Beta Blockers May Boost Immunotherapy, Help Melanoma Patients Live Longer

A common, inexpensive drug that is used to prevent heart attacks and lower blood pressure may also help melanoma patients live longer.

Researchers at Penn State found that melanoma patients who received immunotherapy while taking a specific type of beta blocker lived longer than patients who received immunotherapy alone. In a follow-up experiment with mice, the researchers saw the same results.

Todd Schell, professor of microbiology and immunology at Penn State College of Medicine, said that because beta blockers are already widely available, the findings – published in the journal OncoImmunology – could indicate a simple way for physicians to better treat their patients.

“The type of beta blocker we found to be effective against melanoma – pan beta blockers – was actually the least prescribed,” Schell said. “Most patients are either prescribed beta 1 selective blockers or are not taking beta blockers at all. This means there’s a large population of patients who may be eligible to take pan beta blockers while being treated with immunotherapy. And because beta blockers are already FDA approved, it’s something we know is safe and can be very quickly implemented in patient care.”

Patients with metastatic melanoma, or melanoma that has spread to other parts of the body, often have a poor prognosis, and while some forms of immunotherapy – treatments that boost the body’s immune system to fight disease – are promising, response rates are less than 35 percent.

Previous research has shown that physiological stress prevents the immune system from fighting tumors effectively, while lower stress boosts the benefits of anti-cancer treatments. The researchers were curious about whether lowering stress with beta blockers would improve outcomes in patients treated with immunotherapies.

“Beta blockers slow your heart rhythm, but they can also affect immune cells and improve immune function,” Schell said. “We wanted to see if there would be a correlation between the beta blockers patients were taking for another condition and their response to immunotherapy. For metastatic melanoma, there are currently three different types of immunotherapy approved for use, and we specifically looked at that population of people.”

In studies developed by Dr. Kathleen Kokolus, a postdoctoral fellow, the researchers analyzed data from 195 metastatic melanoma patients who were treated with immunotherapy between 2000 and 2015, 62 of which were also taking beta blockers. They compared survival between the patients taking beta one-selective blockers, pan beta blockers and no beta blockers.

While there was little difference in how long patients taking beta one-selective blockers or no beta blockers lived, the results indicate that patients taking pan beta blockers lived significantly longer than the others. Five years after immunotherapy, about 70 percent of patients receiving pan beta blockers were still alive, versus about 25 percent of those taking beta one-selective blockers or no beta blockers at all.

To help explain the results, the team performed a parallel experiment in mice with melanoma. They treated the mice with immunotherapy and with or without the pan beta blocker propranolol. The researchers found that the propranolol significantly delayed tumor growth and increased survival when combined with immunotherapy.

Dr. Joseph Drabick, professor of medicine, said the results suggest that reducing physiological stress with beta blockers can help improve the effectiveness of immunotherapy and survival for melanoma patients.

“These new immunotherapies are great, but they don’t work for everyone,” Drabick said. “So how can we make these treatments better? We saw that for patients taking pan beta blockers, there was a dramatic improvement in survival, and we were able to duplicate these findings in mice and see the exact same phenomenon.”

Drabick also said the study was a good example of the benefits of finding new uses for drugs that have been around awhile.

“The benefit of this is that beta blockers already have a long history of safety in people, and they’re cheap and generic,” Drabick said. “And now they have the potential to augment some of these newer immunotherapy drugs to help people with cancer.”

Schell said that in the future, they’ll be working on a clinical trial to further explore and understand the role of beta blockers in treating cancer.

Researchers Detect a Loophole in Chronic Lymphocytic Leukemia Treatment

A team of researchers in Italy and Austria has determined that a drug approved to treat chronic lymphocytic leukemia (CLL) may be less effective in a particular subset of patients. The study, which will be published January 4 in the Journal of Experimental Medicine, reveals that ibrutinib has a diminished capacity to delocalize and kill tumor cells expressing an adhesive protein called CD49d, but combining ibrutinib treatment with drugs that block CD49d activation could prevent the tumor cells from sheltering in lymphoid organs.

CLL is the most common leukemia in adults, and it is characterized by the presence of cancerous B cells that accumulate in the lymph nodes, spleen, and liver. Ibrutinib reallocates CLL cells from lymph nodes into the blood by inhibiting Bruton’s tyrosine kinase (BTK), a key enzyme in the B cell receptor (BCR) signaling pathway.

BCR signaling promotes the survival and differentiation of normal, healthy B cells in several ways, including by activating the adhesion receptor VLA-4, which attaches B cells to other, supportive cells within lymph nodes. One of the subunits of VLA-4, CD49d, is highly expressed in about 40% of CLL patients. These patients tend to have poorer outcomes than patients that do not express CD49d, but the role of VLA-4 in CLL is unclear.

A team of researchers led by Antonella Zucchetto and Valter Gattei of the CRO Aviano National Cancer Institute in Italy and Tanja Nicole Hartmann of the Paracelsus Medical University in Salzburg, Austria, found that BCR signaling can activate VLA-4 in CD49d-expressing CLL cells, thereby enhancing the cells’ adhesiveness. Even though ibrutinib treatment impaired BCR signaling in these cells, it was unable to fully hinder the pathway from activating VLA-4 and enhancing cell adhesion.

The researchers analyzed three different cohorts of CLL patients from Italy and the United States. In all three groups, patients expressing higher levels of CD49d showed reduced responses to ibrutinib treatment: the drug appeared to be less able to displace tumor cells from lymph nodes into the blood, resulting in decreased lymph node shrinkage and shorter progression-free survival times.

“Our results suggest that VLA-4–expressing CLL cells residing in the secondary lymphoid organs can receive BCR-mediated stimuli that can activate VLA-4 even in the presence of ibrutinib,” says Zucchetto. “This activation leads to enhanced retention of VLA-4–positive CLL cells in tissue sites, thereby affecting patient outcome.”

In addition to the ibrutinib target BTK, BCR signaling can proceed through an alternative enzyme called phosphatidylinositide 3-kinase. The researchers found that simultaneously inhibiting both BTK and phosphatidylinositide 3-kinase completely blocked VLA-4 activation in CLL cells.

“Our data suggest that evaluation of CD49d expression in patients initiating ibrutinib therapy may identify those cases that would benefit from combination therapy approaches designed to completely block VLA-4 activation and VLA-4–mediated retention of leukemic cells in protective tissue compartments,” says Gattei.

Some Cancer Therapies May Provide a New Way to Treat High Blood Pressure

Drugs designed to halt cancer growth may offer a new way to control high blood pressure (hypertension), say Georgetown University Medical Center investigators. The finding could offer a real advance in hypertension treatment because although a number of high blood pressure drugs are now available, they work by different mechanisms that are not suited for all patients.

The study, published in the journal Hypertension, found that fibroblast growth factors, or FGFs, involved in increasing blood vessel growth so that cancer can grow, also have a systemic effect on blood pressure. The study suggests that just as oncologists use FGF inhibitors to control cancer, clinicians may be able to use FGF inhibitors to regulate blood pressure and control disease associated with hypertension.

“It’s rare that a single class of drugs can be used for such different conditions, but that is what our study strongly suggests,” says the study’s senior investigator, Anton Wellstein, MD, PhD, professor of oncology and pharmacology at Georgetown University School of Medicine and a researcher at Georgetown Lombardi Comprehensive Cancer Center.

Wellstein and his collaborators previously found that the FGF pathway, when switched on, drives growth of blood vessels that feed a growing tumor (angiogenesis).  The development of FGF inhibitors is based in part on their ability to inhibit angiogenesis. The current study took a deeper dive into the pathway and found that a protein, FGFBP1, modulates FGF. The gene that produces FGFBP1 to regulate FGF is known as FGF binding protein 1.

Wellstein had learned from a publication by a group in the United Kingdom that a population in Eastern Europe that had hypertension also had a variation of the FGFBP1 gene. Due to this gene variation in these individuals, FGFBP1 was over-expressed in kidney tissue, the major control hubs for blood pressure.

He decided to test the link between FGFBP1 and hypertension in a mouse model his laboratory at Georgetown had created that revealed the link between FGF and cancer. In these mice, FGFBP1 can be switched on or off.

Wellstein partnered with Christopher S. Wilcox, MD, PhD, professor of medicine at Georgetown and the George E. Schreiner Chair of Nephrology, and when investigators switched on FGFBP1 in mice, their blood pressure shot up. “It actually went up [30 mm Hg] from a normal blood pressure to pretty bad hypertension,” says Wellstein. “It was amazing.”

He adds that he turned the gene on “just to a level you see in people in the Eastern European group who have hypertension.” Wellstein also clarified that when a cancer switches on overproduction of the FGF pathway, in order to stimulate blood vessel production, that has only a local tumor effect, not a systemic one. Most patients using cancer treatment have normal blood pressure, he says.

Further research revealed that hypertension regulation by FGFBP1 occurred in the resistance vessels —the end portion of vessels in different tissues that control the flow to that tissue. The aberrant FGFBP1 gene increased the vessel response to a hormone (angiotensin II) that constricts the blood vessels, making blood pressure rise.

“FGF can control how sensitive the blood pressure regulation by angiotensin II is,” says Wellstein. “That tells us that if a person has hypertension, it is possible to target FGF signaling because it contributes to maintenance of high blood pressure by altering sensitivity to a major vasoconstrictive hormone, angiotensin II,” he says.

Investigators then used an FGF inhibitor in mice with a switched on FGFBP1 gene, and found the drug effectively lowered the sensitivity to angiotensin II in several vascular beds.

“Of course, we can’t say that this tactic will work in humans with hypertension, but it will be straightforward to test this rather surprising possibility to target a new mechanism of blood pressure control,” says Wellstein.

Prostaglandin E1 Inhibits Leukemia Stem Cells Targeting leukemia stem cells in combination with standard chemotherapy may improve treatment for chronic myeloid leukemia

Two drugs, already approved for safe use in people, may be able to improve therapy for chronic myeloid leukemia (CML), a blood cancer that affects myeloid cells, according to results from a University of Iowa study in mice.

CML is a relatively common cancer. The American Cancer Society estimates that in 2017 there will be about 8,950 new cases and about 1,080 people will die of the disease.

In its initial, chronic stage, CML is relatively easy to treat. Drugs called tyrosine kinase inhibitors (TKIs) are generally successful at controlling the cancer. However, patients need to continue the expensive treatment for their lifetime. In some cases, even with that treatment, the cancer can progress to a more advanced stage that is no longer controlled.

One reason for this, explains Hai-Hui (Howard) Xue, MD, PhD, UI professor of microbiology and immunology, is that there are two kinds of tumor cells—bulk leukemia cells that can be killed by TKI drugs, and a subset of cells called leukemia stem cells, which are resistant to TKIs and to chemotherapy.

“A successful treatment is expected to kill the bulk leukemia cells and at the same time get rid of the leukemic stem cells. Potentially, that could lead to a cure,” says Xue, who is senior author of the study published in the September issue of the journal Cell Stem Cell as the cover story.

With that goal in mind, Xue and his team joined forces with Chen Zhao, MD, PhD, UI assistant professor of pathology, and used their understanding of CML genetics to look for small molecules or drug compounds that might be able to eradicate the leukemia stem cells.

Focusing on two proteins known as transcription factors, the researchers showed that genetically removing the two transcription factors, Tcf1 and Lef1, in mice is sufficient to prevent leukemia stem cells from persisting. Importantly, this genetic alteration did not affect normal hematopoietic (blood) stem cells.

Next the researchers used an informatics method called connectivity maps to identify drugs or small molecules that can replicate the gene expression pattern that occurs when the two transcription factors are removed. This screening test identified a drug called prostaglandin E1 (PGE1).

The team tested a combination of PGE1 and the TKI drug called imatinib in a mouse model of CML. The mice lived longer than control mice; 30 percent lived longer than 80 days compared to mice treated with only imatinib, all of which died within 60 days.

The team also looked at a different mouse model of CML, where human CML cells were transplanted into an immunocompromised mouse. When the mice received no treatment or were treated with imatinib alone, the human leukemia stem cells propagated and grew to relatively large numbers. In contrast, when the animals were treated with a combination of imatinib and PGE1, those numbers were greatly reduced, and mice did not develop leukemia.

“The results are a pleasant surprise,” says Xue who also is a member of Holden Comprehensive Cancer Center at the UI. “We do these kinds of genetic studies all the time—looking at transcription factors and what they do. This is a good opportunity to connect what we do at the bench to something that could be useful clinically.”

Investigating how the PGE1 works to suppress the leukemia stem cells, the team found that the effect relies on a critical interaction between PGE1 and its receptor EP4. They then tested the effect of a second drug molecule called misoprostol, which also interacts with EP4, and showed that misoprostol also has the ability to combine with TKI and significantly reduce the number of leukemia stem cells.

Both PGE1 and misoprostol are currently approved by the FDA for use in people. PGE1 is an injectable drug that is used to treat erectile dysfunction. Misoprostol is a pill that is used to treat ulcers.

“We would like to be able to test these compounds in a clinical trial,” Xue says. “If we could show that the combination of TKI with PGE1, or misoprostol, can eliminate both the bulk tumor cells and the stem cells that keep the tumor going, that could potentially eliminate the cancer to the point where a patient would no longer need to depend on TKI.”

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.

 

Liver Disease Risk Increased by Type 2 Diabetes, Study Finds

People with type 2 diabetes are at greater risk of serious liver disease than those without the condition, research has shown.

Researchers warn that hospital admissions and deaths caused by liver disease are likely to rise if cases of type 2 diabetes continue to increase at current rates.

The team examined cases of liver diseases among people with diabetes from anonymised, securely linked hospital records and death records in Scotland over a ten year period.

They found that most cases of liver disease in people with type 2 diabetes are not alcohol-related but caused by a build-up of fat within liver cells – a condition known as non-alcoholic fatty liver disease or NAFLD.

NAFLD is commonly linked to obesity, which is also a risk factor for type 2 diabetes. Most people can avoid getting these conditions by following a healthy diet and taking regular exercise.

The research team – led by the Universities of Edinburgh and Southampton – found that men with type 2 diabetes are three times more likely to suffer from NAFLD than men without diabetes.

There are fewer cases of type 2 diabetes and liver disease amongst women but having type 2 diabetes increases the risk of NAFLD by five times, the study found.

People with NAFLD are more susceptible to the effects of alcohol on the liver and should avoid drinking to avoid further complications, the researchers say.

Treatment options for NAFLD – which increases the risk of life-threatening complications such as cirrhosis and liver cancer – are limited.

The study involved researchers from the Scottish and Southampton Diabetes and Liver Disease Group. It is published in the Journal of Hepatology and was funded by the Scottish Government through the Scottish Diabetes Group.

Professor Sarah Wild, of the University of Edinburgh’s Usher Institute for Population Health Sciences, said: “Preventing non-alcoholic fatty liver disease by avoiding unhealthy lifestyles in both people with and without diabetes is important because it is difficult to treat the complications of this condition.”

Professor Chris Byrne of the University of Southampton and University Hospital Southampton’s, NIHR Biomedical Research Centre said: “We have shown for the first time that type 2 diabetes is an important novel risk factor that increases numbers of hospital admissions and deaths, in people with all common chronic liver diseases. Further research is now needed to determine whether all patients with type 2 diabetes should be screened for common chronic liver diseases.”