves introducing genetic material into the body to deliver a correct copy of a gene to a patient’s cells to compensate for a defective one. The genetic material can be delivered to the cells by a variety of means, most frequently using a viral vector such as rAAV. There have been no gene therapy products approved in the U.S. to date.

Hemophilia A is a rare blood disorder caused by a genetic mutation resulting in insufficient activity of Factor VIII, a blood clotting protein the body uses to stop bleeding. There are approximately 16,000 patients in the U.S. and more than 150,000 worldwide with Hemophilia A. SB-525 is comprised of a rAAV vector carrying a Factor VIII gene construct driven by a proprietary, synthetic, liver-specific promoter. The U.S. Food and Drug Administration has cleared initiation of human clinical trials for SB-525, which also has been granted orphan drug designation. Sangamo is on track this quarter to start a Phase 1/2 clinical trial to evaluate safety and to measure blood levels of Factor VIII protein and other efficacy endpoints.

 

Scientists Find Possible Achilles Heel of Treatment Resistant Cancers

Scientists identify two signaling proteins in cancer cells that make them resistant to chemotherapy, and show that blocking the proteins along with chemotherapy eliminate human leukemia in mouse models.

Reporting results March 20 in Nature Medicine, researchers at Cincinnati Children’s Hospital Medical Center suggest that blocking the signaling proteins c-Fos and Dusp1 as part of combination therapy might cure several types of kinase-driven, treatment-resistant leukemia and solid tumor cancers.

These include acute myeloid leukemia (AML) fueled by the gene FLT3, lung cancers fueled by genes EGFR and PDGFR, HER2-driven breast cancers, and BCR-ABL-fueled chronic myeloid leukemia (CML), according to Mohammad Azam, PhD, lead investigator and a member of the Division of Experimental Hematology and Cancer Biology.

“We think that within the next five years our data will change the way people think about cancer development and targeted therapy,” Azam says. “This study identifies a potential Achilles heel of kinase-driven cancers and what we propose is intended to be curative, not just treatment.”

The weak spot is a common point of passage in cells (a signaling node) that appears to be required to generate cancer cells in both leukemia and solid tumors. The node is formed by the signaling proteins c-Fos and Dusp1, according to study authors. The researchers identified c-Fos and Dusp1 by conducting global gene expression analysis of mouse leukemia cells and human chronic myeloid leukemia (CML) cells donated by patients.

CML is a blood cancer driven by an enzyme called tyrosine kinase, which is formed by the fusion gene BCR-ABL. This fusion gene is the product of translocated chromosomes involving genes BCR (chromosome 22) and ABL (chromosome 9). Analysis of human CML cells revealed extremely high levels of c-FOS and DUSP1 in BCR-ABL-positive chemotherapy resistant cells.

Cancer sleeper cells

Cancer cells often become addicted to the mutated gene that causes them, such as BCR-ABL in kinase-driven chronic myeloid leukemia. Most chemotherapies work by blocking molecular pathways affected by the gene to shut down the disease process. In the case of CML, a chemotherapy called imatinib is used to block tyrosine kinase, which initially stops the disease. Unfortunately the therapeutic benefit is temporary and the leukemia comes back.

Azam and colleagues show in their CML models that signaling from tyrosine kinase – and growth factor proteins that support cell expansion (like interleukins IL3, IL6, etc.) – converge to dramatically elevate c-Fos and Dusp1 levels in the cancer cells.

Working together these molecules maintain the survival of cancer stem cells and minimal residual disease. The dormant cells wait around under the radar screen to rekindle the disease by acquiring additional genetic mutations after initially effective chemotherapy.

Azam says Dusp1 and c-Fos support the survival of cancer stem cells by increasing the toxic threshold needed to kill them. This means conventional imatinib chemotherapy will not eliminate the residual disease stem cells. Doctors can’t just increase the dose of chemotherapy because it doesn’t target the Dusp1 and c-Fos proteins that regulate toxic threshold.

Targeting c-Fos and Dusp1

After identifying c-Fos and Dusp1, the authors tested different treatment combinations on mouse models of CML, human CML cells, and mice transplanted with human leukemia cells. They also tested treatments on B-cell acute lymphoblastic leukemia (B-ALL).

The treatment combinations included: 1) solo therapy with just the tyrosine kinase inhibitor, imatinib; 2) solo treatment with just inhibitors of c-Fos and Dusp1; 3) treatment with all three combined – imatinib along with molecular inhibitors of c-Fos and Dusp1.

As suspected, treatment with imatinib alone initially stopped CML progression but the leukemia relapsed with the continued presence of residual disease cells. Treatment with c-Fos and Dusp1 inhibitors alone significantly slowed CML progression and prolonged survival in a majority of mice but wasn’t curative. Treatment for one month with c-Fos/Dusp1 inhibitors and imatinib cured 90 percent of mice with CML, with no signs of residual disease cells.

Azam and his colleagues also point to an interesting finding involving solo treatment with just the deletion of c-Fos and Dusp1. This eliminated expression of the signaling proteins and was sufficient to block B-ALL development, eradicating the disease in mouse models.

Next steps

The authors stress that because the study was conducted in laboratory mouse models, additional research is needed before the therapeutic strategy can be tested in clinical trials.
They are following up the current study by testing c-Fos and Dusp1as treatment targets for different kinase-fueled cancers, including certain types of lung cancer, breast cancers and acute forms of leukemia.

Doctors Treat Deadly Cancerous Disorders with Gene-Guided, Targeted Therapy

Genomic testing of biopsies from patients with deadly, treatment-resistant cancerous blood syndromes called histiocytoses allowed doctors to identify genes fueling the ailments and use targeted molecular drugs to successfully treat them.

Researchers from the Cincinnati Children’s Cancer and Blood Diseases Institute report their data in Journal of Clinical Investigation Insight (JCI Insight). They recommend the regular use of comprehensive genomic profiling at diagnosis to positively impact clinical care, as well as rigorous clinical trials to verify and extend the diagnostic and treatment conclusions in their study.

Histiocytoses are a group of disorders in which abnormal accumulations of white blood cells form tumors on vital organs, leading to systemic organ damage or death. About half of the patients can be treated successfully with chemotherapy, but others are treatment resistant.

Study authors conducted genomic profiling of biopsies from 72 child and adult patients with a variety of treatment-resistant histiocytoses, including the most common one in children, Langerhans cell histiocytosis (LCH), according to the lead investigator, Ashish Kumar, MD, PhD.

Twenty-six patients with treatment-resistant disease had gene mutations involving either BRAF or MAP2K1 that directly activate the MAP-kinase cancer pathway. Researchers determined such patients would benefit from the targeted molecular therapies dabrafenib or trametinib, which block the MAP kinase pathway. The approved cancer drugs were prescribed off label to the histiocytosis patients.

“In the last year, three patients we treated were infants with disease that was resistant to several rounds of intense chemotherapy. In the past, these children either would have suffered serious complications including death or would have had to endure more intensive treatments and the ensuing toxicities, including the risk of death,” Kumar said. “All three are thriving now on one oral medication that put their disease into remission.”

Queen’s Researcher Explores Best Treatments for Glaucoma

Researchers at Queen’s University Belfast together with University of St Andrews and Aberdeen have found that the procedure used to remove cataracts is more successful than current standard treatments with laser in treating Primary Angle-Closure Glaucoma – a leading cause of irreversible blindness worldwide.

Professor Azuara-Blanco at the Centre for Public Health at Queen’s led an international trial comparing two treatments for glaucoma – the standard treatment, or ‘laser iridotomy’, which uses a laser to open a tiny hole in the eye to allow fluid to drain away and reduce the increased eye pressure that causes glaucoma; and ‘lens extraction with intraocular lens implantation’, a surgical procedure to remove the eye’s natural lens and replace it with an artificial plastic lens. The surgical technique of lens extraction and replacement with an artificial plastic lens has been used successfully for decades to restore vision in patients’ with cataracts.

The Queen’s-led Effectiveness in Angle-closure Glaucoma of Lens Extraction (EAGLE) study, supported by the EME Programme, an MRC and NIHR partnership, compared the outcomes for 419 patients – 208 of whom received lens extraction treatment and 211 of whom received laser iridotomy. The patients were treated at hospitals in the UK, Singapore, Malaysia, Hong-Kong and Australia,

The results show that at three years, initial clear lens extraction surgery is more effective than standard laser treatment in terms of patient reported health and vision and for lowering eye pressure. Less eye drops are needed to control the glaucoma. Also, balancing costs and benefits, initial clear lens extraction surgery was more efficient for the NHS. The findings have been published in The Lancet Journal earlier this month.

What is glaucoma?

Glaucoma is an age-related and chronic eye disease typically associated with increased eye pressure and progressive optic nerve damage that may lead to blindness if untreated.

According to the World Health Organisation, glaucoma is the leading cause of irreversible blindness, with the current prevalence of 20 million expected to rise to 34 million by 2040, including 5.3 million with blindness.

Although most people with glaucoma do not become blind, many have substantially impaired quality of life due to restricted peripheral vision and the need for long-term treatment.

Primary angle-closure glaucoma
Explaining the condition, Professor Augusto Azuara-Blanco, from the Centre for Public Health at Queen’s, who led the trial, said: “There are two major types of glaucoma, depending on the drainage channels that take the fluid outside the eye: open or closed angle glaucoma. Angle-closure glaucoma is less common but more severe. It is most prevalent among people of East Asian origin, and in the UK it accounts approximately for 2 out of 10 cases of glaucoma.

“In angle-closure glaucoma, the iris (coloured part of the eye) moves forward and blocks the drainage channels that allow fluids to drain away from the eye. When the drainage channels are closed the inner eye pressure increases, and this leads to damage and impaired vision.

“For many years, this has been treated by using lasers to open tiny holes in the iris of the eye and open the drainage channels, allowing fluid to drain away. But we have found that removing the eye’s own lens opens up the natural drainage channels more effectively, and patients are happier because many do not need to use to use glaucoma eye drops and their vision is improved. This surgical technique has been used successfully for years to restore sight in patients with cataracts. Advances in technology and surgical techniques over the past decade mean that it is quite safe and it can now be used to treat people with this type of glaucoma. This trial is the first in which the two treatments have been compared.”

Improved patient outcomes

Professor Azuara-Blanco continued: “Patients who received the lens extraction and implantation were more likely to report better quality of life and better vision. It is also more cost-effective than the current standard treatment. Both options appear to be equally safe.

“Vision loss is costly to individuals and society and can have a huge impact on an individual’s quality of life. The superiority of clear-lens extraction in terms of patient outcomes and cost-saving , along with the absence of any serious safety issues with this technique, should help contribute to a case for this approach to be considered as the initial treatment for people with primary angle-closure glaucoma.”

Tumor Paint Brings Light To Toddler’s Brain Tumor

In December of last year, Laura Coffman began to notice that something wasn’t quite right with her 2-year-old son, Hunter. He was leaning to one side and seemed to lose his balance easily. When he became lethargic and started vomiting a few days later on Dec. 28, she knew it was time to see the pediatrician.

After all standard tests came back normal, they were sent to Seattle Children’s for further testing and to find an answer. Unfortunately, it was far worse than anything Coffman could have imagined.

“What I thought was probably just Hunter being a wobbly toddler with a virus turned out to be a brain tumor,” said Coffman. “I will never forget that day. It was the most traumatic six hours of our lives.”

Tumor Paint sheds some light

Hunter was immediately scheduled for surgery to remove the brain tumor that was the size of a golf ball. In preparing for the operation, Coffman and her husband, Atom, were also presented with the opportunity to enroll Hunter in Seattle Children’s Phase 1 trial of BLZ-100 Tumor Paint. Since tumor cells can be difficult to distinguish from healthy cells, the drug aims to improve surgical outcomes by acting as a molecular flashlight that allows surgeons to visibly distinguish a tumor from normal brain tissue.

“We didn’t see how it could hurt and we wanted them to use every tool at their disposal so we enrolled him in the trial,” said Coffman.

Dec. 30 was the day of Hunter’s surgery. Another day the Coffman’s will never forget.

“As a parent you know that your child may never be the same after brain surgery – they may not be able to see, walk or speak,” Coffman said. “It’s the risk you have to take to save their life. But we trusted our surgeon, Dr. Amy Lee, with everything we had.”

Prior to surgery, BLZ-100 Tumor Paint was administered by intravenous injection. In the operating room, the tumor glows green when viewed under a laser light and imaged with a near-infrared camera system.

BLZ-100 Tumor Paint was invented by a team led by Dr. Jim Olson, pediatric neuro-oncologist at Seattle Children’s and Fred Hutch and co-founder of Blaze Bioscience: The Tumor Paint Company. While this Phase 1 trial is focused on examining the safety of the drug and how well it targets tumor tissue, the hope is that it will eventually help guide skilled surgeons to prevent the removal of healthy tissue that can lead to serious long-term side effects.

“Cure is not just about successful treatment of a tumor, but successful treatment of a child,” said Dr. Sarah Leary, principal investigator for the trial and Hunter’s oncologist at Seattle Children’s. “Much of cancer treatment for children is a trade-off where curative therapy comes with serious long-term side effects. By lighting the way for expert surgeons, we’re hopeful that BLZ-100 Tumor Paint could help improve the quality of life for children by reducing treatment-related damage to the healthy brain.”

Hunter’s surgery went well and the majority of his tumor was removed. One small piece on his brain stem was intentionally left because removal may have led to serious neurological injury.

After surgery, it was not long until Hunter was back to his young self.

“We were incredibly lucky to have such an amazing surgeon and we were thrilled that he was able to bounce back so quickly,” said Coffman. “He was able to walk, run and put words together only weeks after the operation.”

A terrifying diagnosis, the journey to remission

Once the tumor was removed, the Coffman’s faced their next hurdle as pathology determined that Hunter had a form of aggressive cancer called medulloblastoma. His next phase of treatment quickly began as he underwent seven months of chemotherapy and radiation to target the remaining tumor, as well smaller lesions in his brain and spine.

“I remember how terrifying that diagnosis was to hear, but Dr. Leary was so optimistic and immediately reassured us when she said ‘this is a cancer that we’ve cured many times,’” said Coffman. “And that’s exactly what they did.”

In August, four weeks after Hunter ended treatment, MRI scans confirmed he was in remission.

“The news was phenomenal – all of his cancer was gone,” she said. “You can’t ask for anything more.”

Today, Hunter is thriving.

“You’d never even know he had cancer or brain surgery,” she said. “His hair is growing back, he’s swimming, impressing us with his speaking skills and having playdates with friends.”

When reflecting on their decision to participate in the trial, Coffman is glad they had the opportunity to experience something that could be a game changer for future kids like Hunter.

“Brain surgery is not something you ever want to think about your child going through, but if that dreadful day ever comes, you definitely want a tool like Tumor Paint that could help guide the surgeon in making potentially life-altering decisions,” said Coffman.

What’s next for BLZ-100 Tumor Paint in children

Since the trial began in June 2015, Seattle Children’s has performed 15 brain surgeries with BLZ-100 Tumor Paint. To date, none of the patients have had any negative side effects and Leary and her team are working to determine the best dose. The drug also appears to be doing what it was designed to do – make tumor tissue glow.

“We have been excited to see that BLZ-100 Tumor Paint is binding to many different types of brain tumors in children and so far has not resulted in any side effects,” said Leary. “We are optimistic that in the future it could be an incredible tool when placed in the expert hands of a neurosurgeon that could lead to improved patient outcomes.”

Dr. Amy Lee, the lead neurosurgeon in the trial and Hunter’s surgeon, adds, “We believe BLZ-100 Tumor Paint holds tremendous potential and eventually could be a valuable aid for surgeons in differentiating tumor from healthy tissue, particularly when there are areas of question.”

Leary said their goal is that this Phase 1 trial at Seattle Children’s, which has the largest pediatric Brain Tumor Program and the most pediatric neurosurgeons in the Northwest, will be followed by other studies that lead BLZ-100 Tumor Paint to become a part of standard care for brain tumor surgery. The next step will be to determine the effectiveness of the drug, which will involve a larger collaborative study that will involve 15 of the leading pediatric brain tumor centers across the country.

“In the future, I hope we’ll look back and wonder how these surgeries were ever done without the lights on,” said Leary.

New Class of Medicinals based on Cannabinoid Molecules, Spurs NEMUS Bioscience Inc. into Action

Q&A with Brian Murphy MD, CEO/CMO, NEMUS Bioscience

Humans produce a range of chemical compounds called cannabinoids that keep the human body stable by binding to receptors on cell membranes and controlling the release of chemical messengers that regulate everything from how humans experience pain to our moods. While most people’s endocannabinoid systems naturally help maintain a state of homeostasis, or stability, conditions such as multiple sclerosis or treatments for diseases like cancer can throw off that balance. Introducing cannabinoids made outside the body might help. Marijuana also contains cannabinoids – at least 66 of them.

Drugs based on cannabinoids, which could treat ailments ranging from arthritis to epilepsy, hold untold potential for the pharmaceutical industry.

The BioConnection.com recently spoke with Dr. Brian Murphy, NEMUS Bioscience’s CEO and CMO on the potential of cannabinoid research.

Q: What is NEMUS Bioscience working on?

Murphy: NEMUS Bioscience (OTCQB: NMUS) was formed to bring a new class of medicinals, based on the 100+ cannabinoid molecules in the Cannabis sativa plant, to a variety of therapeutic markets, especially those of unmet medical need.  Almost every organ in the body possesses cannabinoid receptors giving these compounds tremendous versatility in affecting the course of disease.

Q: What are the main diseases or symptoms you are attempting to target with cannabinoid research?

Murphy: The NEMUS developmental pipeline is currently focused on three therapeutic silos:

1) Palliative care addressing specific indications of chemotherapy-induced nausea and vomiting (CINV) and chemotherapy-induced peripheral neuropathy, a particularly severe pain syndrome associated with certain type of cancer chemotherapy.

2) Ophthalmology: the initial therapeutic indication being pursued is glaucoma, with initial animal studies in models of glaucoma exhibiting an average 45% reduction in IOP, exceeding current IOP reduction standards with currently approved medications and those in development using the same models.

3) Anti-infectives: Nemus is developing cannabinoid-based therapeutics against both bacterial and viral targets, with the initial therapeutic target in this silo being methicillin-resistant Staphylococcus aureus (MRSA). The current MRSA epidemic in the United States accounts for close to $4 billion in associated health-care costs as this bacterium has developed resistance to many antibiotics.  Newer therapies are needed.

Q: Describe your partnership with the University of Mississippi and how has the partnership benefited your research?

Murphy: The University of Mississippi (UM) is the only entity in the United States currently licensed by the federal government to grow, cultivate, and research cannabinoids autonomously.  The University has held that license since 1968 and has a tremendous amount of intellectual capital and experience in the chemistry and physiology of cannabinoid molecules.  That library of molecules and associated intellectual property helps distinguishes us from other companies in the cannabinoid therapeutic space.

Q: What difficulties have you encountered working with pharmaceuticals derived from cannabis?

Murphy: While marijuana is not a legal substance, drug companies are permitted to work with and develop derivatives from the plant and develop these molecules into drugs.  Many leading approved medicinals for cardiovascular disease, cancer, and anti-infectives are derived from plants or as is known in pharma development: botanically derived medications.  There is a designated regulatory pathway from both the DEA and FDA for cannabinoids and NEMUS works diligently to be in compliance with those requirements. To-date, we have not experienced any unexpected challenges outside the norm in developing a new class of compounds to address diseases.

Q: What is your opinion on people who smoke/ eat marijuana to relieve painful physical/ mental symptoms? In other words, why are cannabinoids better than the plant itself?

Murphy: For patients who use plant-derived cannabinoids, there are a number of challenges that “pharmaceuticalized” cannabinoids can hope to overcome:

  1. a) with an approved drug, you know what you’re getting- with the plant, random analyses performed by regulatory labs have shown that the advertised content doesn’t always reflect what is in the plant
  2. b) with an approved drug, the cannabinoid is specifically designed to combat a particular disease process both in formulation, route of delivery, and mechanism of action.  With plant-derived treatments, one-route of administration doesn’t always fit all diseases
  3. c) FDA approved medications are covered by insurance reimbursement; plant-derived cannabinoids have historically not been covered by insurance.  A month’s supply of plant-derived cannabinoids can run into the hundreds of dollars versus a $5-$10 monthly copay for FDA approved medications
  4. d) pharmaceuticalized cannabinoids undergo a rigorous testing process (randomized, double-blind, placebo controlled clinical trials),  Plant derived cannabinoids have not undergone this type of rigorous testing and in many cases, rely on anecdotal evidence where bias reporting can creep in; until this type of rigorous testing is conducted in plant-derived cannabinoids, marijuana dispensaries run the risk of violating FTC regulations if they make claims on the efficacy and safety of their products

Q: What has been your biggest success in your research so far?

Murphy: The biggest success has been validating our prodrug design in the molecular engineering of the cannabinoid molecule in animal studies that permit the therapy to enter the body with more predictable bioavailability and steady-state drug concentrations.  These proprietary molecules are designed to optimize safety and efficacy by permitting routes of administration that bypass first-pass metabolism in the liver.  We look forward to upcoming human testing to further validate the potential benefits of this drug design approach.

For more information, log on to www.nemusbiosciences.com

Liquid Biopsies Offer Hope for Earlier Treatment, Better Tracking of Ovarian Cancer

Researchers at the Mayo Clinic Center for Individualized Medicine have found a promising new way to monitor and treat recurrence of ovarian cancer — a hard-to-detect disease that claims many lives. New research from George Vasmatzis, Ph.D., of the Department of Laboratory Medicine and Pathology at Mayo Clinic, finds liquid biopsies from blood tests and DNA sequencing can detect a return of ovarian cancer long before a tumor reappears. That could lead to earlier intervention and more effective, individualized treatment. Dr. Vasmatzis’ research on the “Quantification of Somatic Chromosomal Rearrangements in Circulating Cell-free DNA From Ovarian Cancers” is published in the July 20 edition of Scientific Reports.

“With liquid biopsies, we don’t have to wait for tumor growth to get a DNA sample,” says Dr. Vasmatzis. “This important discovery makes it possible for us detect recurrence of the disease earlier than other diagnostic methods. We can repeat liquid biopsies to monitor the progression of the cancer. That gives hope of a better treatment plan over time.”

The study was done on 10 patients in advanced stages of ovarian cancer. Blood was drawn before and after surgery. Investigators compared DNA from the liquid blood biopsies to DNA tissue samples from the tumor, using mate-pair sequencing — an inexpensive whole exome sequencing that can reveal genetic changes that contribute to tumor growth.

“In this study, the blood drawn before and after surgery and the surgical tissue was used to identify DNA fragments with abnormal junctions that can only be seen in this patient’s tumor DNA,” explains Dr. Vasmatzis. “Next-generation mate-pair sequencing was used to identify specific DNA changes of the tumor to create an individualized monitoring panel for liquid biopsy. This allows us to shape treatment to the individual patient rather than using a standard treatment that may not work for everyone.”

When post-surgery DNA matched that of the tumor, patients were later found to have had a recurrence of ovarian cancer. However, when the post-surgery DNA did not match the DNA of the tumor, patients were found to be in remission.

Ovarian cancer has one of the highest death rates of all gynecological cancers, because the tumor often cannot be detected until the late stages. Most patients go into remission after initial treatment, but the tumor returns 75 percent of the time. The next stage of ovarian cancer that develops typically does not respond to chemotherapy. More than 21,000 women in the U.S. were diagnosed with ovarian cancer, and 14,000 women died of the disease in 2015.

Prevention of Genetic Breast Cancer Within Reach

An international team led by researchers at the Austrian Institute of Molecular Biotechnology (IMBA) in Vienna and the University of Maryland School of Medicine in Baltimore discovered that genetically determined breast cancer can be largely prevented by blocking a bone gene. An already approved drug could be quickly available and would then be the first breast cancer prevention drug.

About one in eight women will develop invasive breast cancer over the course of her lifetime. Causes can be the use of synthetic sex hormones and other environmental factors, but also gene mutations like in the BRCA1 gene (BReast CAncer). US actress Angelina Jolie who underwent a preventive double mastectomy is the most famous carrier of a „faulty“ BRCA1 gene. On average, women with this mutation have an up to 87% lifetime risk of developing breast cancer. Tumors usually develop early in life. Until now, prophylactic surgery is the only procedure which significantly reduces the breast cancer risk, but which is also often associated with postoperative complications.

In 2010, Josef Penninger, the scientific director of IMBA in Vienna and his team have shown that sex hormones can trigger breast cancer (Schramek et al., Nature) through proteins called RANKL and its receptor RANK, which are key factors in bone metabolism. RANKL and RANK also link sex hormones to breast cells by providing signals telling the breast cells to grow. This occurs normally in every woman during pregnancy and the menstruation cycle. However, if deregulated, mammary cells start to divide and multiply and fail to die when they should, ultimately resulting in breast cancer.

A multinational research effort now made the discovery that RANKL is also the main driver of BRCA1 mutation-driven breast cancer. In the current study, Verena Sigl, graduate student from Penninger’s research group, showed that blocking the RANKL/RANK system in BRCA1 mutant mice led to largely normal mammary glands whereas invasive carcinomas could be found in the control group. To determine the relevance of their results for humans, scientists in Vienna and Toronto isolated breast tissue cells from women who had undergone preventive mastectomy because of their BRCA1 mutation. In the human cell culture, too, RANKL inhibition led to a significant reduction of growth and spreading of breast tissue cells. Moreover, the scientists – together with colleagues in Barcelona and from the CIMBA* consortium mapping more than 23,000 women – showed that genetic variants in the RANK gene are associated with a higher risk of developing breast cancer in women who carry BRCA1 and also BRCA2 mutations.

“Our finding is so exciting because there is already an approved drug against RANKL called „Denosumab”. It is an antibody with very few side effects, which binds tightly to RANKL, thereby inhibiting its ability to act. Based on our discovery, the already approved drug Denosumab or other future drugs that will block RANKL/RANK, could be used for breast cancer prevention in BRCA mutation carriers,” explains Verena Sigl.

Scientists at the University of Maryland School of Medicine in Baltimore have already tried the preventive use of a RANKL blocking drug in mice. Animals carrying BRCA1 mutations were divided into two groups. In the control group multiple early breast cancer lesions developed. The second group received RANKL blockade treatment for prevention with the result that virtually no malignant changes in breast tissue could be observed even over a longer period of observation.

Careful phase III clinical trials are now needed to confirm the efficacy in humans. Thereafter, any woman who has been tested positive for a BRCA1 mutation could take RANKL blockade as prevention measure to reduce her dramatically increased breast cancer risk. Josef Penninger adds: “This work is a great example of an international collaboration of many scientists with one grand vision: Prevention of breast cancer. Cancer prevention is one of the key issues we face in medicine today, a world where much fewer women will get breast cancer in the first place. We have also shown that RANKL/RANK are critically involved in sex hormone-driven breast cancer. If the uncovered mechanism indeed works in the prevention of breast cancer in high risk patients, this could possibly be used to prevent breast cancer in general. One door for breast cancer prevention has now been opened and this can be tested very fast.”